Clinical trial NCT03497676
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2019-04-03; Completion date: 2025-04-22
Enrollment: 168 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study was to determine the dosage for oral cabotegravir (CAB) and long-acting cabotegravir (CAB LA) and long-acting rilpiverine (RPV LA) and evaluate the safety, acceptability, tolerability, and pharmacokinetics (PK) of oral CAB, CAB LA, and RPV LA in virologically suppressed children and adolescents living with HIV.

Detailed description:
IMPAACT 2017 was a Phase I/II, multi-center, open-label, non-comparative dose-finding study with the primary objective of evaluating the safety, acceptability, tolerability, and PK of oral cabotegravir (CAB) and long acting cabotegravir (CAB LA) as well as long acting rilpivirine (RPV LA) in adolescents living with HIV-1, who are 12 to \<18 years of age, ≥35kg, and virologically suppressed.

The study design included two cohorts of participants and five study steps. In Cohort 1, Step 1 participants received either oral CAB or oral rilpivirine (RPV) for at least four weeks and up to six weeks (maximum). In Cohort 1, Step 2 participants received intramuscular injectable formulations of the study products, either CAB LA or RPV LA. Cohort 1 participants were assigned either CAB (Cohort 1C) or RPV (Cohort 1R) based on their pre-study combination Antiretroviral Therapy (cART) regimen. Participants on a PI-based and/or NNRTI-based cART regimen were assigned to Cohort 1C, and participants on a non-boosted INSTI-based cART regimen were assigned to Cohort 1R. All participants continued their pre-study cART regimen during Cohort 1.

During Cohort 2, all participants discontinued their pre-study cART regimen and received both study products, CAB and RPV, at the doses established in Cohort 1. Cohort 2 participants enrolled to either Cohort 2A to receive both oral CAB + oral RPV (Step 3) followed by both CAB LA + RPV LA (Step 4) or Cohort 2B to directly receive both CAB LA + RPV LA without an oral lead-in phase (Step 5). If eligible, Cohort 1 participants were able to enroll into Cohort 2 (i.e., Cohort 1 Rollover). However, Cohort 2 participants who were not previously enrolled in Cohort 1 (i.e., Cohort 1-Naïve) were the primary group for analyses and conclusions. No participants enrolled into Cohort 2B, direct to injection (Step 5). Therefore, all references to Cohort 2 refer to Cohort 2A (Steps 3 and 4).

Two interim analyses were planned. The first interim analysis established the doses for Cohort 2 and determined whether to open Cohort 2 to Cohort 1 participants who met criteria to enter Cohort 2. The second interim analysis provided justification to open Cohort 2 to additional participants who were not previously enrolled in Cohort 1. A final analysis of Cohort 1 data was performed to confirm the final doses for Cohort 2.

Safety and PK evaluations were performed during Steps 1-5 and long-term safety follow-up (LSFU). Antiviral activity assessments were performed during Steps 1-5. Acceptability and tolerability were assessed during Steps 1-5 and LSFU, with all participants completing quantitative questionnaires and a subset of participants completing in-depth qualitative interviews. Additionally, parents/caregivers of a subset of U.S. participants from U.S. sites were also enrolled to complete a single in-depth qualitative interview. Because objectives related to parents/caregivers were exploratory, these outcomes are not described here.

Cohort 1 participants were followed for up to 64 weeks. Participants were followed for at least four weeks in Step 1 (oral phase) and at least 12 weeks in Step 2 (injection phase). All Step 2 participants were followed (on cART, off study product) for up to an additional 48 weeks as part of LSFU after their last study product injection. If eligible, Cohort 1 participants enrolled into Cohort 2 before completing LSFU. For Cohort 1, Step 1 participants not progressing to Step 2, the last visit was targeted to be completed 28 days after the participant's last oral study product use.

Cohort 2 participants were followed for up to 188 (Cohort 2B) or 192 (Cohort 2A) weeks. Participants were followed for at least four weeks in Step 3 (oral phase) and 92 weeks in Step 4/Step 5 (injection phase). After completing 92 weeks of follow-up in Step 4/Step 5 (injection phase), Cohort 2 participants who continue access to injectable study products through a mechanism external to the protocol exited the study. If it is not possible for participants to access injections of CAB LA + RPV LA from non-study sources at the completion of their Step 4 Week 96 or Step 5 Week 92 visit, participants remained in the study safety extension for up to 48 weeks. Participants who permanently discontinue injectable study product use during Cohort 2, Step 4/Step 5, or do not wish to continue to access the study products through the external mechanism after their Week 96 visit, were followed (on cART, off study product) for an additional 48 weeks as part of LSFU after their last study product injection, except for participants in the safety extension study. Participants in the study safety extension who decide to permanently discontinue injectable study product or who have not established access to study product after the 48 weeks in the study safety extension would exit the study (not enter LSFU). For Cohort 2, Step 3 participants not progressing to the injection phase, the last visit was targeted to be completed 28 days after the participant's last oral study product use. Female participants who discontinued study product use (either oral or injectable study product) due to pregnancy during Steps 1-5 were followed for an additional 48 weeks in LSFU to assess long-term safety and washout PK of the study products, except for participants in the safety extension study. Participants who became pregnant during the safety extension were only followed until the pregnancy outcome was determined.

Arms: arm 1: Step 1: CAB administered orally as one 30 mg tablet once daily, beginning at the Entry visit, for 4-6 weeks.

Step 2 (Q4W dosing): CAB LA administered as three single intramuscular (IM) injections four weeks apart (600 mg injection at Week 4b, 400 mg injection at Week 8, and 400 mg injection at Week 12).

Step 2 (Q8W dosing): CAB LA administered as two single IM injections four weeks apart (600 mg injection at Week 4b and 600 mg injection at Week 8). arm 2: Step 1: RPV administered orally as one 25 mg tablet once daily, beginning at the Entry visit, for 4-6 weeks.

Step 2 (Q4W dosing): RPV LA administered as three single IM injections four weeks apart (900 mg injection at Week 4b, 600 mg injection at Week 8, 600 mg injection at and Week 12).

Step 2 (Q8W dosing): RPV LA administered as two single IM injections four weeks apart (900 mg injection at Week 4b and 900 mg injection at Week 8). arm 3: Step 3: CAB administered orally as one 30 mg tablet once daily AND RPV administered orally as one 25 mg tablet once daily, beginning at the Entry visit for 4-6 weeks.

Step 4: First and second injections: CAB LA administered as a 600 mg IM injection AND RPV LA administered as a 900 mg IM injection at Week 4b and at Week 8. Subsequent injections: starting at Week 16, CAB LA administered as a 600 mg IM injection AND RPV LA administered as a 900 mg IM injection every eight weeks through Week 96 or final safety extension visit. arm 4: Step 5: First and second injections: CAB LA administered as a 600 mg IM injection AND RPV LA administered as a 900 mg IM injection at Entry and at Week 4. Subsequent injections: starting at Week 12, CAB LA administered as a 600 mg IM injection AND RPV LA administered as 900 mg IM injection every eight weeks through Week 92 or final safety extension visit.
Interventions: intervention 1: Oral Cabotegravir (CAB) intervention 2: Oral Rilpivirine (RPV) intervention 3: Long-Acting Injectable Cabotegravir (CAB LA) intervention 4: Long-Acting Injectable Rilpivirine (RPV LA) intervention 5: Combination Antiretroviral Therapy (cART)
Intervention descriptions: intervention 1: 30 mg tablets administered orally intervention 2: 25 mg tablets administered orally intervention 3: Administered by intramuscular (IM) injection intervention 4: Administered by intramuscular (IM) injection intervention 5: Participants will continue their pre-study cART regimen. The antiretroviral drugs in participants' cART regimens were not provided through the study.

Protocol documents:
SAP_002.pdf: 
 
FINAL 
IMPAACT 2017 
Primary Statistical Analysis Plan  
 
Version 2.0 
 
Phase I/II Study of the Safety, Acceptability, Tolerability, 
and Pharmacokinetics of Oral and Long-Acting Injectable 
Cabotegravir and Long-Acting Injectable Rilpivirine in 
Virologically Suppressed HIV-Infected Children and 
Adolescents 
“MOCHA” 
More Options for Children and Adolescents 
 
Protocol Version 3.0 
 
 
 
Clinical Trials.gov Identifier: NCT03497676  
 
 
September 3, 2020 
 
This is IMPAACT 2017 SAP Version 2.0 with names of authors, names of 
publication writing team members, and analysis timeline redacted.
 
 
 


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Table of Contents 
1. 
Introduction ............................................................................................................................ 3 
Purpose and Reporting Timelines .............................................................................................. 3 
1.1 
Key SAP Updates ............................................................................................................. 4 
2. 
Protocol Overview .................................................................................................................. 4 
2.1 
Study Design .................................................................................................................... 4 
2.2 
Hypotheses ...................................................................................................................... 7 
2.3 
Study Objectives and Outcome Measures ....................................................................... 7 
2.3.1 
Primary Objectives and Outcome Measures .......................................................... 7 
2.3.2 
Secondary Objectives and Outcome Measures ...................................................... 8 
3. 
Definitions .............................................................................................................................. 9 
3.1 
Baseline ........................................................................................................................... 9 
3.2 
Analysis Populations ...................................................................................................... 10 
4. 
Statistical Methods ............................................................................................................... 10 
4.1 
General Considerations ................................................................................................. 10 
4.2 
Analyses ......................................................................................................................... 11 
4.2.1 
Primary Safety Analyses (Cohort 1 and Cohort 2) ................................................ 11 
4.2.2 
Secondary Analyses .............................................................................................. 12 
5. 
Core Manuscript Writing Team ............................................................................................ 13 
6. 
Protocol History .................................................................................................................... 14 
7. 
Appendix ............................................................................................................................... 14 
7.1 Snapshot Approach – Detailed Algorithm Steps (using Cutoff of HIV-1 RNA 200 c/mL as an 
Example) ................................................................................................................................... 14 
 


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1. Introduction 
Purpose and Reporting Timelines 
This Primary Statistical Analysis Plan (SAP) describes analyses that address the primary and secondary 
objectives of IMPAACT 2017 that will be included in the primary manuscript.  The Primary SAP outlines 
the general statistical approaches that will be used in the analysis.  It has been developed to facilitate 
discussion of the statistical analysis components among the study team, and to provide agreement 
between the study team and statisticians regarding the statistical analyses to be performed and 
presented in the Primary Statistical Analysis Reports.  It also describes the results for the primary and 
secondary outcome measures that will be posted on ClinicalTrials.gov.   
 
It is noted here that all PK analyses, including those required to address the primary and secondary 
objectives of the study, will be done by the study pharmacologists based on a separate PK Analysis Plan.  
In addition, the study’s qualitative research team will do the analyses of the data collected through a 
single qualitative phone interview based on the Qualitative Analysis Plan. 
 
Two primary safety analyses will be performed: (1) after the last participant in Cohort 1 has completed the 
Week 16 visit, and (2) after the last participant in Cohort 2 has completed 24 weeks on therapy. Each 
primary safety analysis will be done after all queries have been resolved, and the study database 
closure/data lock has been completed.  
 
The Primary Statistical Analysis Reports will be used for submission of results to ClinicalTrials.gov.  Results 
for primary outcomes are required to be submitted within one year of the primary completion date 
(PCD), which is the date the last participant is examined for the purposes of data collection for the 
primary outcome measure.  For this study, the PCD is the date of the Week 24 visit for the last 
participant in Cohort 2.  At the end of the study, a second submission to ClinicalTrials.gov will be done 
within one year after the last Cohort 2 participant reaches Week 144 (treatment through Week 96 plus 
48 weeks of long-term safety and washout PK follow-up) at which time point the adverse event tables 
will be updated. 
 
Detailed outlines of tables, figures, and coding descriptions that will be included in the Primary Analysis 
Report are included in the Analysis Implementation Plan (AIP). As this study will support regulatory 
submissions, a separate regulatory AIP will be drafted for each regulatory submission. 
 


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1.1 Key SAP Updates  
Version 
Changes Made 
Effective Date 
1 
Original Version based on Version 2.0 of Protocol 
01/22/2019 
2 
Updated Version based on Version 3.0 of Protocol.
Major changes include:  
1. Section 2 was updated to reflect the new treatment
regimen in Version 3.0 for both Cohort 1 and Cohort
2, sample size change in Cohort 1, number of dose-
evaluable participants required for initial dose-
finding evaluation (the first interim analysis), timing
of the second interim analysis for opening Cohort 2
to study-naïve participants, and the new secondary
objective for viral suppression in Cohort 1.  
2. Section 3 was updated to include definitions of
Evaluable Population, Cohort 2 Participants with
Cohort 1 Experience, and Cohort 2 Participants
without Cohort 1 Experience. 
3. “Visits and Evaluation Schedule” was removed from
Section 4 and put in the AIP, and the new secondary
objective for viral suppression in cohort 1 was added
in Section 4. 
09/03/2020 
 
2. Protocol Overview 
2.1 Study Design 
IMPAACT 2017 is a Phase I/II, multi‐center, open‐label, non‐comparative dose-finding study with the 
primary objective of evaluating the safety, acceptability, tolerability, and pharmacokinetics of oral CAB 
and CAB LA as well as RPV LA in virologically suppressed HIV-1 infected children and adolescents 12 to < 
18 years of age.   
 
There will be two cohorts of participants and two steps of study participation in each cohort.  Cohort 1 
Step 1 and Cohort 2 Step 3 are both a lead-in phase in which participants will receive oral formulations 
of the study products for at least 4 weeks, and up to 6 weeks (maximum).  In Cohort 1 Step 2 and Cohort 
2 Step 4, participants will receive injectable formulations of the study products.  There will be two 
groups under Cohort 1: Cohort 1C and Cohort 1R.  The study products are listed as follows. Note that 
since 23 participants were enrolled to Cohort 1 under Protocol Version 2.0, Cohort 1 treatments under 
Protocol Version 2.0 are also listed. Since no participant was enrolled to Cohort 2 under Version 2.0, 
Cohort 2 treatment under Protocol Version 2.0 is not applicable/included. 
 
Cohort 1 Treatment under Protocol Version 2.0: 
• 
Cohort 1C: 30 mg CAB once daily orally for at least four weeks (up to a maximum of 6 weeks) in 
addition to cART (Step 1 oral phase), followed by single intramuscular injections of CAB LA every 


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four weeks over an eight-week period (600 mg first injection, 400 mg second and third 
injections) in addition to cART (Step 2 injection phase).  
• 
Cohort 1R: 25 mg RPV once daily orally for at least four weeks (up to a maximum of 6 weeks) in 
addition to cART (Step 1 oral phase), followed by single intramuscular injections of RPV LA every 
four weeks over an eight-week period (900 mg first injection, 600 mg second and third 
injections) in addition to cART (Step 2 injection phase). 
 
Cohort 1 Treatment under Protocol Version 3.0: 
• 
Cohort 1C: 30 mg CAB once daily orally for at least four weeks (up to a maximum of 6 weeks) in 
addition to cART (Step 1 oral phase), followed by two single intramuscular injections of CAB LA 
four weeks apart (600 mg injections) in addition to cART (Step 2 injection phase). 
• 
Cohort 1R: 25 mg RPV once daily orally for at least four weeks (up to a maximum of 6 weeks) in 
addition to cART (Step 1 oral phase), followed by two single intramuscular injections of RPV LA 
four weeks apart (900 mg injections) in addition to cART (Step 2 injection phase). 
 
Cohort 2 Treatment under Protocol Version 3.0: 
• 
30 mg CAB + 25 mg RPV once daily orally for at least four weeks, and up to a maximum of 6 
weeks, during Step 3 oral phase, followed by intramuscular injections of CAB LA + RPV LA: first 
and second injections four weeks apart (CAB LA 600 mg injection + RPV LA 900 mg injection), 
with subsequent injections every eight weeks through and including Week 96 (CAB LA 600 mg 
injections + RPV LA 900 mg injections) during Step 4 injection phase. 
 
In each cohort, participants will enter the study in the oral lead-in phase (Step 1, or Step 3) and then 
transition to the injectable phase (Step 2, or Step 4) if eligibility criteria for the injectable phase are met.  
Cohort 1 Step 2 and Cohort 2 Step 4 participants, including those who prematurely permanently 
discontinue injectable study product, will continue on-study for an additional 48 weeks after their last 
study product injection, per the long-term safety and washout PK follow-up (LSFU) schedule. 
 
The sample size will be up to 155 adolescents in total, broken down as follows: 
 
Cohort 1: Up to 55 adolescents to achieve approximately 30 to 35 dose-evaluable receiving the oral 
followed by the LA dose of CAB (Cohort 1C) or RPV (Cohort 1R), in addition to the background cART. 
• 
Cohort 1C: Up to 30 adolescents to achieve approximately 15 to 20 dose-evaluable for CAB.  
• 
Cohort 1R: Up to 25 adolescents to achieve approximately 15 dose-evaluable for RPV.  
 
The dose-evaluable population for each group will include at least 4 female adolescents, at least 4 male 
adolescents, at least 5 adolescents weighing 35 kg to less than 50 kg at study entry, and at least 5 
adolescents weighing at least 50 kg at study entry. 
 
Cohort 2: Up to 155 adolescents may participate in Cohort 2.  Up to 100 adolescents, who had not 
previously participated in Cohort 1, will be enrolled to achieve approximately 70 evaluable who had not 
previously participated in Cohort 1.  The Cohort 2 participants will receive the final recommended oral 
doses followed by the LA doses of CAB and RPV.  Adolescents who participated in Cohort 1 (up to 55 
participants) may continue study participation in Cohort 2, if eligible, in addition to the up to 100 Cohort 
2 participants newly enrolled to the study. 
 


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For the qualitative component of the study, up to 60 adolescent participants and up to 60 parents or 
caregivers of adolescent participants will be selected by the qualitative team to complete a single 
qualitative phone interview (U.S. sites only). 
 
In Step 1, data collected through Week 4 (Week 4a and Week 4b study visits) for Cohort 1 participants 
will be assessed to determine eligibility for each participant to enter Step 2 and receive injectable CAB 
LA in Cohort 1C or RPV LA in Cohort 1R, respectively.  Cohort 1 participants who do not meet eligibility 
criteria for Step 2 will discontinue use of oral CAB or RPV and exit the study 28 days after their last oral 
study product dosing. 
 
In Step 2, participants will receive CAB LA (Cohort 1C) or RPV LA (Cohort 1R) while continuing their cART 
regimen.  A single intramuscular (IM) injection of CAB LA or RPV LA will be administered at the Week 4b 
(Step 2 Entry), Week 8, and Week 12 for participants enrolled under Version 2.0, and at the Week 4b 
(Step 2 Entry) and Week 8 for participants enrolled under Version 3.0. Cohort 1 Step 2 participants will 
be followed for safety and PK assessments through their Week 16 visit. 
 
Once seven dose-evaluable Cohort 1C participants and seven dose-evaluable Cohort 1R participants 
have completed injectable study product dosing in Step 2, and have completed safety and PK 
evaluations through the Cohort 1 Step 2 Week 16 visit, the first interim safety and PK analysis will be 
performed to: 
• 
Determine whether criteria have been met to open Cohort 2 to accrual — limited to Cohort 1 
participants 
• 
Determine the doses of the oral and injectable CAB study products, and the injectable RPV study 
product to be provided in Cohort 2 
 
If the seven dose-evaluable participants in each group meet the PK guidelines (see Section 10 of the 
protocol) and there are no safety concerns (see Section 9 of the protocol), then the oral/LA IM doses for 
CAB and LA IM dose for RPV in Cohort 2 will be established and Cohort 2 will begin to accrue, but only 
for Cohort 1 participants who completed the Week 16 visit. 
 
If either group fails the safety or PK criteria and an alternative dose is determined by the study team to 
be needed to safely achieve necessary study product concentrations, another seven dose-evaluable 
participants will be enrolled into that group and administered a modified dose which will be evaluated 
as described above. 
 
If there is more variability than expected in the PK results in each or both groups of Cohort 1, such that a 
confident determination regarding achievement of the PK targets cannot be made, an additional interim 
evaluation of the PK results will be done after an additional four participants have been enrolled into the 
appropriate group/s of Cohort 1 to clarify the PK results as needed.  In this scenario, Cohort 2 accrual 
will be delayed until an interim analysis which includes these extra participants has been reviewed and 
Cohort 2 dosing is confirmed by the study team.  In this case, the safety evaluation criteria will be such 
that failure would consist of either: 1) a death or life-threatening toxicity assessed as related to the 
study drug or 2) more than 25% of the sample having exhibited Grade 3+ toxicities assessed to be 
related to the study drug. 
 
Additional interim analysis of the PK results may also be performed if any of the study cohorts fails the 
safety criteria, which would trigger an SMC review.   


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Cohort 1 study enrollment and study procedures will not be interrupted for the interim analysis to be 
performed on the first seven participants enrolled into each group. 
 
Once approximately 15-20 Cohort 1C participants and approximately 15 Cohort 1R participants 
contributing to the dose-finding algorithm have enrolled, and 80% of these participants have completed 
the Step 2 Week 8 visit, the second interim analysis of all available safety and PK data will be conducted 
to determine if Cohort 2 accrual can be opened to study-naïve participants.  Once all Cohort 1C and 1R 
participants complete Week 16 visit, the final analysis of all safety and PK data for Cohort 1 will be 
conducted to confirm the oral and LA IM doses for Cohort 2.  
 
Upon enrollment into Cohort 2, participants will discontinue their pre-study cART regimen and receive 
oral CAB+RPV for at least 4 weeks (and up to 6 weeks) in Step 3.  Data collected through the Week 4 
(Week 4a and Week 4b study visits) will be assessed to determine eligibility for each participant to enter 
Step 4 and receive injectable CAB LA + RPV LA.  
 
Cohort 2 participants who meet eligibility criteria for Step 4 will receive their last oral dose of CAB+RPV 
on the same day as their first injection of CAB LA + RPV LA, at the Week 4b Step 4 Entry visit. In Step 4, 
participants will receive injectable CAB LA + RPV LA first and second injections four weeks apart with 
subsequent injections every eight weeks through and including Week 96. 
 
At the Week 96 visit, Cohort 2 Step 4 participants continuing to receive injectable CAB LA + RPV LA 
external to the protocol will exit the study. Section 14.11 of the protocol has more information 
regarding post-trial access to study products. Participants who discontinue receiving the injectable CAB 
LA + RPV LA at the Week 96 visit will not exit the study, and will be followed for 48 weeks per the LSFU 
visit schedule. 
 
2.2 Hypotheses  
Cohort 1: CAB (oral and LA) and RPV LA will be safe and will achieve pharmacokinetic targets through 
Week 16 in HIV-infected adolescents at the chosen dose to ultimately allow for a final dose to be 
selected. 
 
Cohort 2: CAB LA and RPV LA, when given as dual therapy to stable, virologically suppressed adolescents 
will maintain viral suppression and will be safe through Week 24 in HIV-infected adolescents at the 
selected dose. 
 
2.3 Study Objectives and Outcome Measures 
2.3.1 Primary Objectives and Outcome Measures 
Primary Objectives: Cohort 1 (continuing a background cART regimen) 
• 
To confirm the doses for oral CAB followed by injectable CAB LA in HIV-infected, virologically 
suppressed adolescents by evaluating: 
o Safety and multiple dose PK of oral CAB through Week 4 
o Safety and multiple dose PK of CAB LA through Week 16 
• 
To confirm doses for injectable RPV LA in HIV-infected, virologically suppressed adolescents by 
evaluating safety and multiple dose PK of RPV LA through Week 16 


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Outcome Measures 
• 
Safety Outcome: All adverse events, regardless of grade 
• 
Number of participants who: 
o Had Grade 3 or higher adverse events 
o Had Grade 3 or higher adverse events assessed as related to study product/s 
o Had serious adverse events meeting ICH criteria assessed as related to study product/s 
o Permanently discontinued study product due to adverse events assessed as related to 
study product/s 
o Died due to adverse events assessed as related to study product/s 
 
• 
PK Outcome measures will be included in the PK Analysis Plan. 
 
Primary Objective: Cohort 2 (discontinuing a background cART regimen) 
• To assess the safety of CAB LA + RPV LA through Week 24 in HIV-infected, virologically suppressed 
adolescents 
 
Outcome Measures 
• 
Safety Outcome: All adverse events, regardless of grade  
• 
Number of participants who:  
o Had Grade 3 or higher adverse events  
o Had Grade 3 or higher adverse events assessed as related to study product/s  
o Had serious adverse events meeting ICH criteria assessed as related to study product/s  
o Permanently discontinued study product due to adverse events assessed as related to 
study product/s  
o Died due to adverse events assessed as related to study product/s  
 
2.3.2  Secondary Objectives and Outcome Measures 
Secondary Objectives: Cohort 1 
Secondary Objective 1: 
• To monitor maintenance of viral suppression through Week 16 in HIV-infected, virologically 
suppressed adolescents 
 
Outcome Measures 
• 
Outcome: HIV-1 RNA through Week 16 for Cohort 1  
• 
Number of participants with HIV-1 RNA < 50 copies/mL 
 
Secondary Objectives 2 and 3: 
• 
To evaluate the tolerability and acceptability of CAB LA through Week 16 in HIV-infected, 
virologically suppressed adolescents 
• 
To evaluate the tolerability and acceptability of RPV LA through Week 16 in HIV-infected, 
virologically suppressed adolescents 
 
Outcome Measures 


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• 
Tolerability measures will include measures of side effects, pain during and after injections, 
injection site reactions, and perceptions of injections from comprehensive surveys of 
adolescents  
• 
Acceptability measures will include assessments of motivation for changing regimens, 
satisfaction with treatment, preferences for injectable versus oral regimen, quality of life, 
changes in attitudes towards the study products from comprehensive surveys of adolescents  
 
Secondary Objectives: Cohort 2 
Secondary Objective 4: 
• 
To assess safety of oral CAB + oral RPV followed by CAB LA + RPV LA through Week 48 in HIV-
infected, virologically suppressed adolescents 
 
Outcome Measures 
• 
Safety Outcome: All adverse events, regardless of grade  
• 
Number of participants who:  
o Had Grade 3 or higher adverse events  
o Had Grade 3 or higher adverse events assessed as related to study product/s  
o Had serious adverse events meeting ICH criteria assessed as related to study product/s  
o Permanently discontinued study product due to adverse events assessed as related to 
study product/s  
o Died due to adverse events assessed as related to study product/s  
 
Secondary Objective 5: 
• 
To evaluate repeat-dose pharmacokinetics of CAB LA + RPV LA through Week 24, and through 
Week 48 in HIV-infected, virologically suppressed adolescents 
 
Outcome Measures 
Will be included in the PK Analysis Plan. 
 
Secondary Objective 6: 
• 
To assess antiviral activity of CAB LA + RPV LA through Week 24, and through Week 48 in HIV-
infected, virologically suppressed adolescents 
 
Outcome Measures 
• 
Outcome: Plasma HIV-1 RNA  
• 
Number of participants with HIV-1 RNA ≥50 copies/mL, HIV-1 RNA ≥200 copies/mL, per 
snapshot algorithm 
 
3. Definitions 
3.1 Baseline 
The baseline value will be the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits.  If time is not collected, Day 1 assessments are assumed to be taken prior to first dose 
and used as baseline.  
 
Unless otherwise stated, if baseline data are missing, no derivation will be performed and baseline will 


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be set to missing. 
 
3.2 Analysis Populations 
The following analysis populations are defined: 
All Treated Population:  All participants who took at least one dose of any study product. 
 
Evaluable Population: For analysis purposes, evaluable participants will be defined as having been 
treated exclusively on the final recommended dose for a given cohort and either (1) having completed 
all treatment regimen through the said week periods (Week 4 or Week 16 for Cohort 1, Week 24 for 
Cohort 2), or (2) having experienced any of the following: 
• 
death that is attributable to the study product/s, OR 
• 
study product-related Grade 3+ events (excluding injection-site AEs) OR 
• 
permanently discontinued from treatment due to study product-related toxicities (regardless 
of grade) during these weeks of treatment. 
 
Notes:  
• 
An additional requirement for inclusion in the primary analyses for Cohort 2 is that the 
participants must be directly accrued to this cohort and be exclusively treated with the 
combination of the two study products without a prior period of exposure to one or the other; 
this will be approximately 70 participants. 
• 
Oral bridging in Cohort 2 will not be counted as a substitute for an injection but as long as the 
recommended number of injections were given through week 24, even if they were out of 
window, the subject will be considered evaluable. 
 
Cohort 2 Participants with Cohort 1 Experience: Cohort 2 participants who were previously enrolled to 
Cohort 1. 
 
Cohort 2 Participants without Cohort 1 Experience: Cohort 2 participants who were enrolled directly to 
Cohort 2 without prior participation in Cohort 1.  
 
4. Statistical Methods 
4.1 General Considerations
For all baseline demographics and exposure analyses, results will be presented for All Treated Population.  
 
Primary Analysis Reports for both Cohort 1 and Cohort 2 include analyses of both primary and secondary 
outcome measures only for evaluable participants (“Evaluable Population” as defined above).  An additional 
requirement for inclusion in the primary analyses for Cohort 2 is that the participants must be directly accrued 
to Cohort 2 without prior exposure to one or the other study treatment drug (“Cohort 2 Participants without 
Cohort 1 Experience” as defined above).  
 
In the Primary Analysis Reports, the appendix will include secondary analyses of safety and virologic analyses 
which will include all participants who received study product/s (“All Treated Population” referenced above).   
 
All safety data will be considered from the first patient exposure to study treatment.  


IMPAACT 2017 
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Note that additional analyses assessing the impact of COVID will be performed and the details will be included 
in the AIP. 
 
4.2 Analyses 
4.2.1 
Primary Safety Analyses (Cohort 1 and Cohort 2) 
The primary safety analyses will focus on the period from the start of study drug through Week 4 (CAB), and 
through Week 16 (CAB LA or RPV LA) for Cohort 1 and through Week 24 (oral CAB and oral RPV followed by CAB 
LA+RPV LA) for Cohort 2, where the primary safety analysis will include only evaluable participants.  As an 
additional requirement, the safety analyses for Cohort 2 will only include Cohort 2 Participants without Cohort 
1 Experience as defined above, which will be approximately 70 participants. 
 
Two primary safety analyses will be performed: (1) after the last participant in Cohort 1 has completed the 
Week 16 visit, and (2) after the last participant in Cohort 2 has completed 24 weeks on therapy. 
 
Each participant’s safety data will be summarized as: 
(1) the worst grade of each AE, and 
(2) the worst grade of each AE judged to be related to study treatment. 
 
Proportions, bounded by exact 95% confidence intervals, will present participants experiencing: 
(1) ≥ Grade 3 AEs, 
(2) ≥ Grade 3 events which have been judged to be related to study product/s, 
(3) serious adverse events meeting ICH criteria assessed as related to study product/s, 
(4) permanent discontinuation of study product due to adverse events assessed as related to study 
product/s, and 
(5) deaths due to product-related adverse events. 
 
Overall proportions of participants meeting any of these criteria will be presented, in addition to specific 
proportions meeting each individual criterion. 
 
Listings of all ≥ Grade 3 events regardless of treatment attribution, ≥Grade 3 events and serious adverse 
events meeting ICH criteria assessed as related to study product/s, as well as AEs which resulted in 
permanent discontinuation of study product/s or deaths will be provided, and will also be summarized and 
broken down by System Organ Class. 
 
The proportions of participants meeting each of the endpoints which would trigger an SMC review will also be 
presented descriptively. 
 
All proportions will be presented together with their 95% confidence intervals. 
 
For regulatory submission purposes, all the above analyses will be performed for all Cohort 1 and Cohort 2 
Evaluable Population and All Treated Population, separately.  For Cohort 2, frequency distributions of the 
safety outcomes will be presented in aggregate and will be broken down by prior participation in Cohort 1 vs. 
exclusive participation in Cohort 2.  In addition, the safety data will be presented separately for those who 
were enrolled under Version 2.0 and enrolled under Version 3.0. 


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Outcome Measures: 
• 
All adverse events, regardless of grade 
• 
Number of participants who: 
o Had Grade 3 or higher adverse events 
o Had Grade 3 or higher adverse events assessed as related to study product/s 
o Had serious adverse events meeting ICH criteria assessed as related to study product/s 
o Permanently discontinued study product due to adverse events assessed as related to study 
product/s 
o Died due to adverse events assessed as related to study product/s 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading 
Table), Corrected Version 2.1, dated July 2017, will be used in this study.  This table is available on the RSC 
website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. 
 
4.2.2 
Secondary Analyses 
Maintenance of Viral Suppression (Cohort 1) 
Virologic outcomes, based on HIV-1 RNA (copies/mL), will be assessed through Week 16 for Cohort 1 
participants. The proportion of participants maintaining suppression (<50 copies/mL) will be presented, along 
with the Exact 95% confidence intervals. 
 
Outcome Measures: 
• 
HIV-1 RNA through Week 16 for Cohort 1  
• 
Number of participants with HIV-1 RNA < 50 copies/mL 
 
Acceptability and Tolerability (Cohort 1) 
Acceptability and tolerability measures on CAB LA or RPV LA reported by the Cohort 1 participants through 
Week 16 will be summarized using descriptive statistics.  
 
Outcome Measures: 
• Tolerability measures will include measures of side effects, pain during and after injections, injection site 
reactions, and perceptions of injections from comprehensive surveys of adolescents 
 
• Acceptability measures will include assessments of motivation for changing regimens, satisfaction with 
treatment, preferences for injectable versus oral regimen, quality of life, changes in attitudes towards the 
study products from comprehensive surveys of adolescents 
 
Safety Analyses (Cohort 2) 
Week 24 (for Cohort 2) analyses described above for the primary analysis will be repeated as secondary 
analyses through Week 48 for the same participants mentioned under the primary analysis. 
 
Outcome Measures: 
• 
All adverse events, regardless of grade 
• 
Number of participants who: 
o Had Grade 3 or higher adverse events 


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o Had Grade 3 or higher adverse events assessed as related to study product/s 
o Had serious adverse events meeting ICH criteria assessed as related to study product/s 
o Permanently discontinued study product due to adverse events assessed as related to study 
product/s 
o Died due to adverse events assessed as related to study product/s 
 
Note for Cohort 1 and Cohort 2: In addition to the primary analyses restricting the sample to appropriate 
participants as described above, further analyses which include safety data from All Treated Population 
through all mentioned periods will be performed.  These secondary safety analyses will cover all safety data 
collected from first patient exposure to the study treatment to the end of the study.  The Cohort 2 secondary 
analyses will include all participants whose treatment started in Cohort 1 at the final recommended dose and 
who progressed to Cohort 2 after completing participation in Cohort 1. 
 
Descriptive and exposure-related analyses will present safety data from participants who were treated on 
doses other than the final recommended dose for their cohorts.  This will include data representing the final 
dose for each cohort, as well as data gathered during the dose finding stage, which may represent exposure to 
doses which have failed.  For each starting dose, every AE of ≥ Grade 3 will be listed, along with participant 
demographics, the dose prescribed to the patient at the time of the event and the protocol team’s assessment 
whether this event was due to the study products. 
 
Virologic Activity (Cohort 2) 
Virologic outcomes, based on HIV-1 RNA (copies/mL), will be assessed at Weeks 24 and 48 for evaluable Cohort 
2 participants.  At both of these time points the virologic outcome will be calculated according to the FDA’s 
snapshot algorithm with three main categories (i.e. HIV-1 RNA<50 copies/mL, HIV-1 RNA≥50 copies/mL, and no 
virologic data).  Full details of the Snapshot algorithm are in the Appendix.  The snapshot outcome will be 
presented at both Week 24 and Week 48.  The Exact 95% confidence intervals for the proportion of 
participants with HIV-1 RNA<50 c/mL will be calculated.  The similar summary and analysis will also be 
performed using the cutoff of HIV-1 RNA 200 copies/mL.  In addition to the snapshot analysis, the proportions 
of participants meeting the criteria for confirmed virologic failure through Week 24 and Week 48 will also be 
presented. 
 
In addition, the above analyses results will also be presented for all treated Cohort 2 participants (“All Treated 
Population” as defined above). 
 
Outcome Measures: 
• 
Plasma HIV-1 RNA 
• 
Number of participants with HIV-1 RNA >200 copies/mL, missing HIV-1 RNA, study treatment 
discontinuations 
 
Note: Secondary outcome measure (Virologic Activity through Week 24) will be evaluated concurrently with 
the primary outcome measures; additional longer-term secondary objectives will be evaluated as outcome 
measures become available and will be posted to ClinicalTrials.Gov.  The final updating of the AE tables will be 
done once the last participant enrolled in Cohort 2 has completed 48 weeks of long-term safety and washout 
PK follow-up (LSFU) [i.e., after reaching Week 144]. 
 
5. Core Manuscript Writing Team  


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Primary Statistical Analysis Plan Version 2.0                                                                  
  
                                                                                                                                                                                  Page 14 of 16 
 
 
 
 
 
6. Protocol History 
Protocol Version 1 
Version 1.0, dated March 2, 2018, however this version was never implemented. 
 
Protocol Version 2 
Version 2.0, dated 16 August 2020, was implemented at sites with the first enrollment occurring on April 3, 
2019. Accrual was paused on 17 March 2020 due to the COVID-19 pandemic. 
 
Protocol Version 3 
Version 3.0, dated 13 August 2020, was finalized and distributed to sites on August 18, 2020. 
 
7. Appendix 
7.1 Snapshot Approach – Detailed Algorithm Steps (using Cutoff of HIV-1 RNA 200 c/mL as an Example) 
Condition  
(‘Week 24’ indicates Week 24 window) 
Response  
Reasons 
1. If non-permitted change in background therapy prior to 
Week 24  
HIV1-RNA ≥ 200  
Change in ART 
2.  If permitted change in background therapy prior to Week 
24 AND the latest on-treatment VL prior to/on the date of 
change is ≥ 200 c/m 
HIV1-RNA ≥ 200  
Change in ART 
3:  If non-permitted change in background therapy during 
Week 24    
 
 
• Last on-treatment VL during Week 24 prior to/on the 
date of change ≥ 200 c/mL 
HIV1-RNA ≥ 200  
Data in window and HIV-1 
RNA >= 200 copies/mL 
• Last on-treatment VL during Week 24 prior to/on the 
date of change <200   c/mL 
HIV1-RNA < 200  
 
• No VL during Week 24 prior to/on the date of change    HIV1-RNA ≥ 200  
Change in ART 
4: If permitted change in background therapy during Week 24 
AND the last on-treatment VL prior to/on the date of change 
is ≥ 200 c/mL 
 
 
4.1    this last on-treatment VL occurs prior to Week 24  
HIV1-RNA ≥ 200 
Change in ART 
4. 2   this last on-treatment VL occurs during Week 24 but 
prior to/on the date of change 
HIV1-RNA ≥ 200  
Data in window and HIV-1 
RNA >= 200 copies/mL 
5: If none of the above conditions met 
 
 
5.1 VL available during Week 24  
 
 
• Last on-treatment VL during Week 24 ≥ 200 c/mL 
HIV1-RNA ≥ 200  
Data in window and HIV-1 
RNA >= 200 copies/mL 
• Last on-treatment VL during Week 24 <200 c/mL 
HIV1-RNA < 200  
 
 


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                                                                                                                                                                                  Page 15 of 16 
 
 
Condition  
(‘Week 24’ indicates Week 24 window) 
Response  
Reasons 
5.2 No VL during Week 24    
 
 
i. 
if subjects still on study (i.e. IP has not been 
permanently stopped up to Week 24) 
No virologic data 
at Week 24 
Window  
On study but missing data 
in window 
ii. 
If subjects withdraw before/during Week 24 due to 
 
 
1. Safety reasons (e.g. AE/death, liver chemistry 
stopping criteria, renal toxicity withdrawal criteria, 
QTc withdrawal criteria et al, as recorded in eCRF 
Conclusion form) 
No virologic data 
at Week 24 
Window 
Disc due to AE/death 
2.  Non-safety related reasons (e.g. Lack of efficacy, 
protocol deviation, withdrew consent, loss to 
follow-up, study closed/terminated, investigator 
discretion et al, as recorded in eCRF Conclusion 
Form) 
 
 
• Last on-treatment VL <200 c/mL OR no on-
treatment VL available during study   
No virologic 
Data at Week 24 
Window 
Disc for other reasons 
• Last on-treatment VL ≥ 200 c/mL AND withdrawal 
due to Lack of efficacy 
HIV1-RNA ≥ 200  
Disc. for lack of efficacy 
• Last on-treatment VL ≥ 200 c/mL AND withdrawal 
due to all other non-safety related reasons 
HIV1-RNA ≥ 200  
Dis. for other reason and 
HIV-1 RNA >= 200 
copies/mL 
Note the same process will be mapped out for Week 48.   
Examples from FDA guidance (cut-off of 50 copies/mL): 
Data in Window 
Virologic outcome should be determined by the last available measurement while the patient is on treatment 
and continued on trial within the time window: 
• HIV-RNA = 580 copies/mL at Day 336, HIV-RNA below 50 copies/mL on Day 350. This should be 
categorized as HIV-RNA below 50 copies/mL. 
No Data in Window 
Discontinued study due to Adverse Event or Death: 
• Any patient who discontinues because of an AE or death before the window should be classified as 
Discontinued due to AE or Death (as appropriate), regardless of the HIV-RNA result, even if the HIV-RNA 
is below 50 copies/mL at the time of discontinuation.  
• However, if a patient has an HIV-RNA value in the time window and also discontinues in the time 
window, the viral load data should be used to classify the patient’s response. This is the Virology First 
hierarchy: 
a. HIV-RNA below 50 copies/mL at Day 336 and discontinues because of AE or even dies on Day 
360 — this person is categorized as having HIV-RNA below 50 copies/mL.  
b. HIV-RNA is 552 copies/mL on Day 336 and the patient discontinues on Day 360, the patient is 
categorized as having HIV-RNA greater than or equal to 50 copies/mL. 
Discontinued for Other Reasons: 


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• 
Only patients who have achieved virologic suppression can be counted as Discontinued for Other 
Reasons. 
• 
If a patient discontinues the study before the window because of lack of efficacy then the patient 
should be included in the HIV-RNA greater than or equal to 50 row and not in the Discontinued for 
Other Reasons row. 
• 
If a patient discontinues because of subject withdrew consent and his or her HIV-1 RNA result at the 
time of discontinuation was equal to or above 50 copies/mL, then he or she should be categorized as 
HIV-RNA greater than or equal to 50 and NOT as Discontinued for Other Reasons.  
• 
If a patient discontinued because of Lost to Follow-Up and the last HIV-RNA result was 49 copies/mL, 
then the patient can be categorized as Discontinued for Other Reasons. 
• 
If patients changed background treatment — not permitted by protocol— they should be considered an 
efficacy failure and captured in the HIV-RNA greater than or equal to 50 copies/mL row. 
On study but missing data in window: 
• If there are no data during Days 294 to 377, but there is an HIV-RNA below 50 copies/mL on Day 380, 
this patient should be considered On Study but Missing Data in Window. 
• If there are no data during Days 294 to 377, but there is an HIV-RNA equal to or above 50 copies/mL on 
Day 280, this patient also should be classified as On Study but Missing Data in Window. 
Optimized Background Therapy Substitutions After Randomization (not relevant to this study as there is no OBT 
in this study) 
• 
OBT substitutions (in-class or cross-class) permitted per protocol for documented toxicity reasons can 
be permitted on or before the first trial visit without penalty.  
If OBT substitutions for toxicity reasons occur after the first trial visit, then patients should be categorized as 
having HIV-RNA greater than or equal to 50 copies/mL if they have HIV-RNA above 50 copies/mL at the time of 
switch. 
 
 

SAP_003.pdf: 
IMPAACT 2017 
Primary Statistical Analysis Plan 
Version 3.1   
 
 25 August 2023 
Phase I/II Study of the Safety, Acceptability, Tolerability, and 
Pharmacokinetics of Oral and Long-Acting Injectable 
Cabotegravir and Long-Acting Injectable Rilpivirine in 
Virologically Suppressed HIV-Infected Children and 
Adolescents 
“MOCHA” 
More Options for Children and Adolescents 
ClinicalTrials.gov Identifier: NCT03497676 
Protocol Version 4.0, LOA #1  
 
 
 
This is IMPAACT 2017 SAP Version 3.0 with names of authors, names of 
publication writing team members, and analysis timeline redacted.
 
 
 


IMPAACT 2017 Version , LOA #1 
Primary Statistical Analysis Plan Version 3.1 
 
25 August 2023 
 
Table of Contents 
 
TABLE OF CONTENTS ................................................................................................................... 2 
VERSION HISTORY ........................................................................................................................ 3 
1 
INTRODUCTION ........................................................................................................................ 4 
1.1 
Purpose ............................................................................................................................ 4 
1.2 
Version History ............................................................................................................... 4 
2 
STUDY OVERVIEW ................................................................................................................... 5 
2.1 
Overview of Study Design .............................................................................................. 5 
2.2 
Hypothesis ....................................................................................................................... 6 
2.3 
Study Objectives ............................................................................................................. 6 
2.3.1 
Primary Objective ................................................................................................. 6 
2.3.2 
Secondary Objectives .......................................................................................... 6 
2.4 
Overview of Sample Size Considerations .................................................................... 7 
2.5 
Overview of Formal Interim Monitoring ........................................................................ 7 
3 
OUTCOME MEASURES ........................................................................................................... 7 
3.1 
Primary Outcome Measures .......................................................................................... 7 
3.2 
Secondary Safety and Viral Suppression Outcome Measures .................................. 8 
4 
ANALYSIS SETS ....................................................................................................................... 8 
5 
GENERAL CONSIDERATIONS ................................................................................................ 9 
6 
ESTIMANDS AND ANALYSIS ................................................................................................ 10 
6.1 
Primary Estimands and Analysis ................................................................................ 10 
6.2 
Secondary Estimands and Analysis ........................................................................... 12 
6.2.1 
Safety Estimands ............................................................................................... 12 
6.2.2 
Virologic Estimands ............................................................................................ 15 
7 
REPORT CONTENTS ............................................................................................................. 18 
8 
ASSOCIATED DOCUMENTS ................................................................................................. 19 
 
 
 


IMPAACT 2017 Version , LOA #1 
Primary Statistical Analysis Plan Version 3.1 
 
25 August 2023 
 
Version History 
Version 
Changes Made 
Date Finalized 
1 
Original Version based on Version 2.0 of Protocol 
January 22, 2019 
2 
Updated Version based on Version 3.0 of Protocol. Major 
changes include:  
1. Section 2 was updated to reflect the new treatment regimen in 
Version 3.0 for both Cohort 1 and Cohort 2, sample size 
change in Cohort 1, number of dose-evaluable participants 
required for initial dose-finding evaluation (the first interim 
analysis), timing of the second interim analysis for opening 
Cohort 2 to study-naïve participants, and the new secondary 
objective for viral suppression in Cohort 1.  
2. Section 3 was updated to include definitions of Evaluable 
Population, Cohort 2 Participants with Cohort 1 Experience, 
and Cohort 2 Participants without Cohort 1 Experience. 
“Visits and Evaluation Schedule” was removed from Section 4 
and put in the AIP, and the new secondary objective for viral 
suppression in cohort 1 was added in Section 4. 
September 3, 2020 
3 
Updated Version based on Version 4.0 of Protocol.  
Major changes include: 
a. Removed references to Cohort 1 analyses. The primary 
analysis for Cohort 1 was performed using SAP Version 
2.0. 
b. Included all necessary changes from Protocol Version 
3.0 to Version 4.0, including the modification of the 
study design of Cohort 2 to allow the oral lead-in phase 
to be an optional component of Cohort 2 study 
participation.  
i. 
Modified Cohort 2 to include two groups: Cohort 
2A (oral lead-in followed by injections) and 
Cohort 2B (direct to injections). 
c. Restructured the SAP to include the following sections:  
i. 
Overview of Sample Size Calculations 
ii. 
Overview of Formal Interim Monitoring 
iii. Outcome Measures 
iv. Estimands and Analysis 
v. Report Contents 
September 6, 2022 
3.1 
Minor Version change based on LOA #1. No changes needed. 
August 25, 2023 


IMPAACT 2017 Version , LOA #1 
Primary Statistical Analysis Plan Version 3.1 
 
25 August 2023 
 
1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary estimands that 
will address the Cohort 2 primary and secondary objectives of IMPAACT 2017. The Primary SAP 
includes general analytic approaches for all estimands and other outcome measures in the 
primary manuscript(s) or submitted to ClinicalTrials.gov (regardless of the reporting timeline). The 
Primary SAP facilitates discussion of the statistical analysis components among the lead study 
investigators and statisticians, helping them agree on the statistical analyses to be performed and 
presented in the primary analysis report. 
It is noted here that all PK analyses, including those required to address the primary and secondary 
objectives of the study, will be done by the study pharmacologists based on a separate PK SAP 
(Version 2.0, dated 16 July 2022). In addition, the study’s qualitative research team will do the 
analyses of the data collected through a single qualitative phone interview based on the Qualitative 
Analysis Plan. 
Two primary safety analyses will be performed: (1) after the last participant in Cohort 1 has 
completed the Week 16 visit and (2) after the last participant in Cohort 2 (A/B) has completed 24/20 
weeks on therapy. A secondary safety analysis will be performed after the last participant in Cohort 
2 (A/B) has completed 48/44 weeks on therapy. Each primary safety analysis will be done after all 
queries have been resolved, and the study database closure/data lock has been completed. The 
primary safety analysis for Cohort 1 will be performed using Version 2.0 of the Primary SAP, dated 
3 September 2020. This version of the Primary SAP will focus on the primary and secondary safety 
outcome measures for Cohort 2. Descriptions of analyses for other objectives and outcome 
measures not included in this Primary SAP will be provided in a separate SAP. 
Detailed outlines of tables, figures, and coding descriptions that will be included in the Cohort 2 
primary analysis report(s) are included in the Cohort 2 Analysis Implementation Plan(s) (AIP). As 
this study will support regulatory submissions, a separate regulatory AIP will be drafted for each 
regulatory submission.  
1.2 
Version History 
The current Version 3.1 of the IMPAACT 2017 Primary SAP is based on protocol Version 4.0 and 
Letter of Amendment (LOA) #1. 
Version 3.0 of the IMPAACT 2017 Primary SAP is based on protocol Version 4.0. The new 
version reflects all necessary changes from protocol Version 3.0 to Version 4.0, including the 
modification of the study design of Cohort 2 to allow the oral lead-in phase to be an optional 
component of Cohort 2 study participation. To accommodate this, Cohort 2 has been modified to 
include two groups: Cohort 2A (oral lead-in followed by injections) and Cohort 2B (direct to 
injections). In addition, references to Cohort 1 were removed, as the primary analysis for Cohort 1 
will be performed using Version 2.0 of the Primary SAP. Details of the Cohort 1 primary analysis 
can be found in Version 2.0. 


IMPAACT 2017 Version , LOA #1 
Primary Statistical Analysis Plan Version 3.1 
 
25 August 2023 
 
2 
Study Overview 
2.1 
Overview of Study Design 
IMPAACT 2017 is a Phase I/II, multi‐center, open‐label, non‐comparative dose-finding study with 
the primary objective of evaluating the safety, acceptability, tolerability, and pharmacokinetics of 
oral cabotegravir (CAB) and long-acting injectable cabotegravir (CAB LA) as well as long-acting 
injectable rilpivirine (RPV LA) in virologically suppressed children and adolescents living with HIV-
1 aged 12 to < 18 years.   
The study design includes two cohorts of participants (Cohort 1 and Cohort 2) and five study 
steps. In Cohort 1 Step 1, participants received either oral CAB or oral RPV for at least 4 weeks 
and up to 6 weeks (maximum). In Cohort 1 Step 2, participants received injectable formulations of 
the study products, either CAB LA or RPV LA. Cohort 1 participants were assigned either CAB 
(Cohort 1C) or RPV (Cohort 1R) based on their pre-study cART regimen, and all participants 
continued their pre-study cART regimen during Cohort 1. 
Cohort 2 participants discontinue their pre-study cART regimen and receive both study products, 
CAB and RPV, at the doses established in Cohort 1. Cohort 2 participants may enroll to either 
Cohort 2A to receive both oral CAB + oral RPV (Step 3) followed by both CAB LA + RPV LA 
(Step 4) or Cohort 2B to directly receive both CAB LA + RPV LA without an oral lead-in phase 
(Step 5). Unless otherwise specified, the term ‘Cohort 2’ applies to participants in both Cohort 2A 
and Cohort 2B. 
Cohort 2 Treatment under Protocol Version 4.0: 
• 
Cohort 2A (oral lead-in followed by injections): 30 mg CAB + 25 mg RPV once daily orally 
for at least four weeks, and up to a maximum of 6 weeks, during Step 3 oral phase, 
followed by intramuscular (IM) injections of CAB LA + RPV LA: first and second injections 
four weeks apart (CAB LA 600 mg injection + RPV LA 900 mg injection), with subsequent 
injections every eight weeks through and including Week 96 (CAB LA 600 mg injections 
+ RPV LA 900 mg injections) during Step 4 injection phase.  
• 
Cohort 2B (start with injections): IM injections of CAB LA + RPV LA: first and second 
injections four weeks apart (CAB LA 600 mg injection + RPV LA 900 mg injection), with 
subsequent injections every eight weeks through and including Week 92 (CAB LA 600 
mg injections + RPV LA 900 mg injections) during Step 5 injection phase.  
Participants who prematurely discontinue injectable study product permanently, will continue on-
study for an additional 48 weeks after their last study product injection, per the long-term safety 
and washout PK follow-up (LSFU) schedule.  
The sample size for Cohort 2 will be up to 155 adolescents in total. Up to 100 adolescents, who 
had not previously participated in Cohort 1 (i.e., Cohort 1-naïve), will be enrolled to achieve 
approximately 70 evaluable. Cohort 2A participants will receive the final recommended oral doses 
followed by the LA doses of CAB and RPV. Cohort 2B participants will receive the final 
recommended LA doses of CAB and RPV. Adolescents who participated in Cohort 1 (i.e., Cohort 


IMPAACT 2017 Version , LOA #1 
Primary Statistical Analysis Plan Version 3.1 
 
25 August 2023 
 
1 rollovers; up to 55) may continue study participation in Cohort 2, if eligible, in addition to the up 
to 100 Cohort 2 participants newly enrolled to the study. 
At the Week 96/92 visit, Cohort 2A Step 4 and Cohort 2B Step 5 participants continuing to receive 
injectable CAB LA + RPV LA external to the protocol will exit the study. Section 14.11 of protocol 
Version 4.0 has more information regarding post-trial access to study products. Participants who 
discontinue injectable CAB LA + RPV LA at the Week 96/92 visit will not exit the study. These 
participants will be followed for 48 weeks per the LSFU visit schedule. 
2.2 
Hypothesis 
Cohort 2: The selected dose of CAB LA and RPV LA, when given as dual therapy to stable, 
virologically suppressed adolescents living with HIV will maintain viral suppression and will be 
safe through Week 24 (for Cohort 2A oral followed by injectable) and through Week 20 (for 
Cohort 2B injectable only) in adolescents. 
2.3 
Study Objectives 
2.3.1 
Primary Objective 
The primary objective for Cohort 2 (discontinuing a background cART regimen) is:  
2.3.1.1 
To assess the safety of CAB + RPV in adolescents living with HIV who are virologically 
suppressed through:  
• 
Week 24 (Cohort 2A: oral followed by injectable);  
• 
Week 20 (Cohort 2B: injectable only). 
2.3.2 
Secondary Objectives 
The secondary objectives for Cohort 2 (discontinuing a background cART regimen) are:  
2.3.2.1 
To assess safety of CAB LA + RPV LA in adolescents living with HIV who are 
virologically suppressed through:   
• 
Week 48 (Cohort 2A: oral followed by injectable);  
• 
Week 44 (Cohort 2B: injectable only).  
2.3.2.2 
To evaluate repeat-dose pharmacokinetics of CAB LA + RPV LA in adolescents living 
with HIV who are virologically suppressed through:  
• 
Week 24 and through Week 48 (Cohort 2A: oral followed by injectable);  
• 
Week 20 and through Week 44 (Cohort 2B: injectable only).  
2.3.2.3 
To assess antiviral activity of CAB LA + RPV LA in adolescents living with HIV who are 
virologically suppressed through:  
• 
Week 24 and through Week 48 (Cohort 2A: oral followed by injectable);  
• 
Week 20 and through Week 44 (Cohort 2B: injectable only). 


IMPAACT 2017 Version , LOA #1 
Primary Statistical Analysis Plan Version 3.1 
 
25 August 2023 
 
2.4 
Overview of Sample Size Considerations 
Details of sample size considerations are provide in Section 9.4 of protocol Version 4.0. Briefly, 
the sample was driven primarily by safety considerations. Table 1 below presents exact (Clopper-
Pearson) 95% confidence intervals (CI) around various potential rates (0% and 20%) of Grade 3 
or higher adverse events (AE) which might be observed in a total sample of 70 participants who 
enrolled directly into Cohort 2A or 2B (i.e., the primary analysis set for the Cohort 2 safety 
assessment) as well as for 100 participants who might contribute data to the safety analysis (i.e., 
all those exposed to the final recommended dose for Cohort 2). 
Table 1. Percent of Participants Experiencing Grade 3 or Higher Adverse Events with Exact 
(Clopper-Pearson) 95% Confidence Intervals. 
N 
n (%) with Grade 3 of higher Adverse 
Events 
95% CI 
70 
0 (0%) 
0.00, 0.05 
100 
0 (0%) 
0.00, 0.04 
 
 
 
70 
14 (20%) 
0.11, 0.31 
100 
20 (20%) 
0.13, 0.29 
 
2.5 
Overview of Formal Interim Monitoring 
Interim Analysis #1 took place on 19 June 2020. Based upon study data from the first seven 
evaluable participants in each Cohort 1C and Cohort 1R, the IMPAACT 2017 CMC concluded 
that dosing regimens for oral CAB, CAB LA, and RPV LA achieved the PK targets as per protocol 
Version 2.0. Additionally, the LSFU PK results indicate both CAB and RPV concentrations 
maintain pharmacologically relevant concentrations, above the IC90, for several weeks after their 
final IM injection. This interim analysis confirmed that the doses implemented for both Cohort 1C 
and Cohort 1R passed the safety guidelines in Section 9.5.1.3 of protocol Version 2.0 for the first 
seven evaluable participants in each group. The CMC concluded that protocol criteria to open 
Cohort 2 to Cohort 1 graduates had been met, and the SMC agreed with this conclusion. 
Interim Analysis #2 was conducted on 18 April 2022. The doses implemented for both Cohort 1C 
and Cohort 1R passed the safety guidelines per Section 9.5.1.3 of protocol Version 3.0. The CMC 
concluded that the analysis supported opening Cohort 2 accrual to participants who were not 
previously enrolled in Cohort 1, and the SMC agreed with this conclusion. 
A final analysis of Cohort 1 data will be performed to confirm the final doses for Cohort 2 (using 
Version 2.0 of the Primary SAP). 
3 
Outcome Measures 
3.1 
Primary Outcome Measures 
Safety through Week 24 (Cohort 2A)/through Week 20 (Cohort 2B): 


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• 
Any adverse event, regardless of grade 
• 
Grade 3 or higher adverse event 
• 
Grade 3 or higher adverse event assessed as related to study product(s) 
• 
Serious adverse event meeting ICH criteria assessed as related to study product(s) 
• 
Permanent discontinuation of study product due to adverse event assessed as related to 
study product(s) 
• 
Death due to adverse event assessed as related to study product(s) 
3.2 
Secondary Safety and Viral Suppression Outcome Measures 
Safety through Week 48 (Cohort 2A)/through Week 44 (Cohort 2B): 
• 
Any adverse event, regardless of grade 
• 
Grade 3 or higher adverse event 
• 
Grade 3 or higher adverse event assessed as related to study product(s) 
• 
Serious adverse event meeting ICH criteria assessed as related to study product(s) 
• 
Permanent discontinuation of study product due to adverse event assessed as related to 
study product(s) 
• 
Death due to adverse events assessed as related to study product(s) 
Virologic activity through Week 24 and through Week 48 (Cohort 2A)/through Week 20 and 
through Week 44 (Cohort 2B): 
• 
Plasma HIV-1 RNA ≥50 copies/mL, per snapshot algorithm 
• 
Plasma HIV-1 RNA ≥200 copies/mL, per snapshot algorithm 
NOTE: PK outcome measures are described in the PK SAP. 
4 
Analysis Sets 
The following analysis sets are defined: 
All Treated:  All participants who took at least one dose of any study product in Cohort 2 
Evaluable: For analysis purposes, evaluable participants will be defined as having been treated 
exclusively on the final recommended dose and either (1) having completed all treatment regimen 
through Week 24 (Cohort 2A)/Week 20 (Cohort 2B) or (2) having experienced any of the 
following: 
• 
death that is attributable to the study product(s), OR 
• 
study product-related Grade 3 or higher event (excluding injection-site AEs), OR 
• 
permanently discontinued from treatment due to study product-related toxicities 
(regardless of grade) during these weeks of treatment. 
Notes:  
• 
An additional requirement for inclusion in the primary analyses for Cohort 2 is that the 
participants must be directly accrued to this cohort and be exclusively treated with the 
combination of the two study products; this will be approximately 70 participants. 


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• 
Oral bridging in Cohort 2 will not be counted as a substitute for an injection but as long as 
the recommended number of injections were given through Week 24/Week 20, even if 
they were out of window, the participantwill be considered evaluable. 
Cohort 1 Rollover: Cohort 2 participants who were previously enrolled to Cohort 1. 
Cohort 1-Naïve: Cohort 2 participants who were enrolled directly to Cohort 2 without prior 
participation in Cohort 1. 
5 
General Considerations 
The derivation of PK parameters will be performed by the IMPAACT 2017 protocol 
pharmacologists, as described in the PK SAP. The statistical summaries to be prepared by the 
statisticians are described in this Primary SAP. 
Continuous variables will be summarized by N, N missing, mean, standard deviation, and 
quantiles of minimum, 25th percentile, median, 75th percentile, and maximum. Categorical 
variables will be summarized by N (%) in each category, excluding the missing category in the 
denominator. 
For all baseline demographics and exposure analyses, results will be presented for the All 
Treated analysis set. The baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline. Unless otherwise 
stated, if baseline data are missing, no derivation will be performed and baseline will be set to 
missing. 
All safety data will be considered from the first patient exposure to study treatment. Each 
participant’s safety data will be summarized as: (1) the worst grade of each AE and (2) the worst 
grade of each AE judged to be related to study treatment. 
Listings of all Grade 3 or higher AEs regardless of treatment attribution, serious AEs meeting ICH 
criteria assessed as related to study product(s), and AEs which resulted in permanent 
discontinuation of study product(s) or death will be provided. These categories of AEs will also be 
summarized and broken down by System Organ Class. The Division of AIDS Table for Grading 
the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 
2.1, dated July 2017, will be used in this study. This table is available on the RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. 
Analyses of primary and secondary outcome measures will include Cohort 1-naïve evaluable 
participants, as defined above. Supplementary analyses of safety and virologic outcome 
measures will include all participants (Cohort 1-naïve and Cohort 1 rollovers) who received study 
products (All Treated analysis set referenced above).   


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6 
Estimands and Analysis 
6.1 
Primary Estimands and Analysis 
Primary Objective 1: To assess the safety of CAB + RPV in adolescents living with HIV who 
are virologically suppressed through Week 24 (Cohort 2A)/Week 20 (Cohort 2B). 
Estimand  
Probability of a virologically suppressed adolescent (aged 12 to <18 years) 
living with HIV-1, who was either exclusively treated with the combination of 
RPV and CAB at the final recommended dose for 24 weeks (for oral lead-in) 
or 20 weeks (for direct to injection), experienced a severe, potentially life-
threatening, or death event attributable to CAB and/or RPV, or permanently 
discontinued CAB and/or RPV due to a related toxicity, having at least one 
event (any adverse event; severe, potentially life-threatening, or death 
event; severe, potentially life-threatening, or death event assessed as 
related to CAB and/or RPV; serious adverse event assessed as related to 
CAB and/or RPV; permanent discontinuation of CAB and/or RPV due to 
adverse event assessed as related to CAB and/or RPV; death due to 
adverse event assessed as related to CAB and/or RPV). 
Treatment 
30 mg CAB + 25 mg RPV once daily orally for four weeks followed by IM 
injections of 600 mg CAB LA + 900 mg RPV LA (first and second injections 
four weeks apart with subsequent injections every eight weeks) or direct to 
IM injections of 600 mg CAB LA + 900 mg RPV LA (first and second 
injections four weeks apart with subsequent injections every eight weeks). 
Target population  
Analysis set  
Virologically suppressed children and 
adolescents 12 to <18 years of age living with 
HIV-1 exclusively treated with the combination 
of RPV and CAB at the final recommended dose 
for either 24 weeks (for oral lead-in) or 20 weeks 
(for direct to injection). 
Participants who are exclusively treated 
with the combination of RPV and CAB at 
the final recommended dose and either 
completed all treatment regimen through 
the Week 24 (Cohort 2A)/Week 20 (Cohort 
2B) visit or experienced any of the 
following: 
• 
death that is attributable to the 
study product(s), OR 
• 
study product-related Grade 3 or 
higher adverse event (excluding 
injection-site AEs), OR 
• 
permanent discontinuation from 
treatment due to study product-
related toxicities (regardless of 
grade) during these weeks of 


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treatment. 
Variable(s) 
Outcome measure(s)  
Occurrence of each of the following through 24 
weeks (for oral lead-in) or 20 weeks (for direct to 
injection): 
• 
Any adverse event 
• 
Severe, potentially life-threatening, or 
death event 
• 
Severe, potentially life-threatening, or 
death event assessed as related to CAB 
and/or RPV 
• 
Serious adverse event related to CAB 
and/or RPV 
• 
Permanent discontinuation of CAB 
and/or RPV due to adverse event 
assessed as related to CAB and/or RPV 
• 
Death due to adverse event assessed 
as related to CAB and/or RPV 
Occurrence of each of the following through 
Week 24 (Cohort 2A)/through Week 20 
(Cohort 2B): 
• 
Any adverse event, regardless of 
grade 
• 
Grade 3 or higher adverse event 
• 
Grade 3 or higher adverse event 
assessed as related to study 
product(s) 
• 
Serious adverse event meeting ICH 
criteria assessed as related to 
study product(s) 
• 
Permanent discontinuation of study 
product due to adverse event 
assessed as related to study 
product(s) 
• 
Death due to adverse event 
assessed as related to study 
product(s) 
Handling of intercurrent events  
Handling of missing data 
The following intercurrent events are relevant to 
the estimand:  
1. Discontinuation of CAB and/or RPV due 
to toxicity 
2. Death related to CAB and/or RPV 
These intercurrent events (1, 2) will be 
addressed using a while on treatment strategy. 
3. Discontinuation of CAB and/or RPV due 
to non-toxicity reasons 
4. Death unrelated to CAB and/or RPV 
These intercurrent events (3, 4) will be 
addressed using a principal stratum approach. 
Missing data will be addressed using a 
“complete case” approach, defined per 
outcome measure. 
Population-level summary measure 
Analysis approach 
Probability of having at least one event (any 
adverse event; severe, potentially life-
threatening, or death event; severe, potentially 
Proportion of participants with at least one 
event (any adverse event; Grade 3 or 
higher adverse event; Grade 3 or higher 


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life-threatening, or death event assessed as 
related to CAB and/or RPV; serious adverse 
event assessed as related to CAB and/or RPV; 
permanent discontinuation of CAB and/or RPV 
due to adverse event assessed as related to 
CAB and/or RPV; death due to adverse event 
assessed as related to CAB and/or RPV) 
through 24 weeks (for oral lead-in) or 20 weeks 
(for direct to injection). 
adverse event assessed as related to study 
product(s); serious adverse event meeting 
ICH criteria assessed as related to study 
product(s); permanent discontinuation of 
study product due to adverse event 
assessed as related to study product(s); 
death due to adverse event assessed as 
related to study product(s)) through Week 
24 (Cohort 2A)/through Week 20 (Cohort 
2B), bounded by an exact (Clopper-
Pearson) 95% CI. 
Sensitivity Analyses 
Because complete case approach assumes data are missing completely at random, we will use 
multiple imputation that assumes missing at random as a sensitivity analysis. We will create 100 
imputed data sets using appropriate fully conditional specified (FCS) model and combine results 
using Rubin’s rules. We will also present estimates assuming “best case” (i.e., probability of event 
= 0) and “worst case” (i.e., probability of event = 1) scenarios. Of note, only participants who are 
deemed evaluable will be included in this primary analysis; therefore, very little (if any) missing 
data is expected. Sensitivity analyses related to missing data in the All Treated analysis set will 
be addressed in the supplementary analyses. 
Supplementary Analyses 
Supplementary analyses for the primary outcome measures will include all participants (Cohort 1-
naïve and Cohort 1 rollovers) who received study products. All intercurrent events will be 
addressed using a while on treatment strategy, and missing data will be handled using a 
complete case approach. Because this approach assumes data are missing completely at 
random, we will use multiple imputation that assumes missing at random as a sensitivity analysis. 
We will create 100 imputed data sets using appropriate FCS model and combine results using 
Rubin’s rules. We will also present estimates assuming “best case” (i.e., probability of event = 0) 
and “worst case” (i.e., probability of event = 1) scenarios. 
6.2 
Secondary Estimands and Analysis 
6.2.1 
Safety Estimands 
Secondary Objective 1: To assess the safety of CAB + RPV in adolescents living with HIV 
who are virologically suppressed through Week 48 (Cohort 2A)/Week 44 (Cohort 2B). 
Estimand  
Probability of a virologically suppressed adolescent (aged 12 to <18 years) 
living with HIV-1, who was either exclusively treated with the combination of 
RPV and CAB at the final recommended dose for 48 weeks (for oral lead-in) 
or 44 weeks (for direct to injection), experienced a severe, potentially life-
threatening, or death event attributable to CAB and/or RPV, or permanently 


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discontinued CAB and/or RPV due to a related toxicity, having at least one 
event (any adverse event; severe, potentially life-threatening, or death 
event; severe, potentially life-threatening, or death event assessed as 
related to CAB and/or RPV; serious adverse event assessed as related to 
CAB and/or RPV; permanent discontinuation of CAB and/or RPV due to 
adverse event assessed as related to CAB and/or RPV; death due to 
adverse event assessed as related to CAB and/or RPV). 
Treatment 
30 mg CAB + 25 mg RPV once daily orally for four weeks followed by IM 
injections of 600 mg CAB LA + 900 mg RPV LA (first and second injections 
four weeks apart with subsequent injections every eight weeks) or direct to 
IM injections of 600 mg CAB LA + 900 mg RPV LA (first and second 
injections four weeks apart with subsequent injections every eight weeks). 
Target population  
Analysis set  
Virologically suppressed children and 
adolescents 12 to <18 years of age living with 
HIV-1 exclusively treated with the combination 
of RPV and CAB at the final recommended dose 
for either 48 weeks (for oral lead-in) or 44 weeks 
(for direct to injection). 
Participants who are exclusively treated 
with the combination of RPV and CAB at 
the final recommended dose and either 
completed all treatment regimen through 
the Week 48 (Cohort 2A)/Week 44 (Cohort 
2B) visit or experienced any of the 
following: 
• 
death that is attributable to the 
study product(s), OR 
• 
study product-related Grade 3 or 
higher adverse event (excluding 
injection-site AEs), OR 
• 
permanent discontinuation from 
treatment due to study product-
related toxicities (regardless of 
grade) during these weeks of 
treatment. 
Variable(s) 
Outcome measure(s)  
Occurrence of each of the following through 48 
weeks (for oral lead-in) or 44 weeks (for direct to 
injection): 
• 
Any adverse event 
• 
Severe, potentially life-threatening, or 
death event 
• 
Severe, potentially life-threatening, or 
death event assessed as related to CAB 
and/or RPV 
Occurrence of each of the following through 
Week 48 (Cohort 2A)/through Week 44 
(Cohort 2B): 
• 
Any adverse event, regardless of 
grade 
• 
Grade 3 or higher adverse event 
• 
Grade 3 or higher adverse event 
assessed as related to study 
product(s) 


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• 
Serious adverse event related to CAB 
and/or RPV 
• 
Permanent discontinuation of CAB 
and/or RPV due to adverse event 
assessed as related to CAB and/or RPV 
• 
Death due to adverse event assessed 
as related to CAB and/or RPV 
• 
Serious adverse event meeting ICH 
criteria assessed as related to 
study product(s) 
• 
Permanent discontinuation of study 
product due to adverse event 
assessed as related to study 
product(s) 
• 
Death due to adverse event 
assessed as related to study 
product(s) 
Handling of intercurrent events  
Handling of missing data 
The following intercurrent events are relevant to 
the estimand:  
1. Discontinuation of CAB and/or RPV due 
to toxicity 
2. Death related to CAB and/or RPV 
These intercurrent events (1, 2) will be 
addressed using a while on treatment strategy. 
3. Discontinuation of CAB and/or RPV due 
to non-toxicity reasons 
4. Death unrelated to CAB and/or RPV 
These intercurrent events (3, 4) will be 
addressed using a principal stratum approach. 
Missing data will be addressed using a 
“complete case” approach, defined per 
outcome measure. 
Population-level summary measure 
Analysis approach 
Probability of having at least one event (any 
adverse event; severe, potentially life-
threatening, or death event; severe, potentially 
life-threatening, or death event assessed as 
related to CAB and/or RPV; serious adverse 
event assessed as related to CAB and/or RPV; 
permanent discontinuation of CAB and/or RPV 
due to adverse event assessed as related to 
CAB and/or RPV; death due to adverse event 
assessed as related to CAB and/or RPV) 
through 48 weeks (for oral lead-in) or 44 weeks 
(for direct to injection). 
Proportion of participants with at least one 
event (any adverse event; Grade 3 or 
higher adverse event; Grade 3 or higher 
adverse event assessed as related to study 
product(s); serious adverse event meeting 
ICH criteria assessed as related to study 
product(s); permanent discontinuation of 
study product due to adverse event 
assessed as related to study product(s); 
death due to adverse event assessed as 
related to study product(s)) through Week 
48 (Cohort 2A)/through Week 44 (Cohort 
2B), bounded by an exact (Clopper-
Pearson) 95% CI. 


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Sensitivity Analyses 
Because complete case approach assumes data are missing completely at random, we will use 
multiple imputation that assumes missing at random as a sensitivity analysis. We will create 100 
imputed data sets using appropriate FCS model and combine results using Rubin’s rules. We will 
also present estimates assuming “best case” (i.e., probability of event = 0) and “worst case” (i.e., 
probability of event = 1) scenarios. Of note, only participants who are deemed evaluable will be 
included in this primary analysis; therefore, very little (if any) missing data is expected. Sensitivity 
analyses related to missing data in the All Treated analysis set will be addressed in the 
supplementary analyses. 
Supplementary Analyses 
Supplementary analyses for the secondary safety outcome measures will include all participants 
(Cohort 1-naïve and Cohort 1 rollovers) who received study products. All intercurrent events will 
be addressed using a while on treatment strategy, and missing data will be handled using a 
complete case approach. Because this approach assumes data are missing completely at 
random, we will use multiple imputation that assumes missing at random as a sensitivity analysis. 
We will create 100 imputed data sets using appropriate FCS model and combine results using 
Rubin’s rules. We will also present estimates assuming “best case” (i.e., probability of event = 0) 
and “worst case” (i.e., probability of event = 1) scenarios, as a sensitivity analysis. 
6.2.2 
Virologic Estimands 
Secondary Objective 3: To assess antiviral activity of CAB LA + RPV LA in adolescents living 
with HIV who are virologically suppressed through Week 24 and through Week 48 (Cohort 2A: 
oral followed by injectable)/through Week 20 and through Week 44 (Cohort 2B: injectable 
only). 
Estimand  
Probability of a virologically suppressed adolescent (aged 12 to <18 years) 
living with HIV-1, who was either exclusively treated with the combination of 
RPV and CAB at the final recommended dose for 24 weeks (for oral lead-in) 
or 20 weeks (for direct to injection), experienced a severe, potentially life-
threatening, or death event attributable to CAB and/or RPV, or permanently 
discontinued CAB and/or RPV due to a related toxicity, having virologic 
failure (plasma HIV-1 RNA ≥50 copies/mL; plasma HIV-1 RNA ≥200 
copies/mL) through 24/48 weeks (for oral lead-in) or 20/44 weeks (for direct 
to injection). 
Treatment 
30 mg CAB + 25 mg RPV once daily orally for four weeks followed by IM 
injections of 600 mg CAB LA + 900 mg RPV LA (first and second injections 
four weeks apart with subsequent injections every eight weeks) or direct to 
IM injections of 600 mg CAB LA + 900 mg RPV LA (first and second 
injections four weeks apart with subsequent injections every eight weeks). 
Target population  
Analysis set  


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Virologically suppressed children and 
adolescents 12 to <18 years of age living with 
HIV-1 exclusively treated with the combination 
of RPV and CAB at the final recommended dose 
for either 24/48 weeks (for oral lead-in) or 20/44 
weeks (for direct to injection). 
Participants who are exclusively treated 
with the combination of RPV and CAB at 
the final recommended dose and either 
completed all treatment regimen through 
the Week 24/48 (Cohort 2A)/Week 40/44 
(Cohort 2B) visit or experienced any of the 
following: 
• 
death that is attributable to the 
study product(s), OR 
• 
study product-related Grade 3 or 
higher adverse event (excluding 
injection-site AEs), OR 
• 
permanent discontinuation from 
treatment due to study product-
related toxicities (regardless of 
grade) during these weeks of 
treatment. 
Variable(s) 
Outcome measure(s)  
Occurrence of virologic failure through 24/48 
weeks (oral lead in)/through 20/44 weeks (direct 
to injection): 
• 
Plasma HIV-1 RNA ≥50 copies/mL 
• 
Plasma HIV-1 RNA ≥200 copies/mL 
Occurrence of virologic failure through 
Week 24 and through Week 48 (Cohort 
2A)/through Week 20 and through Week 44 
(Cohort 2B): 
• 
Plasma HIV-1 RNA ≥50 copies/mL, 
per snapshot algorithm 
• 
Plasma HIV-1 RNA ≥200 
copies/mL, per snapshot algorithm 
Handling of intercurrent events  
Handling of missing data 
The following intercurrent events are relevant to 
the estimand:  
1. Discontinuation of CAB and/or RPV due 
to toxicity 
2. Death related to CAB and/or RPV 
These intercurrent events (1, 2) will be 
addressed as specified in the snapshot 
algorithm. 
3. Discontinuation of CAB and/or RPV due 
to non-toxicity reasons 
Missing data will be handled as described in 
the snapshot algorithm.  


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4. Death unrelated to CAB and/or RPV 
These intercurrent events (3, 4) will be 
addressed using a principal stratum approach. 
Population-level summary measure 
Analysis approach 
Probability of virologic failure (plasma HIV-1 
RNA ≥50 copies/mL; plasma HIV-1 RNA ≥200 
copies/mL) through 24/48 weeks (for oral lead-
in) or 20/44 weeks (for direct to injection). 
Proportion of participants with virologic 
failure (plasma HIV-1 RNA ≥50 copies/mL, 
per snapshot algorithm; plasma HIV-1 RNA 
≥200 copies/mL, per snapshot algorithm) 
through Week 24/48 (Cohort 2A)/through 
Week 40/44 (Cohort 2B), bounded by an 
exact (Clopper-Pearson) 95% CI. 
Sensitivity Analyses 
Lower Limit of Quantification 
To correspond with the Cohort 1 primary analysis, results in the form of “< Lower Limit of 
Quantification” will be imputed as lower limit of quantification (LLoQ) – 1. For HIV-1 RNA results 
where the LLoQ is greater than the cut-off value (e.g., 60 copies/mL), we will perform four 
sensitivity analyses: 
(1) impute all values as < cut-off value, 
(2) multiply impute plasma RNA HIV-1 values using a uniform distribution (1 to LLoQ), 
(3) set values to missing, 
(4) impute values as < cut-off value if the target was not detected in the assay and set values 
to missing if the target was detected. 
Missing Data 
Because the snapshot algorithm is a single imputation method that includes a “No virologic data” 
category (i.e., data can still be missing), we will use multiple imputation that assumes missing at 
random as a sensitivity analysis. We will create 100 imputed data sets using appropriate FCS 
model and combine results using Rubin’s rules. We will also present estimates assuming “best 
case” (i.e., probability of event = 0) and “worst case” (i.e., probability of event = 1) scenarios, as a 
sensitivity analysis. Of note, we will impute whether the participant was < or ≥ the cut-off value 
(50 or 200), not the plasma RNA HIV-1 value, for missing study visits prior to implementing the 
snapshot algorithm. 
Supplementary Analyses 
Supplementary analyses for the secondary virologic outcome measures will include all 
participants (Cohort 1-naïve and Cohort 1 rollovers) who received study products. All intercurrent 


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events and missing data will be handled as described in the snapshot algorithm. The sensitivity 
analyses described above will be implemented. 
7 
Report Contents 
This section lists the major report contents that may be included the Primary Analysis Reports. 
Detailed descriptions of the content of each of the following sections are given in the AIP. 
1 
Introduction 
2 
Background 
I. 
Study Design 
II. 
Objectives 
III. 
Outcome Measures 
IV. 
Study History and Monitoring History 
3 
Statistical Considerations 
I. 
Analysis Populations 
II. 
General Considerations 
III. 
Estimands and Estimation 
4 
Disposition  
I. 
CONSORT Diagram 
II. 
Screening 
III. 
Accrual 
IV. 
Protocol Deviations 
V. 
Evaluability 
5 
Baseline Characteristics 
6 
Study Status and Retention 
7 
Status of Drugs under Study  
8 
Primary Analyses  
9 
Secondary Analyses 
10 Other Analyses 
11 Summary 
 


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8 
Associated Documents 
Attachment 1: Writing Team Roster 
 
 


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Attachment 2: Snapshot Algorithm (using cut-off of HIV-1 RNA 200 copies/mL) 
Condition  
(‘Week 24’ indicates Week 24 window/’Week 20’ 
indicates Week 20 window) 
Response  
Reasons 
1. If non-permitted change in background 
therapy prior to Week 24/Week 20  
HIV1-RNA ≥ 200  
Change in ART 
2.  If permitted change in background therapy 
prior to Week 24/Week 20 AND the latest on-
treatment VL prior to/on the date of change is ≥ 
200 copies/mL 
HIV1-RNA ≥ 200  
Change in ART 
3.  If non-permitted change in background 
therapy during Week 24/Week 20    
 
 
• Last on-treatment VL during Week 
24/Week 20 prior to/on the date of change 
≥ 200 copies/mL 
HIV1-RNA ≥ 200  
Data in window and 
HIV-1 RNA ≥ 200 
copies/mL 
• Last on-treatment VL during Week 
24/Week 20 prior to/on the date of change 
<200 copies/mL 
HIV1-RNA < 200  
 
• No VL during Week 24/Week 20 prior to/on 
the date of change     
HIV1-RNA ≥ 200  
Change in ART 
4. If permitted change in background therapy 
during Week 24/Week 20 AND the last on-
treatment VL prior to/on the date of change is ≥ 
200 copies/mL 
 
 
4.1 This last on-treatment VL occurs prior to 
Week 24/Week 20  
HIV1-RNA ≥ 200 
Change in ART 
4.2 This last on-treatment VL occurs during 
Week 24/Week 20 but prior to/on the date 
of change 
HIV1-RNA ≥ 200  
Data in window and 
HIV-1 RNA ≥ 200 
copies/mL 
5. If none of the above conditions met 
 
 
5.1 VL available during Week 24/Week 20  
 
 
• Last on-treatment VL during Week 
24/Week 20 ≥ 200 copies/mL 
HIV1-RNA ≥ 200  
Data in window and 
HIV-1 RNA ≥ 200 
copies/mL 
• Last on-treatment VL during Week 
24/Week 20 < 200 copies/mL 
HIV1-RNA < 200  
 
5.2 No VL during Week 24    
 
 
• If subjects still on study (i.e. IP has not 
been permanently stopped up to Week 24) 
No virologic data 
at Week 24 
Window  
On study but 
missing data in 
window 
• If subjects withdraw before/during Week 24 
due to 
 
 


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Note the same process will be mapped out for Week 48.   
Examples from FDA guidance (cut-off of 50 copies/mL): 
Data in Window 
Virologic outcome should be determined by the last available measurement while the patient is on 
treatment and continued on trial within the time window: 
HIV-RNA = 580 copies/mL at Day 336, HIV-RNA below 50 copies/mL on Day 350. This should be 
categorized as HIV-RNA below 50 copies/mL. 
No Data in Window 
Discontinued study due to Adverse Event or Death: 
Any patient who discontinues because of an AE or death before the window should be classified 
as Discontinued due to AE or Death (as appropriate), regardless of the HIV-RNA result, even if 
the HIV-RNA is below 50 copies/mL at the time of discontinuation.  
However, if a patient has an HIV-RNA value in the time window and also discontinues in the time 
window, the viral load data should be used to classify the patient’s response. This is the Virology 
First hierarchy: 
HIV-RNA below 50 copies/mL at Day 336 and discontinues because of AE or even dies on Day 
360 — this person is categorized as having HIV-RNA below 50 copies/mL.  
‒ 
Safety reasons (e.g. AE/death, liver 
chemistry stopping criteria, renal toxicity 
withdrawal criteria, QTc withdrawal 
criteria et al, as recorded in eCRF 
Conclusion form) 
No virologic data 
at Week 24 
Window 
Disc due to 
AE/death 
‒ 
Non-safety related reasons (e.g. Lack of 
efficacy, protocol deviation, withdrew 
consent, loss to follow-up, study 
closed/terminated, investigator 
discretion et al, as recorded in eCRF 
Conclusion Form) 
 
 
o 
Last on-treatment VL <200 c/mL OR 
no on-treatment VL available during 
study   
No virologic Data 
at Week 24 
Window 
Disc for other 
reasons 
o 
Last on-treatment VL ≥ 200 c/mL AND 
withdrawal due to Lack of efficacy 
HIV1-RNA ≥ 200  
Disc. for lack of 
efficacy 
o 
Last on-treatment VL ≥ 200 c/mL AND 
withdrawal due to all other non-safety 
related reasons 
HIV1-RNA ≥ 200  
Dis. for other reason 
and HIV-1 RNA ≥ 
200 copies/mL 


IMPAACT 2017 Version , LOA #1 
Primary Statistical Analysis Plan Version 3.1 
 
25 August 2023 
 
HIV-RNA is 552 copies/mL on Day 336 and the patient discontinues on Day 360, the patient is 
categorized as having HIV-RNA greater than or equal to 50 copies/mL. 
Discontinued for Other Reasons: 
Only patients who have achieved virologic suppression can be counted as Discontinued for Other 
Reasons. 
If a patient discontinues the study before the window because of lack of efficacy then the patient 
should be included in the HIV-RNA greater than or equal to 50 row and not in the Discontinued 
for Other Reasons row. 
If a patient discontinues because of subject withdrew consent and his or her HIV-1 RNA result at 
the time of discontinuation was equal to or above 50 copies/mL, then he or she should be 
categorized as HIV-RNA greater than or equal to 50 and NOT as Discontinued for Other 
Reasons.  
If a patient discontinued because of Lost to Follow-Up and the last HIV-RNA result was 49 
copies/mL, then the patient can be categorized as Discontinued for Other Reasons. 
If patients changed background treatment — not permitted by protocol— they should be 
considered an efficacy failure and captured in the HIV-RNA greater than or equal to 50 copies/mL 
row. 
On study but missing data in window: 
If there are no data during Days 294 to 377, but there is an HIV-RNA below 50 copies/mL on Day 
380, this patient should be considered On Study but Missing Data in Window. 
If there are no data during Days 294 to 377, but there is an HIV-RNA equal to or above 50 
copies/mL on Day 280, this patient also should be classified as On Study but Missing Data in 
Window. 
 

Prot_001.pdf: 
IMPAACT 2017 
 
Phase I/II Study of the Safety, Acceptability, Tolerability, and 
Pharmacokinetics of Oral and Long-Acting Injectable Cabotegravir 
and Long-Acting Injectable Rilpivirine in Virologically Suppressed 
HIV-Infected Children and Adolescents 
 
“MOCHA” 
More Options for Children and Adolescents 
 
 
A Study of the International Maternal Pediatric Adolescent  
AIDS Clinical Trials Network 
 
Sponsored by: 
National Institute of Allergy and Infectious Diseases 
Eunice Kennedy Shriver 
National Institute of Child Health and Human Development 
National Institute of Mental Health 
 
 
Pharmaceutical Support Provided by: 
ViiV Healthcare 
 
 
DAIDS ID #30070 
IND #138,754 Held By DAIDS 
 
 
 
Protocol Co-Chairs: 
Carolyn Bolton Moore, MSc, MBBCh 
 
Aditya H. Gaur, MD 
 
NIAID Medical Officer:  
Adeola Adeyeye, MD, MPA 
 
NICHD Medical Officer: 
Bill Kapogiannis, MD 
 
Clinical Trials Specialists: 
Katherine Calabrese, MPH  
Sarah Buisson, MSW, MPH 
 
 
 
 
FINAL Version 3.0 
 
13 August 2020


 
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IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics 
of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable 
Rilpivirine in Virologically Suppressed HIV-Infected Children and Adolescents 
 
TABLE OF CONTENTS 
 
Protocol Signature Page ......................................................................................................... 6 
ABBREVIATIONS AND ACRONYMS ....................................................................................... 7 
PROTOCOL TEAM ROSTER ...................................................................................................11 
STUDY SITE ROSTER .............................................................................................................15 
SCHEMA ..................................................................................................................................22 
1 
INTRODUCTION ...........................................................................................................30 
1.1 
Background ....................................................................................................................... 30 
1.2 
Prior Research ................................................................................................................... 31 
1.3 
Study Rationale ................................................................................................................. 43 
1.4 
Risk/Benefit Assessment .................................................................................................. 53 
1.5 
Hypotheses ........................................................................................................................ 55 
2 
OBJECTIVES ................................................................................................................55 
2.1 
Primary Objective: Cohort 1 (continuing a background cART regimen) ......................... 55 
2.2 
Primary Objective: Cohort 2 (discontinuing a background cART regimen) .................... 55 
2.3 
Secondary Objectives: Cohort 1 ....................................................................................... 55 
2.4 
Secondary Objectives: Cohort 2 ....................................................................................... 56 
2.5 
Other Objectives ............................................................................................................... 56 
3 
STUDY DESIGN ...........................................................................................................57 
3.1 
Cohort 1 ............................................................................................................................ 58 
3.2 
Cohort 2 ............................................................................................................................ 59 
3.3 
Long-term Safety and Washout PK Follow-up (LSFU) ................................................... 60 
4 
STUDY POPULATION ..................................................................................................61 
4.1 
Inclusion Criteria: Cohort 1 Step 1 and Cohort 2 Step 3 .................................................. 61 
4.2 
Exclusion Criteria: Cohort 1 Step 1, or Cohort 2 Step 3................................................... 64 
4.3 
Inclusion/Exclusion Criteria, Step 2 (Cohort 1 Progression Criteria, Step 1 to Step 2) ... 66 
4.4 
Inclusion/Exclusion Criteria, Step 4 (Cohort 2 Progression Criteria, Step 3 to Step 4) ... 67 
4.5 
Inclusion/Exclusion Criteria: Parents/Caregivers ............................................................. 68 
4.6 
Co-Enrollment Considerations.......................................................................................... 68 
4.7 
Recruitment, Screening, and Enrollment Process ............................................................. 69 
4.8 
Participant Retention ......................................................................................................... 70 
5 
STUDY PRODUCT ........................................................................................................70 
5.1 
Study Product Regimen and Administration .................................................................... 70 
5.2 
Study Product Formulation ............................................................................................... 73 
5.3 
Study Product Supply ....................................................................................................... 74 
5.4 
Study Product Accountability ........................................................................................... 74 
5.5 
Final Disposition of Study Product ................................................................................... 75 
5.6 
Concomitant Medications ................................................................................................. 75 
5.7 
Prohibited Medications ..................................................................................................... 75 
5.8 
Precautionary Medications................................................................................................ 75 
6 
STUDY VISITS AND PROCEDURES ...........................................................................75 
6.1 
Study Visit Windows, Split and Interim Visits, and Off-site Visits ................................. 76 
6.2 
Cohort 1 Step 1, and Cohort 2 Step 3 Screening Visit ...................................................... 78 
6.3 
Cohort 1 ............................................................................................................................ 80 


 
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6.4 
Cohort 2 ............................................................................................................................ 88 
6.5 
Long-Term Safety and Washout PK Follow-Up (LSFU) Visits ..................................... 101 
6.6 
Confirmation of Virologic Failure Visit ......................................................................... 105 
6.7 
Study Exit ....................................................................................................................... 106 
6.8 
Post-Study Contacts ........................................................................................................ 107 
6.9 
Procedures for Continued Oral and Injectable Study Product Administration ............... 107 
6.10 
Medical and Medications History ................................................................................... 107 
6.11 
Physical Examinations .................................................................................................... 109 
6.12 
Performing an Electrocardiogram (ECG/EKG) .............................................................. 110 
6.13 
Pregnancy Testing and Contraceptive Counseling ......................................................... 111 
6.14 
Study Product Adherence Assessment and Adherence Counseling (Study Product, cART 
Regimen, Study Visits) ................................................................................................... 112 
6.15 
Acceptability and Tolerability Assessments ................................................................... 113 
6.16 
Additional Considerations for Laboratory Procedures ................................................... 113 
7 
SAFETY ASSESSMENT, MONITORING, AND REPORTING .................................... 115 
7.1 
Safety-Related Roles and Responsibilities ..................................................................... 115 
7.2 
Safety-Related Data Collection....................................................................................... 116 
7.3 
Expedited Adverse Event (EAE) Reporting ................................................................... 117 
8 
PARTICIPANT MANAGEMENT .................................................................................. 118 
8.1 
Management of Adverse Events ..................................................................................... 118 
8.2 
Monitoring and Management of QTc Prolongation ........................................................ 126 
8.3 
Management of Contraception and Pregnancy ............................................................... 126 
8.4 
Monitoring and Management of HIV Viral Load ........................................................... 127 
8.5 
Substitution or Dose Modification of cART for Cohort 1 Participants .......................... 128 
8.6 
Deferring Study Product and Criteria for Temporary Hold of Study Product ................ 128 
8.7 
Criteria for Premature Permanent Discontinuation of Study Product ............................. 129 
8.8 
Participant Withdrawal or Termination from the Study ................................................. 130 
9 
STATISTICAL CONSIDERATIONS ............................................................................ 131 
9.1 
General Design Issues ..................................................................................................... 131 
9.2 
Outcome Measures ......................................................................................................... 132 
9.3 
Randomization and Stratification ................................................................................... 135 
9.4 
Sample Size and Accrual ................................................................................................ 135 
9.5 
Monitoring ...................................................................................................................... 136 
9.6 
Analyses .......................................................................................................................... 144 
10 
CLINICAL PHARMACOLOGY PLAN ......................................................................... 148 
10.1 
Clinical Pharmacology Objectives .................................................................................. 148 
10.2 
Primary and Secondary Data: Cohorts 1 and 2 ............................................................... 150 
10.3 
Endpoints and Outcome Measures .................................................................................. 151 
10.4 
Study Design, Data Analysis, and Modeling .................................................................. 151 
10.5 
Expected Outcome .......................................................................................................... 153 
11 
QUALITATIVE PHONE INTERVIEWS (U.S. Sites Only)............................................ 154 
11.1 
Sample Size and Selection Process ................................................................................. 155 
11.2 
Qualitative Phone Interview Procedural Window .......................................................... 155 
11.3 
Consenting Considerations and Scheduling Qualitative Phone Interviews .................... 155 
11.4 
Conducting Qualitative Phone Interviews ...................................................................... 156 
11.5 
Disclosure of Harm ......................................................................................................... 156 
11.6 
Qualitative Phone Interview Data Analyses ................................................................... 157 
12 
DATA HANDLING AND RECORD KEEPING ............................................................. 157 
12.1 
Data Management Responsibilities ................................................................................. 157 
12.2 
Essential and Source Documents and Access to Source Data ........................................ 158 
12.3 
Quality Control and Quality Assurance .......................................................................... 159 


 
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13 
CLINICAL SITE MONITORING ................................................................................... 159 
14 
HUMAN SUBJECTS PROTECTIONS......................................................................... 159 
14.1 
Institutional Review Board/Ethics Committee Review and Approval ........................... 159 
14.2 
Vulnerable Participants ................................................................................................... 160 
14.3 
Informed Consent ........................................................................................................... 160 
14.4 
Potential Benefits ............................................................................................................ 162 
14.5 
Potential Risks ................................................................................................................ 163 
14.6 
Reimbursement/Compensation ....................................................................................... 164 
14.7 
Privacy and Confidentiality ............................................................................................ 164 
14.8 
Communicable Disease Reporting .................................................................................. 164 
14.9 
Management of Incidental Findings ............................................................................... 165 
14.10 Management of New Information Pertinent to Study Participation................................ 165 
14.11 Post-Trial Access to Study Product ................................................................................ 165 
15 
ADMINISTRATIVE PROCEDURES ............................................................................ 165 
15.1 
Regulatory Oversight ...................................................................................................... 165 
15.2 
Protocol Registration ...................................................................................................... 166 
15.3 
Study Implementation ..................................................................................................... 166 
15.4 
Protocol Deviation Reporting ......................................................................................... 166 
15.5 
Critical Event Reporting ................................................................................................. 167 
15.6 
ClinicalTrials.gov ........................................................................................................... 167 
16 
PUBLICATIONS ......................................................................................................... 167 
17 
REFERENCES ............................................................................................................ 167 
Appendix I: Schedule of Evaluations .................................................................................. 170 
Appendix I-A: Schedule of Evaluations for Cohort 1 Adolescents (Cohort 1C and Cohort 
1R) .............................................................................................................................. 170 
Appendix I-B: Schedule of Evaluations for Cohort 2 Adolescents .................................... 172 
Appendix I-C: Schedule of Evaluations for Long-Term Safety and ................................... 174 
Appendix II: Sample Parental Informed Consent Forms .................................................... 175 
Appendix II-A:  Sample Parental Informed Consent Form for Participation in Cohort 1 ........... 175 
Appendix II-B:  Sample Parental Informed Consent Form for Participation in Cohort 2 ........... 195 
Appendix II-C:  Sample Parental Informed Consent Form for Specimen Storage and Future Use
 ........................................................................................................................................ 216 
Appendix III: Sample Informed Consent Forms .................................................................. 219 
Appendix III-A:  Sample Informed Consent Form for Participation in Cohort 1 ........................ 219 
Appendix III-B:  Sample Informed Consent Form for Participation in Cohort 2 ........................ 238 
Appendix III-C:  Sample Informed Consent Form for Specimen Storage and Future Use ......... 258 
Appendix IV: Sample Informed Assent Forms .................................................................... 261 
Appendix IV-A: Sample Informed Assent Form for Participation in Cohort 1 ........................... 261 
Appendix IV-B: Sample Informed Assent Form for Participation in Cohort 2 ........................... 267 
Appendix IV-C: Sample Assent Form for Specimen Storage and Future Use for Participants ... 273 
Appendix V: Parent/Caregiver Participation in Qualitative Phone Interviews (U.S. Sites 
Only) ........................................................................................................................... 276 
Appendix V-A: Parent/Caregiver Qualitative Phone Interviews ................................................. 276 
Appendix V-B: Parent/Caregiver Phone Interview Sample Informed Consent Form ................. 281 
Appendix V-C: Parent/Caregiver Phone Interview Sample Informed Consent Verbal Script .... 284 
Appendix VI:  Injectable Study Product Preparation .......................................................... 287 
Appendix VI-A: Preparation of CAB LA .................................................................................... 288 
Appendix VI-B: Preparation of RPV LA ..................................................................................... 291 
Appendix VII:  Operational Guidance for Sites Responding to COVID-19 ........................ 294 


 
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 LIST OF FIGURES 
 
Figure 1. Overview of Study Design for Cohort 1 Participants .................................................................. 26 
Figure 2. Overview of Study Design for Cohort 2 Participants .................................................................. 27 
Figure 3. Overview of Study Participation Flow for Cohort 1 Participants ................................................ 28 
Figure 4. Overview of Study Participation Flow for Cohort 2 Participants ................................................ 29 
Figure 5.  Observed preliminary IMPAACT 2017 Cohort 1C CAB concentrations in adolescents 
compared to model predicted concentrations based on POP PK analyses from adult studies .................... 45 
Figure 6. Observed IMPAACT 2017 Cohort 1R preliminary data and predicted RPV plasma 
concentrations in adolescents after PO RPV 25 mg once daily (left panel) and IM RPV LA 900-600-600 
mg (right panel)........................................................................................................................................... 46 
Figure 7. Observed trough RPV plasma concentrations in Cohort 1R adolescents (blue dots) and adults 
(boxplots, ATLAS/FLAIR) after PO RPV 25 mg once daily (Week 0; last day of PO lead-in), and IM 
RPV LA 900-600-600 mg (Weeks 4, 8 and 12; concentrations 4 weeks after injection) ........................... 46 
 
LIST OF TABLES 
 
Table 1: Adverse Drug Reactions Observed in Adult Patients Treated with RPV in Combination with 
CAB ............................................................................................................................................................ 43 
Table 2. Predicted Steady State CAB Exposures following Oral CAB 30mg and 60mg QD in Adolescents 
compared to Observed Adult Values .......................................................................................................... 51 
Table 3. Predicted Steady State CAB Parameters following CAB LA IM Q8W regimen compared with 
Observed and Estimated data in Adults ...................................................................................................... 52 
Table 4.  Predicted RPV Trough Concentrations following RPV LA IM Q8W in Adolescents, compared 
with Observed Data in Adults ..................................................................................................................... 53 
Table 5. Cohort 1: Study Product Regimen and Administration ................................................................ 71 
Table 6. Cohort 2: Study Product Regimen and Administration ................................................................ 72 
Table 7. Documentation Requirements for Medical and Medication Histories ........................................ 108 
Table 8. Visits Requiring Complete Physical Examination ...................................................................... 109 
Table 9. Percent of Participants Experiencing ≥ Grade 3 Adverse Events (or ≥ Grade 3 Adverse Events 
Attributed to the Study Medications) with Exact 95% Confidence Intervals ........................................... 136 
Table 10. Probability of Failing Dose Guidelines Under Potential Rates of True Toxicity ..................... 141 
Table 11. Probability of Failing Dose Guidelines Under Potential Rates of True Toxicity ..................... 142 
Table 12. Percent of Participants with HIV-1 RNA<50 c/mL per Snapshot algorithm with Exact 95% 
Confidence Intervals ................................................................................................................................. 146 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics 
of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable 
Rilpivirine in Virologically Suppressed HIV-Infected Children and Adolescents 
 
DAIDS Study ID #30070 
 
 
Version 3.0 
Protocol Signature Page 
 
 
 
I will conduct this study in accordance with the provisions of this protocol amendment and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) Health 
and Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonisation Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
__ 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 
 
 


 
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IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics 
of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable 
Rilpivirine in Virologically Suppressed HIV-Infected Children and Adolescents 
 
ABBREVIATIONS AND ACRONYMS  
 
3TC 
Lamivudine 
ABC 
Abacavir 
ADR 
Adverse drug reaction 
AE 
Adverse Event  
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine Transaminase 
ARV 
Antiretroviral 
ART 
Antiretroviral Therapy 
AST 
Aspartate Aminotransferase 
ATV 
Atazanavir 
AUC 
Area under the plasma concentration-time curve 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
C28D 
Concentration at 28 days 
CAB 
Cabotegravir 
CAB LA 
Long-Acting Injectable Cabotegravir 
cART 
Combination Antiretroviral Therapy 
CAR 
Continued Antiretroviral Regimen 
CBC 
Complete Blood Count 
CD4 
Cluster of differentiation 4 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CHOP 
Children’s Hospital of Philadelphia 
CI 
Confidence intervals 
CK 
Creatine Kinase 
CL/F 
Apparent total body clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum concentration 
CM 
Clarification Memorandum 
CMC 
Clinical Management Committee 
COVID-19 
Coronavirus disease 2019 
CPK 
Creatine phosphokinase 
CrCl 
Creatinine clearance 
CRMS 
NIAID Clinical Research Management System 
CRPMC 
NIAID Clinical Research Products Management Center 
CT 
Cohort 
C 
Trough concentration 
CNDx 
Concentration at a specified time (x) after administration of a specific dose number (ND) 
CV% 
Coefficient of variation 
CVF 
Confirmed Virologic Failure 
DAIDS 
Division of AIDS  
DAIDS RSC 
DAIDS Regulatory Support Center 


 
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DAIDS PRO 
DAIDS Protocol Registration Office 
DAERS 
DAIDS Adverse Experience Reporting System 
DILI 
Drug-induced liver injury 
DMC 
Data Management Center 
DMPK  
Drug Metabolism and Pharmacokinetics 
DTG 
Dolutegravir 
EAE 
Expedited Adverse Event 
EC 
Ethics Committee 
ECG/EKG 
Electrocardiogram 
 
eCRF  
Electronic Case Report Form 
EFV 
Efavirenz 
EIA  
Enzyme immunoassay 
ETV 
Etravirine 
EU 
European Union 
FDA 
Food and Drug Administration 
FSTRF 
Frontier Science and Technology Research Foundation 
FTC 
Emtricitabine 
GCLP 
Good Clinical Laboratory Practice 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practice 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C virus 
HDPE 
High density polyethylene 
HIV 
Human Immunodeficiency Virus 
HPLC/MS/MS High-performance liquid chromatography and tandem mass spectrometry 
HSP 
Human Subject Protection 
HVTN 
HIV Vaccine Trials Network 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
IC90 
90% inhibitory concentration 
ICH 
International Council on Harmonisation 
IM 
Intramuscular 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
IND 
Investigational New Drug 
INSTI 
Integrase Strand Transfer Inhibitor 
IoR 
Investigator of Record  
IRB  
Institutional review board 
ISR 
Injection site reaction 
ITT-E 
Intention to treat-efficacy 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
z 
Terminal slope 
LA 
Long-acting 
LDMS 
Laboratory Data Management System 
LoA 
Letter of Amendment 
LPC 
Laboratory processing chart 
LSFU 
Long-term Safety and Washout PK Follow-Up 
MC 
Monte Carlo simulations 
MOCHA 
More Options for Children and Adolescents 
MOP 
Manual of Procedures 


 
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NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NNRTI 
Non-nucleoside Reverse Transcriptase Inhibitor 
NOAEL 
No-observed-adverse-effect-level 
NRTI  
Nucleoside Reverse Transcriptase Inhibitors 
NTD 
Neural Tube Defect  
OHRP 
US Office for Human Research Protection 
OLI 
Oral lead-in 
PCR 
Polymerase Chain Reaction 
PDVF 
Protocol defined virologic failure 
pH 
proton concentration 
PI 
Protease Inhibitor 
PID 
Participant Identification Number 
PK 
Pharmacokinetics 
PO 
By mouth 
POP PK 
Population PK 
PoR 
Pharmacist of Record 
PPN 
Pre- and postnatal 
Q4W 
Study drug administration every 4 weeks 
Q8W 
Study drug administration every 8 weeks 
q.d. 
One a day 
QTc 
Corrected Q-T interval 
QTcB 
Corrected QT interval according to Bazett 
QTcF 
Corrected QT interval according to Fridericia 
RNA 
Ribonucleic Acid 
RPV 
Rilpivirine 
RPV LA 
Long-acting injectable rilpivirine 
RSC 
DAIDS Regulatory Support Center 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SD 
Standard deviation 
SDMC               Statistical and Data Management Center 
SES 
Subject Enrollment System 
SID 
Study Identification Number 
SMC 
Study Monitoring Committee 
SMR 
Sexual Maturity Rating 
SoC 
Standard of Care 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected, Unexpected Serious Adverse Reactions 
TAF 
Tenofovir alafenamide 
TDF 
Tenofovir disoproxil fumarate 
Tmax 
Time of maximum concentration 
TQT 
Thorough QT 
ULN 
Upper Limit of Normal 
US 
United States of America 
V/F 
 
Apparent volume of distribution 
VL 
 
Viral load 
VQA 
 
Virology Quality Assurance Program 


 
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WHO  
World Health Organization 
 
 
 


 
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IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics 
of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable 
Rilpivirine in Virologically Suppressed HIV-Infected Children and Adolescents 
 
PROTOCOL TEAM ROSTER 
 
Protocol Co-Chairs 
Carolyn Bolton Moore, MSc, MBBCh  
Centre for Infectious Disease Research in 
Zambia/University of Alabama Birmingham 
Plot # 34620, Off Alick Nkhata Road 
Mass Media, Lusaka, 10101, Zambia 
Phone: +260973876922 
Email: Carolyn.bolton@cidrz.org 
 
Aditya H. Gaur, MD 
Department of Infectious Diseases 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Phone: 901-595-2862 
Email: aditya.gaur@stjude.org 
 
Clinical Trials Specialists 
Katherine Calabrese, MPH 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: 919-544-7040 x11306 
Email: kcalabrese@fhi360.org 
 
Sarah Buisson, MSW MPH 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: 919-544-7040 x11585 
Email: sbuisson@fhi360.org 
 
NIAID Medical Officer 
Adeola Adeyeye, MD, MPA 
Prevention Science Program, DAIDS, NIAID, 
NIH  
Room 8B36 MSC 9831, 5601 Fishers Lane 
Rockville, MD 20852-9831  
Phone: 240-669-5005  
Email: adeyeyeao@niaid.nih.gov 
NICHD Medical Officer 
Bill Kapogiannis, MD 
Eunice Kennedy Shriver National Institute of 
Child Health and Human Development 
(NICHD)  
6710B Rockledge Drive, Room 2150  
Bethesda, MD 20817  
Phone: (301) 402-0698  
E-mail: kapogiannisb@mail.nih.gov 
 
Protocol Pharmacist 
Irene Rwakazina, PharmD, CCRP 
Pharmaceutical Affairs Branch 
NIH/NIAID/DAIDS/OCSO 
5601 Fishers Lane 
Room 9E14 MSC 9830 
Rockville, MD 20852 
Phone: +1-301-761-7269 
Email: irene.rwakazina@nih.gov 
 
Protocol Pharmacologists 
Edmund V. Capparelli, PharmD 
School of Medicine and Skaggs School of 
Pharmacy and Pharmaceutical Sciences 
University of California San Diego 
9500 Gilman Drive MC 0657 
La Jolla, CA 92093-0657 
Phone: 858-246-0009 
Email: ecapparelli@ucsd.edu 
 
Brookie M. Best, PharmD, MAS 
Skaggs School of Pharmacy and Pharmaceutical 
Sciences 
University of California San Diego 
9500 Gilman Drive MC 0657 
La Jolla, CA 92093-0657 
Phone: 858-822-5550 
Email: brookie@ucsd.edu  
 
Mark Marzinke, PhD, DABCC 
Johns Hopkins University School of Medicine 
1800 Orleans Street, Sheikh Zayed Tower, 
Room B1-1020G 


 
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Baltimore, MD 21287 
Office: (443) 287-7516 
CPAL Office: (410) 550-9702 
Email:  mmarzin1@jhmi.edu 
 
Protocol Statisticians 
Pearl Samson, MS 
Statistical and Data Management Center 
(SDMC) 
Frontier Science Foundation (FSTRF) 
1371 Beacon Street, Suite 203,  
Brookline MA 02446 
Phone: 617-632-2000 ext 4030 
Email: psamson@sdac.harvard.edu 
 
Yan Wang, MS 
Statistical and Data Management Center 
(SDMC) 
Frontier Science Foundation (FSTRF) 
1371 Beacon Street, Suite 203,  
Brookline MA 02446 
Phone: 716-834-0900 x7215 
Email: ywang@sdac.harvard.edu 
 
Protocol Investigators 
Jennifer Chapman, MPH 
Qualitative Project Manager 
Children's Hospital of Philadelphia  
Roberts Building, 11232 
2716 South Street, 
Philadelphia, PA 19146 
Phone: 267-426-1247 
Email: ChapmanJ1@email.chop.edu 
 
Elizabeth Lowenthal, MD 
Departments of Pediatrics and Epidemiology 
University of Pennsylvania Perelman School of 
Medicine 
Children’s Hospital of Philadelphia 
Phone: 267-426‐2306  
Email: lowenthale@email.chop.edu 
 
Sharon Nachman, MD 
SUNY Stony Brook 
Stony Brook, NY 11794-8111 
Phone: 631-444-7692 
Email: 
Sharon.nachman@stonybrookmedicine.edu 
 
Allison Agwu, MD, ScM 
Johns Hopkins School of Medicine 
200 North Wolfe Street, Rm 3145 
Baltimore, MD  21287 
Phone: 410-614-3917 
Email: ageorg10@jhmi.edu 
 
Pharmaceutical Representatives 
Cindy McCoig, MD 
ViiV Healthcare 
Severo Ochoa, 2 
28760 Tres Cantos (Madrid), Spain 
Phone:  +34 608 831 611 
Email: cynthia.c.mccoig@viivhealthcare.com 
 
David Margolis, MD, MPH 
ViiV Healthcare 
5 Moore Drive 
Research Triangle Park, NC 27709 
Phone: +1 919 766 0755 
Email: david.a.margolis@viivhealthcare.com 
 
Conn M. Harrington 
ViiV Healthcare 
5 Moore Drive 
Research Triangle Park, NC 27709 
Phone: +1 919 272 4513 
Email: conn.m.harrington@viivhealthcare.com 
 
Mark Baker, PhD 
ViiV Healthcare 
GlaxoSmithKline, Nyon 
Route de l'Etraz 2, Case postale 1279,  
CH-1260 Nyon 1, Switzerland 
Phone: +41 (0) 22 567 2788 
Email: mark.x.baker@viivhealthcare.com 
 
Navin Goyal 
GlaxoSmithKline 
UP4-2200 
1250 S Collegeville Road 
Collegeville PA 19426 
Phone: +1 610-917-5945 
Email: navinkumar.s.goyal@gsk.com 
 
Jenny Huang 
GlaxoSmithKline 
7333 Mississauga Road 
Mississauga, Canada, L5N 6L4 
Phone: +1 647-787-2286 
Email: jenny.o.huang@gsk.com  
 
 


 
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Herta Crauwels, PhD 
Janssen Research and Development 
Turnhoutseweg 30 
2340 Beerse, Belgium 
Phone:  +32 (0)14 64 1054 
Email: hcrauwel@its.jnj.com 
 
Kati Vandermeulen M.Sc. 
Janssen Research and Development 
Turnhoutseweg 30 
2340 Beerse, Belgium 
Phone: +32 14641233 
Email: kvanderm@its.jnj.com 
 
Rodica M. Van Solingen-Ristea, MD 
Janssen Research & Development 
Bldg. K102, Rm. 244 
Turnhoutseweg 30 
Beerse 2340, Belgium 
Phone: +32 478 63 2199 
Email: rvsolin1@its.jnj.com 
 
Protocol Data Managers 
Barbara Heckman, BS 
Frontier Science and Technology Research 
Foundation, Inc 
4033 Maple Road 
Buffalo, NY 14226-1056 
Phone: 716-834-0900 x7231 
E-mail: bheckman@frontierscience.org 
 
Yvonne Woolwine-Cunningham  
Frontier Science and Technology Research 
Foundation, Inc 
4033 Maple Road 
Buffalo, NY 14226-1056 
Phone: 716-834-0900 x7332 
E-mail: woolwine@frontierscience.org 
 
Jared L. Kneebone, PhD 
Frontier Science and Technology Research 
Foundation, Inc 
4033 Maple Road  
Buffalo, NY 14226-1056 
Phone: 716-834-0900 x7263 
E-mail: kneebone@frontierscience.org 
 
Protocol Laboratory Data Managers 
Kyle Whitson, MA 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7273 
E-mail: whitson@frontierscience.org 
 
Katie Trabert, BA 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7373 
E-mail: trabert@frontierscience.org 
 
Laboratory Center Representatives 
Frances Whalen, MPH, MT(ASCP) 
University of California Los Angeles 
11075 Santa Monica Blvd., Suite 200 
Los Angeles, CA 90025 
Phone: 704-422-4055 
E-mail: fwhalen@milabcentral.org 
 
Protocol Laboratory Technologists 
Patrick Karugaba, BMLS, MPH 
MU-JHU Core Laboratory 
Infectious Diseases Institute 
College of Health Sciences, 
Makerere University Kampala 
P.O. BOX 22418, Kampala 
Phone: 256-77-242-8549 
Email: pkarugaba@idi.co.ug 
 
Westat Clinical Research Associates 
Scott Watson, BS, RN  
Westat, Inc.  
1441 W. Montgomery Ave  
Rockville, MD 20850  
Phone: 415-494-5575 
Email: ScottWatson@westat.com 
 
Community Program Manager 
Cheryl D. Blanchette, BS  
IMPAACT Operations Center  
FHI 360 359 Blackwell St., Suite 200  
Durham, NC 22701 USA  
Phone: 919-544-7040 x11359  
Email: ccokley@fhi360.org 
 
Community Advisory Board Member 
Joel Pagan-Lizardi, MD 
University of Puerto Rico 
Medical Sciences Campus- School of Medicine  


 
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Proyecto ACTU Biomedical Building II-1st 
Floor-Room 125 
San Juan, Puerto Rico 00936-6528 
Phone: 787-759-9595 
Email: jplizardi@hotmail.com  
 
 


 
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STUDY SITE ROSTER 
 
Site 3801, Texas Children's Hospital 
Mary E. Paul MD, 
IoR 
Texas Children’s Hospital 
1102 Bates Ave., Feigin Center 6th Floor 
Retrovirology ＆ Global Health  
Houston, TX 77030 
Phone: 832-824-1038 
Email: mepaul@texaschildrens.org 
 
Chivon McMullen-Jackson, RN, BSN, CCRP 
Study Coordinator 
Texas Children’s Hospital 
1102 Bates, Suite FC330 
Houston, TX 77030 
Phone: 832-824-1339 
Email: cdmcmull@texaschildrens.org 
 
Site 4001, Ann & Robert H. Lurie Children's 
Hospital of Chicago 
Ellen Chadwick, MD 
IoR  
Lurie Children's Hospital 
225 East Chicago Ave, Box 20 
Chicago IL 60611-2605 
Phone: 312-227-4080 
Email: egchadwick@luriechildrens.org 
 
Margaret Ann Sanders, MPH 
Study Coordinator 
Lurie Children's Hospital 
225 East Chicago Ave, Box 155 
Chicago IL 60611-2605 
Phone: 312-227-8275 
Email: msanders@luriechildrens.org 
 
Site 4201, Pediatric Perinatal HIV Clinical 
Trials Unit 
Gwendolyn B. Scott, MD 
IoR 
University of Miami Miller School of Medicine 
BCRI Room 286 
1580 NW Tenth Avenue 
Miami, Florida 33136 
Phone: 305-243-6522 
Email: gscott@med.miami.edu 
 
 
 
Grace A. Alvarez A. FMD, MPH 
Study Coordinator 
University of Miami School of Medicine 
Pediatric Infectious Diseases and Immunology 
Batchelor's Children's Research Institute 
1580 N.W. 10th Ave., Suite 286 
Miami, FL 33136 
Phone:  305-243-4447 
Email:  galvarez2@miami.edu 
 
Site 4601, University of California, UC San 
Diego 
Stephen Spector, MD 
IoR 
9500 Gilman Drive 
Stein Clinical Research Building 
Room 430, Mail Code 0672 
La Jolla, CA 92093 
Phone: 858-534-7170 
Email: saspector@ucsd.edu 
 
Megan Loughran, BA 
Study Coordinator 
4076 3rd Avenue 
Suite 301 
San Diego, CA 92103 
Phone: 858-534-9218 
Email: meloughran@ucsd.edu 
 
Site 5011, Boston Medical Center Pediatric HIV 
Program 
Ellen R. Cooper, MD  
IoR 
Boston Medical Center/Pediatric Infectious 
Diseases 
670 Albany St., Rm. 623 
Boston, MA 02118 
Phone 617-414-5588 
Email: ercooper@bu.edu 
 
Debra McLaud, RN  
Study Coordinator 
Boston Medical Center/Pediatric Infectious 
Diseases 
670 Albany St., Rm. 614 
Boston, MA 02118 
Phone 617-414-5813 
Email: debra.mclaud@bmc.org 
 


 
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Site 5013, Jacobi Medical Center 
Andrew Wiznia, MD 
IoR 
Jacobi Medical Center 
1400 Pelham Parkway South 
Building # 1, Suite 1W5 
Bronx, NY 10461 
Phone: 718-918-4664 or 914-450-6462 
Email: andrew.wiznia@einsteinmed.org or 
Andrew.Wiznia@nychhc.org 
 
Marlene Burey, MSN, PNP 
Study Coordinator 
Jacobi Medical Center 
1400 Pelham Parkway South 
Building # 1, Suite 1W5 
Bronx, NY 10461 
Phone: 718-918-4783 or 718- 918-4518 
Email: Marlene.Burey@nychhc.org 
 
Site 5030, Emory University School of Medicine  
Andres Camacho-Gonzalez MD, MSc. 
IoR 
Emory University School of Medicine 
Children’s Healthcare of Atlanta 
2015 Uppergate Drive Office 550 
Atlanta, GA, 30322 
Phone: 404-727-5642 
Email: acamac2@emory.edu 
 
LaTeshia Seaton, MS, APRN 
Study Coordinator 
Grady-Family and Youth Clinic at Ponce 
341 Ponce de Leon Avenue, Room 201 
Atlanta, GA 30308 
Phone: 404-616-5936 
Email:  lseaton@emory.edu 
 
Site 5031, San Juan City Hospital 
Nicolás Rosario, MD 
IoR 
San Juan Hospital 
Research Unit 
3rd Floor room FP-04 
San Juan, P.R. 00935 
Phone: 787-764-3083 or 787-765-4186 
Email: nrosario@sanjuanciudadpatria.com 
 
Lourdes Angeli, RN, MPH 
Study Coordinator 
San Juan Hospital 
Research Unit 
3rd Floor room FP-04 
San Juan, P.R. 00935 
Phone: 787-764-3083 or 787-765-4186 
Email: langeli@sanjuanciudadpatria.com  
 
Site 5040, SUNY Stony Brook  
Sharon Nachman, MD  
IoR        
Stony Brook Children’s Hospital 
Stony Brook, NY 11794-8111 
Phone: 631-444-7692 
Email: 
Sharon.Nachman@stonybrookmedicine.edu 
 
Cristina Witzke, MPH 
Study Coordinator 
Stony Brook Children’s Hospital 
Stony Brook, NY 11794-8224 
Phone: 631-444-1313 
Email: 
Cristina.Witzke@stonybrookmedicine.edu 
 
Site 5048, The University of Southern 
California- LA 
Allison Bearden, MD 
IoR 
USC Keck School of Medicine 
1640 Marengo St. Suite #300 MC 9264 
Los Angeles, Ca 90033-9033 
Phone: 213-509-9811 
Email: allison.bearden@usc.edu 
 
Yvonne T. Morales, LVN 
Study Coordinator 
USC Keck School of Medicine 
1640 Marengo St. Suite #300 MC 9264 
Los Angeles, Ca 90033-9033 
Phone: 323-865-1561 
Email: ytr@usc.edu  
 
Site 5051, University of Florida- Jacksonville 
Mobeen H. Rathore, MD, CPE, FAAP, FPIDS, 
FIDSA, FACPE, FSHEA 
IoR 
University of Florida Center for HIV/AIDS, 
Research, Education & Service (UFCARES) 
655 West 8th Street, Clinical Center 3rd Floor 
|Jacksonville, FL  32209 
Phone: 904-798-4179 
Email: Mobeen.Rathore@jax.ufl.edu 


 
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Saniyyah Mahmoudi. MSN, ARNP, AGPCNP 
Study Coordinator  
University of Florida Center for HIV/AIDS, 
Research, Education & Service (UFCARES) 
655 West 8th Street, Clinical Center 3rd Floor| 
Jacksonville, FL  32209 
Phone: 904-244-5331 or 904-244-4881 
Email: saniyyah.mahmoudi@jax.ufl.edu  
 
Site 5052, University of Colorado- Denver 
Christiana Smith-Anderson, MD, MSc 
IoR 
University of Colorado School of Medicine 
Department of Pediatrics, Section of Infectious 
Diseases 
13123 East 16th Ave B055 
Aurora, CO  80045 
Phone: 720-777-8990 
Email: christiana.smith@childrenscolorado.org 
 
Emily Barr CPNP, CNM, MSN 
Study Coordinator  
13123 East 16th Avenue B055 
Aurora, Colorado 80045 
Phone: 720-777-8233 
Email: emily.Barr@childrenscolorado.org 
 
Site 5055, South Florida CDTC Ft. Lauderdale 
Lisa-Gaye Robinson, MD, MPH  
IoR 
Children’s Diagnostic & Treatment Center 
1401 S Federal Highway 
Fort Lauderdale, Florida 33316 
Phone: 954-728-1136 
Email: lerobinson@browardhealth.org 
 
Feiona Heaven, RN, BSN, MBA 
Clinical Research Nurse Coordinator 
Children’s Diagnostic & Treatment Center 
1401 South Federal Highway 
Fort Lauderdale, FL 33316 
Telephone:  954-728-1054 
Fax:  954-712-5072 
Email:  Fheaven@browardhealth.org 
 
Site 5083, Rush University Cook County 
Hospital  
Mariam Aziz, MD 
IoR 
600 S Paulina, ste 140 
Chicago IL 60612 
Phone: 312-942-4265 
Email: mariam_aziz@rush.edu 
  
Maureen McNichols, RN, MSN 
Study Coordinator 
2020 W Harrison, Rm 2130 
Chicago IL 60612 
Phone: 312-572-4541 
Email: maureen_mcnichols@rush.edu 
 
Site 5092, Johns Hopkins University  
Allison Agwu, MD, ScM 
IoR 
Johns Hopkins School of Medicine 
200 North Wolfe Street, Rm 3145 
Baltimore, MD  21287 
Phone: 410-614-3917 
Email: ageorg10@jhmi.edu 
 
Aleisha Collinson-Streng, RN, ACRN 
Study Coordinator 
Johns Hopkins University 
200 N Wolfe St., Suite 3096 
Baltimore, MD 21287 
Phone: 443-287-8888 
Email: Acolli14@jhmi.edu 
 
Site 5112, David Geffen School of Medicine at 
UCLA 
Jaime G. Deville, MD 
IoR 
UCLA Department of Pediatrics, Infectious 
Diseases 
10833 Le Conte Avenue 
MDCC 22-442 
Los Angeles, CA 90095-1752 
Phone: 310-825-9660 
Email: jdeville@mednet.ucla.edu  
 
Michele Carter, RN 
Study Coordinator 
UCLA Department of Pediatrics, Infectious 
Diseases 
10833 Le Conte Avenue 
MDCC 22-442 
Los Angeles, CA 90095-1752 
Phone: 310-206-2165 
Email: mfcarter@mednet.ucla.edu  
 
 


 
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Site 5114, Bronx-Lebanon Hospital Center 
Murli U. Purswani, MBChB, FAAP 
IoR 
Suites 1E and 1G, 1685 Morris Avenue, 
Bronx, NY 10457 
Phone: 718-960-1010 
Email: mpurswan@bronxleb.org 
  
Martha Cavallo, MS, CPNP 
Study Coordinator 
1685 Morris Ave Suite 1 G 
Bronx, NY 10457 
Phone: 718-960-1016  
Email: mcavallo@bronxleb.org 
 
Site 6501, St. Jude Children’s Research Hospital 
Aditya H. Gaur, MD 
IoR 
Department of Infectious Diseases 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Phone: 901-595-2862 
Email: aditya.gaur@stjude.org 
 
Adrienne English, RN 
Study Coordinator 
262 Danny Thomas Place, MS 600 
Memphis, TN 38105 
Phone: 901-595-3078 
Email: adrienne.english@stjdue.org  
 
Site 6601, University of Puerto Rico Pediatric 
HIV/AIDS Research Program 
Irma Febo, MD 
IoR 
University of Puerto Rico  
Medical Sciences Campus -School of Medicine  
Gamma Project  
Proyecto ACTU Biomedical Building II-1st 
Floor-Room 125 
San Juan, Puerto Rico 00936-6528 
Phone: 787-759-9595 
Email: irma.febo2@upr.edu 
 
Ruth Santos, RN, MPH, 
Study Coordinator  
University of Puerto Rico  
Medical Sciences Campus -School of Medicine  
Gamma Project  
Proyecto ACTU Biomedical Building II-1st 
Floor-Room 125 
San Juan, Puerto Rico 00936-6528 
Phone: 787-759-9595 
Email: ruth.santos@upr.edu 
 
Site 33001, University of South Florida (USF) 
College of Medicine ATN CRS 
Carina Rodriguez, MD 
IoR 
Pediatrics Division of Infectious Diseases 
17 Davis Blvd., Suite 200 
Tampa, FL 33606 
Phone: [TBA] 
Email: crodrig1@health.usf.edu 
 
Denise Casey, RN, BSN 
Study Coordinator 
17 Davis Blvd., Suite 200 
Tampa, FL 33606 
Phone: 813-259-8750 
Email: dcasey1@health.usf.edu 
 
Site 33010, Tulane University Health Sciences 
Center ATN CRS 
Susan Abdalian, MD 
IoR 
Department of Pediatrics 
1430 Tulane Avenue 
SL-37 
New Orleans, LA 70112 
Phone: 504-988-5348 
Email: sabdali@tulane.edu 
 
Leslie Kozina, RN, CCRC 
Study Coordinator 
Tulane University 
1430 Tulane Avenue 
SL-37 
New Orleans, LA 70112 
Phone: 504-988-3619 
Email: lkozina@tulane.edu 
 
Site 33019, Wayne State University ATN CRS 
Elizabeth Secord, MD 
IoR 
3901 Beaubien 
Detroit, MI, 48201 
Phone: 313-745-4450 
Email: esecord@med.wayne.edu 
 


 
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Charnell Cromer, RN, MSN 
Study Coordinator 
Department of Pediatrics 
4201 St. Antoine 
Detroit, MI 48201 
Phone: 313-966-0622 
Email: ccromer@med.wayne.edu 
 
Site 5115, Siriraj Hospital CRS 
Kulkanya Chokephaibulkit, MD. 
Pediatric Infectious Diseases Unit,  
Department of Pediatrics,  
Fl. 8th, Chao-fah Building, 
Siriraj Hospital, 
2 Wanglang Road, Bangkok-noi,  
Bangkok 10700, Thailand 
Phone: +66-2-418-0544 
Email: Kulkanya.cho@mahidol.ac.th 
 
Watcharee Lermankul, B.Pharm., PhD. 
Pediatric Infectious Diseases Unit,  
Department of Pediatrics,  
Fl. 3rd, Chao-fah Building, 
Siriraj Hospital, 
2 Wanglang Road, Bangkok-noi,  
Bangkok 10700, Thailand 
Phone: +66-2-866-0225; +66-2-419-5695 
Email: Watchareeped@gmail.com 
 
Site 5116, Chiangrai Prachanukroh Hospital 
CRS 
Pradthana Ounchanum, MD 
IoR 
1039 Sathanpayaban Road 
Chiang Rai, 57000, Thailand 
Phone: +66 (0) 53520 359 
Email: doctorbaiplu@gmail.com 
 
Tim Cressey, PhD 
Study Coordinator 
195 Kaew Nawarat Road (3-4 Fl.) 
Wat Ked, Muang 
Chiang Mai 50000 Thailand 
Phone: +66 (0) 5324 0910 
Email: tim.cressey@phpt.org 
 
Site 8051, Wits RHI Shandukani Research 
Centre CRS 
Faeezah Patel, MBBCh 
Investigator of Record  
Shandukani Research, Wits RHI, 2nd floor, 
Hillbrow Health Precinct  
Corner Esselen and Klein Street, Hillbrow  
Johannesburg, Gauteng, 2001, South Africa 
Phone: +2783 532 1814 
Email: fpatel@wrhi.ac.za 
 
Sibongile Phathokuhle Mncube  
Study Coordinator  
Shandukani Research, Wits RHI, 2nd floor, 
Hillbrow Health Precinct  
Corner Esselen and Klein Street, Hillbrow  
Johannesburg, Gauteng, 2001, South Africa 
Phone: 27-11-358-5500 
Email: smncube@wrhi.ac.za 
 
Site 8052, Soweto IMPAACT CRS 
Avy Violary, MD, FCPaed 
Co-IoR 
Perinatal HIV Research Unit Chris Hani 
Baragwanath Academic Hospital  
PO Box 114,  
Diepkloof Soweto Johannesburg,  
South Africa 
Phone: +27 11 989 9707 
Email: violari@mweb.co.za 
 
Sisinyana Ruth Mathiba, MBCHB 
Co-IoR 
Perinatal HIV Research Unit Chris Hani 
Baragwanath Academic Hospital  
PO Box 114,  
Diepkloof Soweto Johannesburg,  
South Africa 
Phone: +27 11 989 9761 
Email: mathibas@phru.co.za 
 
Nastassja Ramsagar, BSc 
Study Coordinator 
Perinatal HIV Research Unit Chris Hani 
Baragwanath Academic Hospital  
PO Box 114,  
Diepkloof Soweto Johannesburg,  
South Africa  
Phone: +27 11 989 9858 
Email: choonilaln@phru.co.za 
 
Site 8950, FAMCRU CRS 
Samantha Fry, MD, MMED 
IoR 
Department of Paediatrics and Child Health          


 
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FAMCRU, Stellenbosch University 
PO Box 19063 
South Africa 
Phone: +27-21-9384153 
Email: fry@sun.ac.za 
 
Jeanne Louw, MSc 
Study Coordinator 
Department of Paediatrics and Child Health          
FAMCRU, Stellenbosch University 
PO Box 19063 
South Africa 
Phone: +27-21-9384290 
Email: Jeannes@sun.ac.za 
 
Site 12701, Gaborone CRS 
Gaerolwe R. Masheto, MD 
IoR 
Botswana Harvard AIDS Institute Partnership 
Plot 1836, North Ring Road, 
Princess Marina Hospital Grounds,  
Gaborone, Botswana 
Phone: +267 3975999; +267 72371278 
Email: gmasheto@bhp.org.bw 
 
Ponego L, Ponatshego, MD 
Study Coordinator 
Plot 2403, Hospital Way 
Gaborone, Botswana 
Phone: +267 3930335; +267 75600305 
Email: pponatshego@bhp.org.bw 
 
Site 12702, Molepolole CRS  
Gaerolwe R. Masheto, MD 
IoR 
Botswana Harvard AIDS Institute Partnership 
Plot 1836, North Ring Road, 
Princess Marina Hospital Grounds,  
Gaborone, Botswana 
Phone: +267 3975999; +267 72371278 
Email: gmasheto@bhp.org.bw 
 
Ponego L, Ponatshego, MD 
Study Coordinator 
Plot 2403, Hospital Way 
Gaborone, Botswana 
Phone: +267 3930335; +267 75600305 
Email: pponatshego@bhp.org.bw 
 
 
Site 30293, MU-JHU Research Collaboration 
CRS 
Maxensia Owor, MBChB, MMed, MPH 
Investigator of Record 
Makerere University- Johns Hopkins University 
Research Collaboration 
Upper Mulago Hill Road, P.O. Box 23491, 
Kampala, Uganda 
Phone: +256 787952048 
Email: maxowor@mujhu.org 
 
Hajira Kataike, MBChB 
Study Coordinator 
Makerere University -Johns Hopkins University 
Research Collaboration 
Upper Mulago Hill Road, P.O.BOX 23491, 
Kampala, Uganda 
Phone: +256 774885488 
Email: hkataike@mujhu.org 
 
Site 30300, Umlazi CRS 
Sherika Hanley, MBChB, MMedFamMed, 
FCFP 
IoR 
Prince Mshiyeni Memorial Hospital,  
1358 Mangosuthu Highway,  
Philasande Clinic, 4066 
Umlazi, 4060, South Africa 
Phone: +27 31 2602731; +2772 516 0566 
Email: hanley@ukzn.ac.za 
 
Dhayendre Moodley, MMedSc, PhD 
Co-IoR 
Prince Mshiyeni Memorial Hospital,  
1358 Mangosuthu Highway,  
Philasande Clinic, 4066 
Umlazi, 4060, South Africa 
Phone: +27 31 2601935 
Email: moodleyd1@ukzn.ac.za 
 
Vani Govender, ND Biotechnology, BSc Honors 
Medical Biochemistry, B-tech Business 
administration. 
Study Coordinator 
Prince Mshiyeni Memorial Hospital,  
1358 Mangosuthu Highway,  
Philasande Clinic, 4066 
Umlazi, 4060, South Africa 
Phone: +27 31 2601998 
Email: Vani.Govender@caprisa.org 
 


 
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Site 31784, Chiang Mai University HIV 
Treatment CRS 
Linda Aurpibul, MD, MPH   
IoR 
Research Institute for Health Sciences 
Chiang Mai University 
110 Intavaroros Road, Muang 
Chiang Mai 50200, Thailand 
Phone: +66 53936148 ext 445 
Email: lindaa@rihes.org   
 
Chintana Khamrong, M.Sc. 
Study Coordinator 
Research Institute for Health Sciences 
Chiang Mai University 
110 Intavaroros Road, Muang 
Chiang Mai 50200, Thailand 
Phone: +66 53936148 ext 446 
Email: chintanak@rihes.org   
 
Site 31798, Baylor-Uganda CRS 
Violet Korutaro, MBChB MScPH 
IoR 
Baylor College of Medicine Children’s 
Foundation-Uganda 
Block 5 Mulago Hospital. BOX 72052  
Kampala, Uganda 
Phone: +256 417-119200/100    
Email: vkorutaro@baylor-uganda.org  
 
Sarah Nanyunja, BSc Nursing, MPH 
Study Coordinator 
Baylor College of Medicine Children’s 
Foundation-Uganda 
Block 5 Mulago Hospital. BOX 72052  
Kampala, Uganda 
Phone: +256 417-119200/100    
Email: snanyunja@baylor-uganda.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics 
of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable 
Rilpivirine in Virologically Suppressed HIV‐Infected Children and Adolescents 
 
SCHEMA 
 
Purpose: 
To confirm the dose and evaluate the safety, tolerability, acceptability, and 
pharmacokinetics (PK) of oral cabotegravir (CAB), long-acting injectable cabotegravir 
(CAB LA), and long-acting injectable rilpivirine (RPV LA) in virologically 
suppressed HIV‐1 infected children and adolescents aged 12 to <18 years.  
  
Design: 
Phase I/II, multi‐center, open‐label, non‐comparative study 
 
Study Population: HIV‐1 infected children and adolescents, 12 to <18 years of age, who are 
virologically suppressed on stable cART consisting of 2 or more drugs from 2 or 
more classes of antiretroviral drugs, and selected parents/caregivers.  
 
Sample Size: 
Up to 155 adolescents in total 
 
Cohort 1:  Up to 55 adolescents to achieve approximately 30 to 35 dose-evaluable 
receiving the oral followed by the LA dose of CAB (Cohort 1C) or RPV (Cohort 1R), 
in addition to cART, which, passing safety and PK guidelines, are recommended as 
dosing for Cohort 2. Cohort 1C and Cohort 1R assignment is based on the 
adolescent’s pre-study cART regimen. 
 
• Cohort 1C:  Up to 30 adolescents to achieve approximately 15 to 20 dose-
evaluable for CAB. The dose-evaluable population will include at least 4 female 
adolescents, at least 4 male adolescents, at least 5 adolescents weighing 35 kg to 
less than 50 kg at study entry, and at least 5 adolescents weighing at least 50 kg at 
study entry.  
 
• Cohort 1R:  Up to 25 adolescents to achieve approximately 15 dose-evaluable for 
RPV. The dose-evaluable population will include at least 4 female adolescents, at 
least 4 male adolescents, at least 5 adolescents weighing 35 kg to less than 50 kg 
at study entry, and at least 5 adolescents weighing at least 50 kg at study entry. 
 
Cohort 2:  Up to 155 adolescents may participate in Cohort 2. Up to 100 adolescents, 
who had not previously participated in Cohort 1, to achieve approximately 70 
evaluable, who had not previously participated in Cohort 1, receiving the final 
recommended oral followed by the LA doses of CAB and RPV. Adolescents who 
participated in Cohort 1 (up to 55 participants) may enroll into Cohort 2, if eligible, 
in addition to the up to 100 Cohort 2 participants newly enrolled to the study.  
 
Up to 60 parents or caregivers of adolescent participants, as selected by the protocol 
team, to complete a single qualitative phone interview (U.S. sites only). 
 
Note: For definition of “dose-evaluable”, please refer to Section 9.5.1.3 of the 
protocol. For definition of “evaluable”, please refer to Section 9.1 (General Design 
Issues) of the protocol. 


 
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Study Product: 
Cohort 1: 
• Cohort 1C:  30 mg CAB once daily orally for at least four weeks (up to a 
maximum of 6 weeks) in addition to cART (Step 1 oral phase), followed by two 
single intramuscular injections of CAB LA four weeks apart (600 mg injections) 
in addition to cART (Step 2 injection phase). 
 
• Cohort 1R:  25 mg RPV once daily orally for at least four weeks (up to a 
maximum of 6 weeks) in addition to cART (Step 1 oral phase), followed by two 
single intramuscular injections of RPV LA four weeks apart (900 mg injections) 
in addition to cART (Step 2 injection phase). 
 
Dose adjustments are not anticipated but may occur as described in protocol Section 
9 and 10. 
 
Cohort 2: 
• 30 mg CAB + 25 mg RPV once daily orally for at least four weeks, and up to a 
maximum of 6 weeks, during Step 3 oral phase, followed by intramuscular 
injections of CAB LA + RPV LA: first and second injections four weeks apart 
(CAB LA 600 mg injection + RPV LA 900 mg injection), with subsequent 
injections every eight weeks through and including Week 96 (CAB LA 600 mg 
injections + RPV LA 900 mg injections) during Step 4 injection phase. 
Duration of  
Follow-Up: 
Adolescents in Cohort 1 will be followed for up to 64 weeks. Adolescents will be 
followed for at least four weeks in Step 1 (oral phase) and at least 12 weeks in Step 2 
(injection phase). All Step 2 adolescents will be followed (on cART, off study 
product) for up to an additional 48 weeks as part of long-term safety and washout PK 
follow-up (LSFU) after their last study product injection. Cohort 1 participants enroll 
into Cohort 2, if eligible, prior to completing long-term safety and washout PK 
follow-up. 
 
Adolescents in Cohort 2 will be followed for up to 144 weeks. Adolescents will be 
followed for at least four weeks in Step 3 (oral phase) and 92 weeks in Step 4 
(injection phase). After completing 92 weeks of follow-up in Step 4 (injection phase), 
Cohort 2 adolescents may continue access to injectable study products through a 
mechanism external to the protocol and will exit the study. Adolescents who 
permanently discontinue injectable study product use at any time during Cohort 2 
Step 4, or do not continue to access the study products through the external 
mechanism, will be followed (on cART, off study product) for an additional 48 
weeks as part of long-term safety and washout PK follow-up after their last study 
product injection.   
 
Enrolled parents/caregivers will complete a single qualitative phone interview. 
 
Study Duration: 
Approximately 7 years total. Accrual into Cohort 1 is expected to require 
approximately two years. Following reviews of data from Cohort 1, accrual into 
Cohort 2 is expected to require approximately 18 months. Adolescents in Cohort 2 
will be followed for up to three years. 
 


 
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Primary Objectives: Cohort 1 (continuing a background cART regimen) 
• 
To confirm the doses for oral CAB followed by injectable CAB LA in HIV-infected, virologically 
suppressed adolescents by evaluating: 
o Safety and multiple dose PK of oral CAB through Week 4 
o Safety and multiple dose PK of CAB LA through Week 16 
 
• 
To confirm doses for injectable RPV LA in HIV-infected, virologically suppressed adolescents by 
evaluating safety and multiple dose PK of RPV LA through Week 16 
 
Primary Objective: Cohort 2 (discontinuing a background cART regimen) 
• 
To assess the safety of CAB LA + RPV LA through Week 24 in HIV-infected, virologically 
suppressed adolescents 
 
Secondary Objectives: Cohort 1 
• 
To monitor maintenance of viral suppression through Week 16 in HIV-infected, virologically 
suppressed adolescents 
 
• 
To evaluate the tolerability and acceptability of CAB LA through Week 16 in HIV-infected, 
virologically suppressed adolescents  
 
• 
To evaluate the tolerability and acceptability of RPV LA through Week 16 in HIV-infected, 
virologically suppressed adolescents 
 
Secondary Objectives: Cohort 2 
• 
To assess safety of oral CAB + oral RPV followed by CAB LA + RPV LA through Week 48 in HIV-
infected, virologically suppressed adolescents 
 
• 
To evaluate repeat-dose pharmacokinetics of CAB LA + RPV LA through Week 24, and through 
Week 48 in HIV-infected, virologically suppressed adolescents. 
 
• 
To assess antiviral activity of CAB LA + RPV LA through Week 24, and through Week 48 in HIV-
infected, virologically suppressed adolescents 
 
Other Objectives 
• 
To evaluate the tolerability and acceptability of CAB LA + RPV LA through Week 24, through Week 
48, and through Week 96 in HIV‐infected, virologically suppressed adolescents (Cohort 2) 
 
• 
To evaluate the safety, antiviral and immunologic activity, and characterize PK of CAB LA + RPV 
LA through Week 96 in HIV-infected, virologically suppressed adolescents (Cohort 2) 
 
• 
To evaluate adolescent participant’s experience of CAB LA and/or RPV LA, and parent/caregiver’s 
experience and perceptions of adolescent acceptability and tolerability of CAB LA and/or RPV LA 
(Cohort 1 and Cohort 2) 
 
• 
To evaluate the tolerability and acceptability, and characterize long-term safety and washout PK 
through 48 weeks following permanent discontinuation of CAB LA or RPV LA (Cohort 1) 
 
• 
To evaluate the tolerability and acceptability, and characterize long-term safety and washout PK 
through 48 weeks following permanent discontinuation of CAB LA + RPV LA (Cohort 2) 
 


 
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• 
To describe HIV-1 resistance in participants experiencing virologic failure (Cohort 1 and Cohort 2) 
 
 


 
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IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV‐Infected 
Children and Adolescents 
 
Figure 1. Overview of Study Design for Cohort 1 Participants 
  
 


 
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Figure 2. Overview of Study Design for Cohort 2 Participants  
 


 
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Figure 3. Overview of Study Participation Flow for Cohort 1 Participants 
 


 
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Figure 4. Overview of Study Participation Flow for Cohort 2 Participants 
 


 
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1 
INTRODUCTION  
 
1.1 
Background  
 
Contemporary antiretroviral therapy (ART) for management of HIV infection includes many 
potent, safe dosing options, some of which are available for adolescents and adults as one-pill, 
once-a-day, combination ART regimens. The long term success of HIV treatment remains 
dependent upon sustaining adherence to daily ART, which can be challenging (1, 2). In 
pediatrics, this is often further nuanced by factors specific to adolescents and their caregivers (3). 
Successful progression through the continuum of HIV care is poorer among adolescents than 
adults in the United States of America (US), with as many as 43% failing to reach and sustain 
HIV viral suppression (4). Unstructured treatment interruptions are a major issue for youth with 
perinatally acquired HIV-1 infection, with medication fatigue being the most common cited 
reason for such interruptions (5). While the current ART standard of care includes a backbone of 
two nucleoside reverse transcriptase inhibitors (NRTIs) plus another antiretroviral (ARV), 
alternative approaches are being examined that simplify treatment, reduce lifelong drug exposure 
and drug burden, preserve future treatment options, and minimize or avoid ART toxicities, 
particularly of NRTIs. Regimens being explored are "NRTI-reducing" or “NRTI-sparing”, 
including two-drug ART (from two independent classes) as initial treatment or a switch strategy 
(in virologically suppressed individuals) (6).  
 
Long‐acting (LA) injectable antiretrovirals are promising new therapies both for HIV treatment 
(7) and HIV prevention (8) that may change the treatment paradigm, although present unique 
implementation challenges. If proven safe and efficacious, these monthly/2-monthly 
intramuscular (IM) injections, and other long-acting ART drug delivery platforms, could provide 
options to the current daily oral ART standard of care. These regimens would potentially 
optimize treatment adherence and ultimately maximize the benefits of ART. This approach is 
similar to modern contraceptive product development, which has greatly expanded client choices 
and includes a diversity of drug delivery options, such as oral tablets, intramuscular injections, 
long-acting implants and skin patches.  
 
Cabotegravir (CAB) is a potent integrase strand transfer inhibitor (INSTI) with attributes 
allowing formulation and delivery as a LA parenteral product. Rilpivirine (RPV), also formulated 
as a LA product, is a diarylpyrimidine derivative and a potent non-nucleoside reverse 
transcriptase inhibitor (NNRTI) with in vitro activity against wild type HIV-1 and select NNRTI-
resistant mutants. Long-acting CAB LA and RPV LA have been shown in clinical trials in HIV-
infected adults to be safe, well tolerated and efficacious as a dual injectable ART in treatment-
naïve settings (step down, maintenance therapy after an oral three drug ARV induction therapy 
(9, 10) (Phase 3 Clinical trial ongoing; FLAIR, 201584, ClinicalTrials.gov Identifier: 
NCT02938520). A Phase 3 clinical trial of CAB LA plus RPV LA as a dual therapy approach in 
treatment experienced, virologically suppressed individuals (ATLAS 201585) showed that the 
regimen of monthly injections of CAB LA + RPV LA was noninferior to continued 3-drug oral 
ART at Week 48 and is currently ongoing, [ClinicalTrials.gov Identifier: NCT02951052] (11). 
Another study, ATLAS-2M [ClinicalTrials.gov Identifier: NCT03299049], demonstrated the non-
inferior antiviral activity and acceptable safety profile of CAB LA + RPV LA administered every 
8 weeks (Q8W) compared to CAB LA + RPV LA administered every 4 weeks (Q4W) over a 48-
week treatment period in virologically suppressed adults (12). These studies support both Q4W 
and Q8W duration regimens as treatment choices. A two-drug combination therapy with CAB LA 
plus RPV LA may therefore offer a comparable tolerability and resistance profile, as well as 
improved adherence and treatment satisfaction in virologically suppressed patients (9).  
 


 
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Building on the experience to date with CAB LA and RPV LA in HIV-infected adults, 
IMPAACT 2017 Cohort 1 will assess the safety and PK of sequentially dispensed oral CAB 
followed by CAB LA (Cohort 1C), as well as oral RPV followed by RPV LA (Cohort 1R) in 
HIV-infected, virologically suppressed adolescents who continue their oral cART regimen. 
IMPAACT 2017 Cohort 2 will then establish if HIV-1 infected, virologically suppressed 
adolescents remain suppressed upon switching to a two-drug intramuscular (IM) regimen of CAB 
LA plus RPV LA. The age studied will be adolescents aged 12 to <18 years and ≥35kg.  
 
1.2 
Prior Research 
 
1.2.1 
Cabotegravir 
 
Cabotegravir (GSK1265744) is an investigational HIV INSTI that has attributes favorable for 
both HIV treatment and prevention indications. CAB is being developed as both oral and 
injectable long acting formulations.  
 
Summary of Cabotegravir Drug Metabolism and Pharmacokinetics (DMPK) 
 
CAB is rapidly absorbed following oral administration of the micronized tablet formulation, with 
median Tmax observed 2 to 3 hours post dose in the fasted state. Co-administration of single dose 
CAB 5 mg and 30 mg tablets with a moderate fat meal demonstrated minimal impact (<15% 
increase in CAB AUC(0-∞) and no impact on Cmax. In clinical studies to date, CAB tablets were 
taken without regard to the timing of or type of food consumed. CAB half-life of 35 to 42 h has 
been noted following oral administration. (13)  
 
To date, cabotegravir has been investigated in 7 HIV-infected adolescents. Their results are 
summarized in Section 1.3. 
 
CAB LA is a 200 mg/mL nanosuspension that has been administered as an IM injection and a SC 
injection of single doses of 100 to 800 mg and repeat doses from 200 to 800 mg. CAB LA 
exhibits absorption-limited (flip-flop) kinetics, and CAB has been detected in plasma up to 52 
weeks or longer after administration of repeat IM injections of CAB LA. Due to limited 
sampling, the observed apparent Tmax is generally observed at approximately one week post IM 
injection in Phase 2 studies. Apparent terminal phase t½ following CAB LA reflects absorption 
and ranges from approximately 18 to 50 days. Steady state appears to be achieved by 20 to 40 
weeks of the first IM injection of CAB LA Q4W or Q8W regimens. Variability in CAB Cmax 
following CAB LA is moderate to high with CV% ranging from 30 to >100%, due to variability 
in absorption rate. However, AUC (0-∞), which reflects the extent of absorption rather than the 
rate of absorption, exhibits lower variability with CV% ranging from 12 to 53%. In addition, 
variability decreases upon repeat administration.(13) 
 
Following administration in humans, CAB is primarily eliminated through metabolism, and renal 
elimination of unchanged CAB represents less than 1% of the total dose administered. In vitro 
and in vivo data indicate that CAB is primarily metabolized by UGT1A1 with some involvement 
from UGT1A9. CYP-mediated CAB metabolism is expected to be minimal as evidenced by the 
lack of effect observed when co-administered with etravirine (ETV), a known CYP3A4 inducer, 
in human participants. Cabotegravir is the predominant circulating compound in plasma, 
representing > 90% of plasma total radiocarbon. Fifty-eight percent of the total oral dose is 
excreted as unchanged CAB in the feces and 26.8% of the total oral dose is excreted in the urine, 
primarily as a glucuronide metabolite (75% of urine radioactivity, 14% of total dose).(13) 
 


 
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CAB LA has been administered intramuscularly to healthy and HIV infected adults at doses of 
100mg to 800mg. In HIV-infected participants, CAB LA has maintained virologic suppression on 
maintenance doses of 400mg IM Q4W and 600mg IM Q8W injections in conjunction with RPV 
LA (200056, 201584, 201585 and 207966). A population PK model including all relevant clinical 
PK data including IM data in 1647 adults (26% female) indicated that gender and BMI were 
statistically significant covariates (but clinically insignificant) affecting the absorption rate 
constant following IM administration, such that absorption was slower in females than males and 
in participants of larger BMI (up to 60kg/m2).(13) The slower absorption in females and high 
BMI participants resulted in lower peaks and higher troughs and was not associated with clinical 
outcome differences. Potential participants with high BMI have been excluded from Cohort 1 to 
minimize variability in characterization of PK parameters but high BMI will not be an exclusion 
for Cohort 2. 
 
CAB has no reported significant effect on cardiac repolarization. (13) 
 
Summary of cabotegravir safety data:  
 
Overall, 2,141 participants were exposed to oral and/or LA CAB + RPV during ViiV Healthcare-
sponsored HIV treatment clinical studies in Phase II and Phase III/IIIb (LA116482, 200056, 
201584, 201585, and 207966) as of October 18, 2019. 
 
The integrated analysis of safety data across the Phase III clinical studies when considered in 
combination with Phase I and Phase II data supports an acceptable safety profile of CAB + RPV.  
Safety conclusions from the clinical development program demonstrate the following: 
 
• 
The most frequently reported adverse events (AEs) in the Phase III program were injection 
site reactions (ISRs), mainly ISR pain.  ISRs were generally mild or moderate with no 
Grade 4 or Grade 5 or serious ISRs.  22 (4%) participants had Grade 3 ISRs, suggesting that 
ISRs generally did not interfere with daily activities.  Most ISRs resolved within 7 days.  The 
percentage of participants reporting ISRs at each visit decreased over time.  Few ISRs led to 
withdrawal. 
• 
Patient acceptance scores for anxiety pre- and post-injection decreased over time during the 
Phase III studies in the CAB + RPV treatment regimen. 
• 
The most common non-ISR AEs (10%) in the Phase III program for CAB + RPV and 
continued antiretroviral regimen (CAR) were nasopharyngitis, upper respiratory tract 
infection, and headache.  The majority of events reported had an intensity of Grade 1 or 
Grade 2.  47 (8%) participants in the CAB + RPV group and 35 (6%) participants in the CAR 
group experienced AEs that were Grade 3 to Grade 5.  No Grade 5 events were reported in 
the Phase III studies for participants receiving CAB + RPV. 
• 
Non-ISR AEs that occurred more frequently with CAB + RPV were hemorrhoids, pyrexia, 
dizziness, fatigue, and headache.  Except for headache, the incidence of these AEs in the 
CAB + RPV group was <10%. 
• 
A higher incidence of non-ISR, drug-related AEs in the CAB + RPV group was noted.  Most 
drug-related AEs were Grade 1, although a few Grade 3 to 4 AEs occurred.  The most 
frequent drug-related Grade 3 to 4 AEs were pyrexia (4%), fatigue (3%), and asthenia (2%). 
Different frequencies of non-ISR, drug-related AEs between treatment groups may be 


 
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expected for an open-label switch study where the participants in the comparator CAR group 
had been on a stable and tolerable ART regimen.   
• 
In the pooled analysis from the Phase III Maintenance Phases, 1 participant in the CAR group 
died due to a serious adverse event (SAE) of methamphetamine overdose.  This case was not 
considered to be related to study drug by the investigator and was the only Grade 5 SAE. 
• 
The rate of SAEs was low overall and was comparable between the CAB + RPV and CAR 
treatment groups.  The most frequently reported SAEs were hepatitis A, colitis, and 
anogenital warts. 
• 
31 (5%) participants in the CAB + RPV group and 26 (4%) participants in the CAR group 
had drug-related, non-ISR SAEs. 
• 
The rate of discontinuation was low overall for the Phase III studies.  Discontinuations from 
the study were more frequent in the CAB + RPV group.  Reasons for discontinuations were 
primarily ISRs and acute viral hepatitis.  22 (4%) participants in the CAB + RPV group and 9 
(2%) participants in the CAR group had AEs leading to withdrawal/permanent 
discontinuation of study drug during the Maintenance Phase.  17 (3%) participants in the 
CAB + RPV group and 9 (2%) participants in the CAR group had non-ISR AEs leading to 
discontinuation.  All individual AEs leading to withdrawal had an incidence of <1%. 
• 
Results from the Phase III studies indicate that CAB + RPV appears to have no clinically 
relevant effect on safety related to QT prolongation, seizures, rhabdomyolysis, pancreatitis, or 
impact on creatinine. 
• 
Incidence of neuropsychiatric events was low overall for suicidal ideation/behavior, 
depression, and anxiety.  Events occurred with similar frequency between treatment groups. 
• 
A higher incidence for mood disorders was observed in the CAB + RPV group compared 
with the CAR group.  
• 
The incidence of sleep disorders events (including drug-related events), particularly 
insomnia, was higher in the CAB + RPV group compared with that of the CAR group during 
the Phase III studies. 
• 
Modest weight gain occurred in both CAB + RPV and CAR treatment groups, although 
median weight gain was greater in the CAB + RPV group.  BMI increased in both CAB + 
RPV and CAR treatment groups, with a greater median change in the CAB + RPV group.  
The clinical significance of this weight gain is not clear.  There were some shifts in BMI for 
the CAB + RPV group that trended toward unfavorable. 
• 
Overall, the frequency and categories of drug related adverse events reported with daily oral 
CAB 30 mg have been similar to those reported with CAB LA and are infrequently treatment 
limiting. 
• 
The majority (74.7% CAB + RPV, 80.2% CAR%) of the maximum post-baseline emergent 
clinical chemistry toxicities were Grade 1 or Grade 2 in intensity.  With the exception of 
creatine kinase and lipase, there were similar frequencies of Grade 3/4 clinical chemistry 
abnormalities between the treatment groups.  No clinically relevant differences were 


 
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observed overall in Grade 3 and Grade 4 post-baseline emergent toxicities between the CAB 
+ RPV and CAR groups. 
• 
Results from the Phase III clinical program do not suggest any effect of age, sex, or race on 
the safety profile of CAB + RPV.  
• 
HIV infected patients with evidence of hepatitis B virus (HBV) coinfection were excluded 
from the CAB + RPV clinical program as CAB + RPV do not have activity against HBV.  No 
conclusions can be made about the safety of CAB + RPV in Hepatitis B co-infected patients.   
• 
In the Phase III studies, 41/591 participants on CAB + RPV and 40/591 participants on CAR 
were determined to be co-infected with hepatitis C virus (HCV) at Baseline, as shown by 
HCV serology testing alone.  The participants without advanced chronic HCV were not at 
increased risk of developing hepatotoxicity or increased transaminases compared with 
participants infected by HIV only.  None of the participants in Studies 201584 and 201585 
who became acutely infected with HCV on study resumed CAB + RPV after temporarily 
discontinuing dosing while the acute HCV infection either spontaneously resolved or 
stabilized. 
• 
No dose adjustment in CAB (oral or LA) or RPV (oral or LA) is required for patients with 
mild or moderate hepatic impairment.  No data are available in severe hepatic impairment. 
• 
No dose adjustment of oral CAB or CAB LA or oral RPV or RPV LA is required for patients 
with mild to moderate renal impairment.  No dose adjustment of oral CAB or CAB LA is 
required for severe renal impairment.  No data are available in severe renal impairment or 
end-stage renal disease for RPV. 
• 
Medication errors and device malfunctions were infrequent occurrences, and no adverse 
events were directly attributable to these errors and no evidence for lack of efficacy has been 
detected as the result of an error.  Overall, no discernable trends or systematic errors were 
identified, apart from an initial lack of familiarity by the health care provided.   
• 
In the Phase IIIb study ATLAS-2M Q8W dosing of CAB+RPV LA was noninferior to Q4W 
dosing and well tolerated. CAB+RPV LA Q8W was noninferior to Q4W dosing in both the 
primary (proportion with plasma HIV-1 ribonucleic acid (RNA) ≥50 c/mL 1.7% vs 1.0%) and 
secondary analysis (proportion with HIV-1 RNA <50 c/mL 94.3% vs 93.5%) at Week 48. 
ISRs were mostly mild or moderate (98% overall) with a median duration of 3 days. (12) 
Results from the CAB + RPV development program support the use of the regimen in virally 
suppressed HIV-1 infected patients.  In clinical studies, a higher incidence of AEs leading to 
withdrawal and Grade 3/4 AEs was reported in the CAB + RPV group.  Overall, CAB + RPV 
appeared to be tolerated as well as comparator regimens.  Although ISRs occurred frequently, few 
were treatment limiting.   
 
Summary of side effects observed and/or monitored for in patients on cabotegravir include:  
 
Long acting properties of cabotegravir injection  
Residual concentrations of CAB remain in the systemic circulation of participants who stop HIV 
treatment (e.g. for tolerability issues or treatment failure) for prolonged periods (up to 12 months 
or more) (13). Participants discontinuing an LA regimen may be at risk for developing viral 


 
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resistance to CAB many weeks after discontinuing injectable therapy; therefore, adoption of an 
alternative, fully suppressive antiretroviral regimen is essential.  
 
Hepatobiliary disorders 
Four participants with possible or probable drug-induced liver injury (DILI) related to CAB have 
been identified in the Phase 2b HIV treatment studies. Three of these participants met liver 
stopping criteria 4-8 weeks after initiation of oral treatment with CAB (60 mg n=2, 30 mg n=1). 
The fourth participant met liver stopping criteria after having received approximately 44 weeks of 
treatment with oral CAB 30 mg. In all cases participants remained asymptomatic, did not develop 
hepatic dysfunction and liver aminotransferase elevations returned to normal or approached pre-
treatment levels following withdrawal of all antiretroviral treatment. A role of CAB in these cases 
could not be ruled out. One of the four participants, with ongoing active chronic hepatitis C 
infection, developed a concomitant increase in total and direct bilirubin. This participant had 
underlying liver fibrosis. The three remaining participants had evidence of hepatosteatosis on 
liver imaging - which may have been pre-existing (13). In addition, a single case of suspected 
DILI was identified in a CAB/rifabutin drug interaction study (205712).  A 55-year-old male 
developed Grade 3 elevations in liver aminotransferases three weeks after co-administration of 
oral CAB and rifabutin ended. Liver workup was unremarkable except for a fatty liver on 
ultrasound examination, the participant was asymptomatic throughout and the findings were 
consistent with a mixed hepatocellular and cholestatic type hepatitis.  The elevated liver 
aminotransferases fully resolved after approximately 23 weeks.   One further case of possible 
DILI occurred in the Phase III study (207966) and involved a 20-30-year-old female who was 
randomized at Baseline to the Q4W group. The participant had previously received standard of 
care (SoC) with lopinavir + ritonavir + abacavir + lamivudine as part of Study 201585. She had 
an asymptomatic increase in alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST).  ALT was 206 U/L [>4x upper limit of normal (ULN)], AST was 137 U/L [>3x ULN] 
with no elevation in bilirubin at Week 4a, after receiving 28 days of oral CAB + RPV. 
Investigations were negative for viral hepatitis; syphilis and an autoimmune screen. The oral lead-
in (OLI) was extended while the participant was investigated for alternative causes. During this 
time ALT and AST remained elevated and the participant was eventually withdrawn from the 
study after receiving a total of 11 weeks of oral CAB + RPV. The participant commenced 
Abacavir (ABC)/Lamivudine (3TC)/Dolutegravir (DTG) and the ALT/AST returned to normal 
after 12 weeks. 
 
Elevated transaminases (AST/ALT) were observed in some participants receiving CAB + RPV 
during the pivotal Phase 3 trials, however, the primary reason for these elevations was the 
occurrence of acute viral hepatitis (Hepatitis A, B, C).  
 
No suspected cases of DILI have emerged to date in participants receiving CAB LA. 
 
Studies to date have incorporated close monitoring of liver chemistries and have adopted liver 
stopping criteria. Participants with known and documented Hepatitis B or Hepatitis C infection, 
with clinically relevant hepatic disease, or ALT Grade 3 or higher are excluded from IMPAACT 
2017, per Section 4. Additionally, studies to date involving exposure to the long acting injection 
have incorporated an oral lead-in period as a precautionary measure to reduce the risk of severe 
hypersensitivity (see below) or liver injury developing during exposure to the LA formulation.  
 
Injection site reactions: ISRs are very common, but generally mild or moderate, most frequently 
comprising pain at the injection site, with localized erythema, pruritis, warmth, swelling, nodule 
formation, induration or bruising occurring less commonly. Severe ISRs were reported in 4% of 
participants.  Abscess and cellulitis at the injection site have been reported uncommonly (<1% of 


 
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participants).  Median duration of the reactions overall was 3 days. To date, most reactions have 
been self-limited.(13) 
 
Hypersensitivity reactions 
Hypersensitivity reactions have not been reported with cabotegravir but have been reported in 
association with other integrase inhibitors including the closely related compound, dolutegravir. 
These reactions were characterized by rash, constitutional findings and sometimes organ, 
including liver, dysfunction. However, no such reactions have been observed to date in 
association with CAB. An oral lead-in is being implemented within clinical studies to reduce the 
risk of a hypersensitivity reaction occurring following the initiation of LA therapy.(13) 
 
Use in pregnancy:  
Data in pregnancy are limited. Non-clinical data from rat pre- and postnatal (PPN) studies have 
indicated reduced survival and viability rates amongst rat pups during the first 4 days of life at the 
maximum tested dose of 1000 mg/kg/day (maternal exposure). No-observed-adverse-effect-level 
(NOAEL) was established at the mid dose 5 mg/kg/day, which remains >20 fold predicted Cmax 
and AUC exposures for anticipated clinical CAB LA exposures. The clinical significance of these 
findings is unknown.(13) 
 
Suicidal Ideation and Behavior Monitoring: 
CAB exposure has not been associated with an increased risk of suicidal ideation or psychiatric 
disorders. However, patients with HIV infection or those in some high-risk categories for HIV 
acquisition may occasionally experience symptoms of depression and/or suicidal ideation or 
behavior. In addition, there have been some reports of depression, suicidal ideation and behavior 
(particularly in participants with a pre-existing history of depression or psychiatric illness) in 
some patients being treated with INSTIs. Dolutegravir (DTG) (a closely related integrase 
inhibitor) has been associated with reports of suicidal ideation or behavior (particularly in patients 
with a pre-existing history of depression or psychiatric illness). (13) 
 
Seizures:  
Overall, there is not convincing evidence that CAB exposure may be causally associated with 
seizure or with reduction of seizure threshold, due to the low frequency of reports, the 
confounders present in the cases received to date and lack of any pre-clinical signal or identified 
plausible mechanism. Three cases of seizures have been documented in the CAB program 
cumulatively through 01 October 2016. Two of the cases occurred in HIV uninfected participants 
with a prior history of seizure and one case involved a participant in study 200056 with 
circumstantial and anecdotal evidence of illicit drug use.(13) 
 
Dolutegravir and Pregnancy 
 
Dolutegravir (DTG) is an INSTI in the same class of pharmaceuticals as CAB. Thus far, limited 
safety or efficacy data for DTG in pregnancy in humans have been published or presented. In 
May 2018, World Health Organization (WHO) and several other regulatory agencies released 
advisories regarding the safety of DTG in early pregnancy.(14) 
 
This was based on information received from the Botswana NICHD-funded Tsepamo Birth 
Outcomes Surveillance Study, the largest body of data related to birth outcomes following the use 
of DTG in pregnancy. This study was designed to evaluate adverse birth outcomes by maternal 
HIV status and ART regimen, and to determine whether there is an increased risk of neural tube 
defects (NTDs) among infants exposed to efavirenz (EFV) from conception. Botswana’s HIV 
program moved to universal ART with dolutegravir/tenofovir disoproxil fumarate/emtricitabine 


 
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(DTG/TDF/FTC) in first line for patients starting ART (including pregnant women) in May of 
2016 (women already on other regimens were not switched to DTG). The previous first-line 
regimen was EFV/TDF/FTC. Almost all women on DTG-based and EFV-based ART took these 
drugs in combination with TDF/FTC. More than 95% of women in Botswana deliver in a 
hospital, and obstetric records were available for >99% of women. The Tsepamo surveillance 
study was originally conducted at 8 of the largest public maternity wards across Botswana 
(representing ~45% of the total births in the country). This was later increased to 18 sites. 
Research assistants abstracted exposure data from the maternity card for all consecutive in-
hospital deliveries (both HIV-infected and HIV-uninfected women). Each newborn, whether 
stillborn or live-born, undergoes a systematic infant surface examination that is completed by 
trained nurse midwives. Reports and photographs (where available) of major abnormalities are 
reviewed by an experienced medical geneticist who is blinded to exposure information.  In the 
birth outcome surveillance study in Botswana there were 5 cases of neural tube defects reported 
(as of March 2019) in 1,683 deliveries (0.3%) to mothers taking dolutegravir-containing regimens 
from the time of conception, compared with 15 cases in 14,792 deliveries (0.1%) to mothers 
taking non-dolutegravir-containing regimens from the time of conception (Prevalence Difference 
0.20%; 95% CI 0.01-0.59). In the same study, one out of 3,840 deliveries (0.03%) to mothers 
who started dolutegravir during pregnancy had a neural tube defect, compared with three out of 
5,952 deliveries (0.05%) to mothers who started non-dolutegravir-containing regimens during 
pregnancy. More recent data from this study suggest an even lower incidence of neural tube 
defects amongst women taking dolutegravir-containing regimens from the time of conception. 
 
A causal relationship of these events to the use of dolutegravir has not been established. 
The incidence of neural tube defects in the general population ranges from 0.5-1 case per 
1,000 live births. As neural tube defects occur within the first 4 weeks of fetal development (at 
which time the neural tubes are sealed) this potential risk would concern women exposed to 
dolutegravir at the time of conception and in early pregnancy. More than 1,000 outcomes from 
second and third trimester exposure in pregnant women indicate no evidence of increased risk of 
adverse birth outcomes. 
 
Cabotegravir is not dolutegravir. While these medications share a common molecular backbone, 
and have a similar mechanism of activity, they are different chemical compounds. It is not known 
if the potential safety signal identified with DTG will be confirmed in other studies and/or 
settings where DTG is being used. There is insufficient data to confirm or refute any potential 
INSTI class effect. 
 
CAB was evaluated in a complete package of reproductive toxicology studies, including 
embryofetal development studies, and no safety findings suggestive of teratogenesis or neural 
tube defects were identified as of the information included in the 17 December 2019 version of 
the Investigator’s Brochure. Given limited clinical experience with use of CAB in pregnancy, as a 
precautionary measure, women of reproductive potential are required to adopt highly reliable 
means of contraception during participation and throughout long term follow up phases of studies 
following exposure to CAB LA as well as have a negative pregnancy test prior to study entry. 
 
1.2.2 
Rilpivirine 
 
Rilpivirine (TMC278, RPV) is a NNRTI with in vitro activity against wild type and NNRTI 
resistant HIV-1. Rilpivirine 25-mg once daily (oral tablet) is approved for the treatment of HIV-1 
infection in ART-naïve patients 12 years of age and older in multiple countries including the US, 
the European Union (EU), Canada, and Japan as EDURANT®(15). In most countries, including 
the US and EU, this indication is further restricted to patients with a plasma viral load (VL) 


 
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≤100,000 HIV-1 RNA copies/mL. RPV (dose 25 mg) as part of a once-daily single-tablet oral 
regimen is also approved for adults and adolescents in several countries as Complera®/Eviplera® 
(FTC/RPV/TDF) or Odefsey® (FTC/RPV/tenofovir alafenamide [TAF]) and as part of a single-
tablet dual regimen for adults, JULUCA® (DTG/RPV).  
 
A parenteral long acting formulation of RPV (RPV LA) is in Phase III of development, in 
combination with a parenteral long acting formulation of CAB (CAB LA). Of note both the oral 
and injectable formulation of RPV needs to be protected from direct exposure to light and are 
dispensed accordingly.  
 
The exposure to RPV as the tablet formulation was approximately 40 -to-50% lower when taken 
under fasting conditions or with only a nutritional drink as compared to intake with a standard or 
high fat breakfast. Therefore, oral RPV must always be taken with a meal.(16) 
 
The exposure to RPV can be affected by modulators of CYP3A4-enzyme activity and by drugs 
that increase the gastric anti-logarithmic proton concentration (pH), the latter being only 
applicable to oral RPV. Proton pump inhibitors (e.g. omeprazole) should not be co administered 
with oral RPV as this will decrease the exposure to RPV due to the increase in gastric pH. H2-
receptor antagonists, however, can be used if administered either at least 12 hours before or at 
least 4 hours after intake of RPV, and antacids can be used if administered either at least 2 hours 
before or at least 4 hours after intake of RPV. Drugs that induce CYP3A4 activity (e.g. rifampin, 
carbamazepine) can reduce the RPV exposure (either as oral or LA formulation) and should not 
be co administered. Drugs that inhibit CYP3A4 activity (e.g. ketoconazole, boosted protease 
inhibitors [PIs]) can increase the exposure to RPV (either as oral or LA formulation) but do not 
require dose adjustments.(16) 
 
The approval of oral RPV 25 mg once daily for adolescents was based on the results of study 
TMC278-TiDP38-C213. The 48-week results of the adolescent cohort (N=36) in this study 
demonstrated that treatment with RPV 25 mg once daily, in combination with an investigator-
selected background regimen, is efficacious, generally safe and well tolerated in adolescents of 
≥12 to <18 years of age (17). The 25 mg once daily dose in adolescents resulted in similar RPV 
exposure as observed in adults. Also, no apparent relationships were observed between the RPV 
pharmacokinetics and efficacy or safety parameters in adolescents at Week 48. In the adult trials 
with the RPV doses of 25 mg once daily, no clear effect of body weight on the RPV exposure was 
seen. Similarly, data in adolescents between 12 and 18 years of age weighing approximately 33 to 
93 kg also showed no effect of body weight on the RPV exposure. (17). The Week 240 long-term 
data in the adolescents who continued treatment in the post-Week 48 treatment extension period 
also demonstrated efficacy and no new safety findings were identified; there were no relevant 
differences from the safety profile in HIV-1 infected adults (16). 
 
Oral RPV 25mg has been co-administered with oral CAB in one Phase 1 study in healthy 
participants and two Phase 2 studies of HIV infected participants. Study LAI116181 
(ClinicalTrials.gov Identifier: NCT01467531) showed that there was no relevant drug interaction 
between CAB and RPV. (16) 
 
Population pharmacokinetic analysis of RPV in HIV infected patients indicate that race has no 
clinically relevant effect on the exposure to RPV. No clinically relevant differences in the 
pharmacokinetics of RPV have been observed between men and women.(16)  
 
The pharmacokinetics of RPV have not been studied in patients with renal insufficiency. Renal 
elimination of RPV is negligible. Therefore, the impact of renal impairment on RPV elimination 


 
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is expected to be minimal. As RPV is highly bound to plasma proteins, it is unlikely that it will be 
significantly removed by hemodialysis or peritoneal dialysis. No dose adjustment of RPV is 
required in patients with renal impairment.(16) 
 
RPV is primarily metabolized and eliminated by the liver. In a study comparing 8 patients with 
mild hepatic impairment (Child Pugh score A) to 8 matched controls, and 8 patients with 
moderate hepatic impairment (Child Pugh score B) to 8 matched controls, the multiple dose 
exposure of RPV was 47% higher in patients with mild hepatic impairment and 5% higher in 
patients with moderate hepatic impairment. No dose adjustment is required in patients with mild 
or moderate hepatic impairment. RPV has not been studied in patients with severe hepatic 
impairment (Child Pugh score C).(16) 
 
The effect of RPV at the recommended dose of 25 mg q.d. (marketed dose) on the QT interval 
corrected for heart rate according to Fridericia (QTcF) interval was evaluated in a randomized, 
placebo and active (moxifloxacin 400 mg q.d.) controlled crossover study thorough QT (TQT) in 
60 healthy adults, with 13 measurements over 24 hours at steady state. RPV at the recommended 
dose of 25 mg q.d. is not associated with a clinically relevant effect on QTc. Higher doses of RPV 
(75 and 300 mg q.d., 3 and 12 times higher than the recommended dose, respectively) examined 
in a previous TQT study, were associated with mean maximum QTcF prolongations > 10 ms, 
which were dose and plasma concentration dependent. Plasma concentrations after administration 
of RPV LA are substantially lower than those obtained with 75 mg q.d. and 300 mg q.d. and 
comparable to or lower than the plasma concentrations achieved with RPV 25 mg q.d. given 
orally. Therefore, no clinically relevant increase in QTcF is expected with the plasma 
concentrations achieved with RPV LA. In the RPV LA studies performed in healthy participants, 
no increases in QTc have been seen.(16) 
 
Data on pregnancy and lactation remain limited; the prescribing information recommends that 
RPV should be used during pregnancy only if the potential benefit justifies the potential risk and 
that the mothers should be instructed not to breastfeed if they are receiving RPV.(15) RPV in 
combination with a background regimen was evaluated in the RPV treatment arm of study 
TMC114HIV3015, in 19 pregnant women during the second and third trimesters, and postpartum. 
RPV was well tolerated during pregnancy and postpartum. There were no new safety findings 
compared with the known safety profile of RPV in HIV-1 infected adults.(16) 
 
RPV LA (formulation G001) has been administered IM to healthy and HIV infected adults at 
doses of 300 mg to 1200 mg. Up to July 2019, in total, 318 healthy volunteers participated in 
studies with the long acting (LA) injectable form of RPV of whom 283 received RPV LA. RPV 
pharmacokinetic parameters following successive monthly intramuscular administration of 
1200/600/600 mg RPV LA in the gluteal muscle in healthy adult participants showed a half-life 
of 91 days +/- 41 days (t/1/2; mean +/- SD) (16). In a Phase IIb study in HIV-infected participants 
(n=230), RPV LA maintained suppression of viral load following monthly (Q4W) IM injections 
of 600 mg or bi-monthly (Q8W) injections of 900 mg, in conjunction with CAB LA monthly or 
bi-monthly (study 200056 or LATTE-2 [ClinicalTrials.gov Identifier: NCT02120352]).(9) 
Currently, a dosing regimen of an RPV LA 900 mg IM loading dose followed by Q4W IM 
injections of 600 mg, in conjunction with CAB LA Q4W, is being evaluated in two Phase 3 
studies in adults (ATLAS [ClinicalTrials.gov Identifier: NCT02951052] and FLAIR 
[ClinicalTrials.gov Identifier: NCT02938520]). and a dosing regimen of RPV LA 900 mg IM 
every 2 months is, in conjunction with CAB LA 600 mg, is being evaluated in Phase III study 
ATLAS-2M. The results of these clinical studies in HIV-infected patients are discussed in Section 
1.2.3 below.  
 


 
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Summary of side effects observed and/or monitored for in patients on rilpivirine include: 
 
Virologic Failure and Development of Resistance: 
In the pooled analysis from the phase III trials of oral RPV with 2 NRTIs through 96 weeks, 
patients treated with oral RPV with a baseline viral load >100,000 HIV-1 RNA copies/mL had a 
greater risk of virologic failure compared to patients with a baseline viral load ≤100,000 HIV-1 
RNA copies/mL. The greater risk of virologic failure for patients in the oral RPV arm was 
observed in the first 48 weeks of these trials while low rates of virologic failure, similar between 
the treatment arms, were observed from week 48 to week 96. Patients with a baseline viral load 
>100,000 HIV-1 RNA copies/mL who experienced virologic failure exhibited a higher rate of 
treatment emergent resistance to the NNRTI class. More patients who failed virologically on oral 
RPV than who failed virologically on EFV developed 3TC/FTC associated resistance. The use of 
RPV in combination with CAB is described in Section 1.2.3. No new findings were identified in 
adolescent patients ≥12 to <18 years of age in trial C213.(16) 
 
Interactions with medicinal products 
Caution should be given to prescribing RPV with medicinal products that may reduce the 
exposure of rilpivirine. 
 
Fat Redistribution 
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement 
(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and ‘cushingoid 
appearance’ have been observed in patients receiving ART. The mechanism and long-term 
consequences of these events are currently unknown. A causal relationship has not been 
established. (16) 
 
Injection Site Reactions 
Intramuscular or SC injections are procedures which, even with physiological saline, occasionally 
induce transient reactions at the site of injection, called ISRs. By preferred term, local pain and 
erythema are the most common expected AEs of this type. 
 
Systemic reactions following RPV LA injections are rare. In two cases, high RPV PK plasma 
concentrations have been observed which may have resulted from an accidental partial IV 
injection of RPV (16). 
 
Further details about oral rilpivirine can be obtained from the FDA approved full prescribing 
information.(15) 
 
1.2.3 
Clinical trial experience using cabotegravir plus rilpivirine as a dual antiretroviral therapy 
regimen 
 
Three Phase III/IIIb studies, Study 201584 (FLAIR), Study 201585 (ATLAS) and study 207966 
(ATLAS-2M), and two Phase IIb studies [Study LAI116482 [LATTE] (18) and Study 200056 
[LATTE-2] (9)] have been conducted with oral CAB and/or IM CAB LA and oral RPV and/or 
IM RPV LA. 
 
Study 201584 (FLAIR) 
The data from Study 201584 indicate that CAB + RPV is effective in maintaining the suppression 
of plasma HIV-1 RNA (<50 c/mL) and non-inferior to CAR at Week 48. The study employed a 
Q4W injection dosing regimen for CAB and RPV following a once daily oral led for 4 weeks. 
 


 
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Of the participants that completed the Induction Phase, a total of 566 participants were 
randomized (1:1) and treated with CAB+ RPV (n=283) or continue CAR (n=283).  Similar 
proportions of participants in each treatment group withdrew from the study (CAB + RPV: 9%; 
CAR: 8%).  The most frequent primary reason for withdrawal was adverse events (CAB + RPV: 
3%; CAR: 1%). 
 
Overall, in the intent to treat -efficacy (ITT-E) population, 2.1% of participants in the CAB + 
RPV group and 2.5% of participants in the CAR group met the ‘virologic failure’ primary 
efficacy endpoint of plasma HIV-1 RNA 50 c/mL at Week 48 (Snapshot algorithm).  Based on a 
6% non-inferiority margin, the efficacy analysis demonstrated that CAB + RPV is non-inferior to 
CAR at Week 48 because the upper bound of the 95% CI for the adjusted treatment difference [-
0.4 (-2.8, 2.1)] is less than 6%.  The results for the per protocol population were consistent with 
those from the ITT-E (primary) population.  Treatment differences across stratification factors 
(Baseline HIV-1 RNA and sex at birth) and across additional subgroup analyses (age, race, 
Baseline CD4+ count, and Baseline Centers for Disease Control and Prevention [CDC] stage of 
disease) are consistent with the finding of non-inferiority observed in the overall population 
analysis of the primary endpoint (HIV-1 RNA 50 c/mL at Week 48).   
 
Study 201585 (ATLAS) 
The data from Study 201585 indicate that CAB + RPV is effective in maintaining the suppression 
of plasma HIV-1 RNA (<50 c/mL) and non-inferior to CAR at Week 48. The study employed a 
Q4W injection dosing regimen for CAB and RPV following a once daily oral led for 4 weeks.  
 
A total of 616 participants were randomized (1:1) and treated with CAB+ RPV (n=308 or 
continue CAR (n=308).  Similar proportions of participants in each treatment group withdrew 
from the study (CAB+ RPV: 8%; CAR: 6%).  The most frequent primary reason for withdrawal 
was adverse events (CAB+ RPV: 4%; CAR: 2%).   
 
Overall, in the ITT-E population, 1.6% of participants in the CAB + RPV group and 1.0% of 
participants in the CAR group met the ‘virologic failure’ primary efficacy endpoint of plasma 
HIV-1 RNA 50 c/mL at Week 48 (Snapshot algorithm). Based on a 6% non-inferiority margin, 
the efficacy analysis demonstrated that CAB + RPV is non-inferior to CAR at Week 48 because 
the upper bound of the 95% CI for the adjusted treatment difference 0.7 (-1.2, 2.5) is less than 
6%. The results for the per protocol population were consistent with those from the ITT-E 
(primary) population.  Treatment differences across stratification factors (baseline third agent 
treatment class and sex at birth) and across additional subgroup analyses (age, race, country, 
baseline viral load, baseline CD4+ count, and baseline CDC stage of disease) are consistent with 
the finding of non-inferiority observed in the overall population analysis of the primary endpoint 
(HIV-1 RNA 50 c/mL at Week 48).   
 
Study 207966 (ATLAS-2M) 
In ATLAS-2M, a total of 1,049 subjects were randomized (1:1) and treated with CAB + RPV 
Q8W (n=524) or CAB + RPV Q4W (n=525). Similar proportions of subjects in each treatment 
group withdrew from the study (CAB + RPV Q8W: 7%); CAB + RPV Q4W: 8%. In the ITT-E 
population, 1.7% of subjects in the CAB + RPV Q8W group and 1.0% of subjects in the CAB + 
RPV Q4W group met the primary efficacy endpoint of plasma HIV-1 RNA > 50 c/mL at Week 
48. A multivariable logistic regression analysis demonstrated that the strongest association of 
Snapshot HIV-1 RNA ≥ 50 c/mL was BMI. Overall, injections for Q8W CAB LA + RPV LA 
were well tolerated with few withdrawals due to injection intolerability (1% in Q8W group and 
2% in Q4W group). The most common AEs in both treatment groups were mild/moderate ISRs.  


 
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The frequency of subjects reporting at least 1 SAE was similar in the 2 treatment groups (Q8W: 
5%; Q4W: 4%). There was 1 fatal (Grade 5) AE; 1 subject in the Q8W group died due to sepsis 
as a result of a complication of acute pancreatitis. Acute pancreatitis was considered related to 
study drug by the investigator. Overall, the data from ATLAS 2M indicate that every 2-month 
(Q8 Week) dosing with CAB + RPV is effective in the suppression of plasma HIV-1 RNA (<50 
c/mL) and non-inferior to monthly (Q4 Week) CAB+ RPV at Week 48. 
 
Study 200056 (LATTE-2) 
In Study 200056, at Week 160, 83% of participants receiving CAB + RPV monthly IM dosing 
(Q4W) and 90% of participants receiving CAB + RPV bimonthly dosing (Q8W) maintained 
virologic suppression (HIV-1 RNA <50 c/mL by the Snapshot algorithm).  The difference in 
virologic success was primarily due to non-virologic reasons.  Of the 44 participants in the oral 
treatment group who opted to switch to CAB + RPV (Q4W or Q8W) at Week 100 (beginning of 
the Extension phase), 100% (Q4W) and 97% (Q8W) maintained virologic suppression (HIV-1 
RNA <50 c/mL) at Week 160.  In the Maintenance and Extension periods of this study there have 
been 3 protocol defined virologic failure (PDVFs), 2 in the Q8W arm and 1 in the oral CAB arm.  
No PDVFs were observed in the Q4W arm throughout the study and no additional PDVFs have 
been observed since Week 48. 
 
Study LAI116482 (LATTE) 
In Study LAI116482, at Week 96, 79% (CAB 10 mg group), 85% (CAB 30 mg group), 93% 
(CAB 60 mg group) and 83% (EFV 600 mg group) of participants maintained virologic 
suppression (HIV-1 RNA <50 c/mL).  After the last participant completed the Week 96 visit the 
study was unblinded and all participants, including those in the EFV group, were transitioned to 
the Sponsor selected regimen of CAB 30 mg + RPV 25 mg.  The transition took place between 
Weeks 108 and 120.  There were 9 PDVFs on the CAB arms with 3 occurring between Week 96 
and Week 144. 
 
Adverse Drug reactions  
 
The safety assessment (and Adverse Drug Reactions [ADR] identification) was performed for the 
CAB + RPV regimen as these agents were administered together in the clinical studies for RPV 
LA. The assessment was based on the analysis of pooled 48-week data from 1,182 virologically 
suppressed participants with HIV-1 infection in 2 international, multicenter, open-label pivotal 
Phase III studies, 201584 (FLAIR) and 201585 (ATLAS). Additional safety information from 
earlier clinical studies in the CAB and RPV programs have been considered in assessing the 
overall safety profile of RPV LA. 
 
The ADR frequencies are based primarily on the pooled data of the Phase III registrational 
program. 
 
The ADRs are listed by System Organ Class (SOC) and frequency. Frequencies are defined as 
very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). 
 


 
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Table 1: Adverse Drug Reactions Observed in Adult Patients Treated with RPV in 
Combination with CAB  
 
 
ISRs were the most frequent AEs associated with the IM use of CAB + RPV. Out of 14,682 
injections, 3,663 ISRs were reported. The percentage of participants reporting ISRs decreased 
over time (Week 4, 70% and Week 48, 16%). A total of 1% of participants discontinued 
treatment with CAB LA and RPV LA injections, because of ISRs. In Phase III studies 201584 
(FLAIR) and 201585 (ATLAS) at the Week 48 analysis, 84% of participants had at least one 
local ISR at some point over the analysis period, consisting primarily of localized pain/discomfort 
(79% of participants), see Table 1 above for overall ISR incidence. Other manifestations of ISRs 
reported in more than 1% of participants over the duration of the analysis period included nodules 
(14%), induration (12%), swelling (8%), erythema (4%), pruritus (4%), bruising (3%), warmth 
(2%), and hematoma (2%). Abscess and cellulitis at the injection site were each reported in <1% 
of patients. The severity of reactions was generally mild (Grade 1, 75% of participants) or 
moderate (Grade 2, 36% of participants). 4% of participants experienced severe (Grade 3) ISRs, 
and no participants experienced Grade 4 ISRs. The median duration of overall ISR events was 3 
days. 
 
1.3 
Study Rationale 
 
The IMPAACT 2017 is a Phase I/II study being conducted to assess the safety, acceptability, 
tolerability, and pharmacokinetics of oral and long-acting injectable cabotegravir and long-acting 
injectable rilpivirine in virologically suppressed HIV-1 infected children and adolescents. The age 
group studied will be adolescents aged 12 to <18 years and ≥35 kg.  
 
1.3.1 
Protocol Version History 
 
Protocol Version 1.0 was finalized on March 2, 2018 but never implemented. Protocol Version 
2.0 was finalized on August 16, 2018. The main purpose of the amendment was to implement 
protocol modifications recommended by the Division of AIDS (DAIDS) responsible as the 


 
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regulatory sponsor of the study relating to information about the study products that became 
available after protocol Version 1.0 was finalized, as well as increasing the flexibility in the 
timing of opening of Cohort 2 to participants who have not previously enrolled to Cohort 1. The 
amendment also incorporated other modifications, clarifications and administrative edits to 
improve consistency across protocol sections. See the Summary of Changes to IMPAACT 2017 
from Protocol Version 1.0 to Version 2.0 for additional details regarding the modifications and 
rationale, which is available upon request to the Protocol Team. Additional protocol 
modifications under Version 2.0 include Clarification Memorandum (CM) #1, CM #2, and Letter 
of Amendment (LoA) #1. See each specific protocol modification document for additional details 
regarding the modifications and rationale and are available upon request to the Protocol Team.   
 
Interim analysis #1, which is further described in this protocol Version 3.0 Sections 3, 9, and 10, 
was conducted under protocol Version 2.0 and using the evaluable participant definitions 
presented in protocol Version 2.0. Participants enrolled to IMPAACT 2017 protocol Version 2.0 
received the Q4W dosing regimen presented in that version. See the Summary of Changes to 
IMPAACT 2017 from Protocol Version 2.0 to Version 3.0 for additional details regarding the 
modifications and rationale, which is available upon request to the Protocol Team.    
 
1.3.2 
Preliminary Review of Study Data 
 
Review of PK Data 
Preliminary PK data were reviewed by the Study Monitoring Committee (SMC) on Jan 17, 2020 
and were found to achieve PK targets.  
 
At the time of the January 2020 SMC review, a total of 16 participants had PK collected and 
analyzed, 7 in Cohort 1C (CAB) and 9 in Cohort 1R (RPV).  The Cohort 1C median PK 
parameters were within the desired median PK target ranges, at Week 2 taken orally (PO) (n=7) 
and Week 16 IM (n=4), - PO AUC 167.4 (131.1-326.8) mcg*h/mL and IM trough 3.1 (1.2-6.2) 
mcg/mL.  Similarly, the median Cohort 1R PK parameter was within the desired median PK 
target range at Week 16 IM troughs (n=6) - observed median (target range): 43.8 (40.7-126) 
ng/mL.   
 
Adult CAB and RPV LA Population (POP) PK models were developed utilizing exposure data 
from adult clinical studies with efficacious dosing regimens having an acceptable safety profile 
with Q4W and Q8W injections. Simulations were conducted with these models, also taking into 
account any potential age and weight related impact on PK, to recommend appropriate doses in 
adolescents that achieve comparable exposures to those seen in adults, initially for a Q4W dosing 
regimen in line with available clinical data in adults at that time. The preliminary adolescent PK 
data from the SMC review were compared against a priori model predictions and are in 
agreement with the predicted exposure range and within thresholds as displayed in Figure 5, 
Figure 6, and Figure 7 for CAB and RPV respectively.  
 


 
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Figure 5.  Observed preliminary IMPAACT 2017 Cohort 1C CAB concentrations in 
adolescents compared to model predicted concentrations based on POP PK analyses 
from adult studies 
 
Note: The plots represent the CAB systemic exposure: solid line and shaded band reflect the population 
pharmacokinetic model predictions (median and 90% interval); the dots represent the observed individual 
subject data. The dashed lines represent the maximum observed geometric mean exposure from the TQT 
study at (22.5 mcg/mL) at supratherapeutic doses following 150 mg q12h x 3 and the target threshold 
concentrations at trough (0.65 mcg/mL). 
 


 
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Figure 6. Observed IMPAACT 2017 Cohort 1R preliminary data and predicted RPV 
plasma concentrations in adolescents after PO RPV 25 mg once daily (left panel) 
and IM RPV LA 900-600-600 mg (right panel) 
Note: Black line and blue shaded area: median and 90% prediction interval for adolescents; black dots: 
observed data in Cohort 1R adolescents. 
 
 
 Figure 7. Observed trough RPV plasma concentrations in Cohort 1R adolescents 
(blue dots) and adults (boxplots, ATLAS/FLAIR) after PO RPV 25 mg once daily 
(Week 0; last day of PO lead-in), and IM RPV LA 900-600-600 mg (Weeks 4, 8 and 
12; concentrations 4 weeks after injection)  
 


 
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Review of Safety Data 
Preliminary safety data were reviewed by the SMC in March 2020, and no safety issues or 
concerns were identified.  All available safety data for the eight enrolled participants in Cohort 
1C and the 15 enrolled participants in Cohort 1R were presented.  At the time of the review, 
based on the available data, the following were deemed evaluable (with PK and Week 16 safety 
data): seven evaluable participants in Cohort 1C, and nine evaluable participants in Cohort 1R. 
 
The safety data used in the March 2020 review showed that out of the seven evaluable 
participants in Cohort 1C, only one participant had a Grade 3 study product-related AE (insomnia 
on day 41 of study that resolved) but remained in the study.  Of the first eight evaluable 
participants in Cohort 1R, only one participant had a Grade 3 study product-related AE (urticaria 
assessed to be an acute allergic reaction related to study product) which resulted in permanent 
discontinuation of study treatment. There were no safety concerns for the other participants in 
both cohorts. 
 
For Cohort 1R, all 8 evaluable participants had already passed the safety guidelines in Section 
9.5.1.3 of protocol Version 2.0.  For Cohort 1C, the current available data confirm that the eighth 
evaluable participant in this cohort has no safety concerns. 
 
1.3.3 
Rationale for use of oral lead-in prior to injectable dosing 
 
The CAB LA and RPV LA formulations have a pharmacokinetic decay rate, resulting from 
gradual release from the IM injection site, that exposes the injected individual to detectable levels 
of cabotegravir and rilpivirine for up to 52 weeks or longer after an injection. A 4-6-week lead-in 
period of daily oral CAB and RPV prior to injectable administration, with serial safety 
assessments, will allow identification of any acute toxicity prior to administration of a non-
dialyzable, non-removable depot injection. A similar oral lead-in period has been employed in 
previous trials in adults using these LA formulations.   
 
The oral lead-in period is also designed to provide uninterrupted study product coverage while 
awaiting the Week 4 safety laboratory test results, which will determine eligibility for receiving 
the LA formulations. The safety assessment is done towards the end of the 4-week oral lead-in 
and, for clarity, has been named the visit 4a. Safety lab results from the 4a study visit will be 
reviewed and, if appropriate, the next visit will be scheduled as soon as possible to administer the 
first study injection; this next visit has been named visit 4b. This nomenclature has been adopted 
to promote consistency across the CAB/RPV studies and allow for clearer interpretation and 
comparisons. Given a participant population with a history of durable viral load suppression at 
and prior to study entry, a viral load assessment at the 2-week visit, and questionable clinical 
meaningfulness of a single HIV viral load blip, a repeat HIV viral load assessment is not part of 
the laboratory assessments done at visit 4a to approve giving the first study injection at visit 4b. A 
HIV viral load sample is collected at visit 4b to time with the first injection(s). 
 
1.3.4 
Rationale for Cohort 1 and the related components of the study design 
 
Oral RPV is approved for use as an antiretroviral medication in adolescents 12 years of age and 
older. In Cohort 1, CAB and RPV will first be studied separately to confirm adult-matched 
exposure/PK and gather initial safety information for oral and injectable CAB (Cohort 1C) as 
well as injectable RPV following lead-in with oral RPV (Cohort 1R). Cohort 1 eligibility criteria 
require study participants to have demonstrated virologic suppression on a stable cART, and this 
cART regimen is continued throughout the Cohort 1 study period to ensure continued virologic 
suppression. Enrollment into Cohort 1C versus Cohort 1R is determined by what cART regimen 


 
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the participants have been receiving in order to avoid drug interactions (e.g. between RPV and 
boosted protease inhibitors or boosted integrase inhibitors) as well as duplication of study agent 
with another ARV from the same drug class. Hence, participants whose background cART 
contains a NNRTI or boosted PI will be enrolled in Cohort 1C and those on a non-boosted INSTI-
based cART will be enrolled in Cohort 1R.  
 
Based on the data presented above, the study target sample size for interim analysis #1 has been 
revised from N=8 to N=7 dose-evaluable participants for Cohort 1C and Cohort 1R.  Interim 
analysis #1 of safety and PK data will be performed (as described in Sections 9 and 10) following 
the first seven evaluable Cohort 1C and the first seven evaluable Cohort 1R participants 
completing their Cohort 1, Step 2 Week 16 study visit.   
 
Safety, not PK, will primarily drive Cohort 1 enrollment and flow. As long as no safety concerns 
are noted, Cohort 1 enrollment will continue uninterrupted while a continuous assessment of PK 
is made (including interim analyses for participants in Cohort 1C and Cohort 1R).  See Section 10 
for the details regarding the interim PK analysis. 
 
1.3.5 
Rationale for Cohort 2 and the related components of the study design 
 
The PK and safety data from the initial group (demonstrating satisfactory agreement of observed 
PK with adult exposures and POP PK model predictions, and the absence of any overt safety 
signals) in Cohort 1 will support the opening of Cohort 2 for Cohort 1 participants, where HIV-1 
infected, virologically suppressed adolescents (including Cohort 1 participants meeting study 
eligibility criteria) will stop their oral cART and switch to CAB plus RPV.  See Section 9 for the 
details regarding opening Cohort 2 to former Cohort 1 participants. Building on the successful 
experience from the trials in adult HIV-1 infected participants in LATTE 2, ATLAS, FLAIR and 
ATLAS-2M , this study will use the same sequential approach of a 4 week (up to 6 week) oral 
lead-in with both agents followed by injections of CAB LA and RPV LA. Based on the most 
recent clinical information in adults, supporting 2-monthly dosing, the Q8W injectable regimen 
has now also been chosen for further evaluation in adolescents, under MOCHA. 
 
General enrollment to Cohort 2 will only open after all participants in Cohort 1 have been 
enrolled and completed Week 16 visits in Cohort 1. The rationale for restricting Cohort 2 to 
Cohort 1 graduates until completion of Cohort 1 is based on safety. The Cohort 1 graduates will 
have completed the PK and safety assessments and will already have their own PK and safety 
profile data on one of the two study agents. This will allow those completing Cohort 1 to stop 
their cART and graduate to Cohort 2 whilst the remaining participants in Cohort 1 are enrolled.  
 
The proposed single arm Cohort 2 component of the study design is consistent with, and 
responsive to, HIV pediatric regulatory guidance from the EU and US, which allow extrapolation 
of adult efficacy data. The week 24 safety assessment time point will serve as the primary 
endpoint for Cohort 2, but safety, acceptability, PK and antiviral efficacy will continue to be 
assessed through week 96 with related study endpoints at weeks 24, 48 and 96 These data will 
provide important information on the short term and long term, through 96 weeks, use of this 2-
monthly, two-drug injectable ART in adolescents.  
 
1.3.6 
Rationale for Change in IM Dosing Regimen (from Q4W to Q8W) 
 
CAB and RPV have demonstrated their efficacy when dosed in a Q8W (ATLAS 2M) regimen in 
addition to earlier Q4W data. Investigating the Q8W regimen in HIV-infected adolescents 
facilitates its use in adolescents and the benefits that a decreased administration regime provides 


 
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including ease of compliance. Adult PK data indicates that Q8W concentrations can be 
extrapolated from Q4W data with one descriptive POP PK model accurately predicting both 
regimens. The current adolescent data indicates that Q4W provided CAB and RPV concentrations 
similar to or higher than those observed in adults and so it is expected that Q8W will perform 
similarly providing efficacious concentrations and trough concentrations. 
 
The agreement of the preliminary observed PK data with the expected criteria and model 
simulations indicated that the respective POP PK models for CAB and RPV are capable of 
accurately predicting PK in adolescents with no unexpected PK issue. Additionally, adolescent 
PK is generally expected to vary only slightly from adult PK for most drugs and it is 
commonplace to use adult dose regimes for adolescents.  Of 92 products assessed by the Food 
and Drug Administration (FDA), 95% had equivalent dosing for adults and adolescent patients 
(19). When given the same CAB and RPV dosage as adults, slightly higher mean exposures are 
expected in adolescents due to their lower body weights. These differences are however not likely 
to be clinically relevant given the broad range of exposures observed in adults.  
 
The observed concentrations following PO and IM administration are well predicted by the POP 
PK models with nearly all the individual participant values within the 90% prediction intervals 
throughout the PK sampling interval.  This dosing provides exposures comparable to those 
previously seen in adults and it is highly unlikely that collection of additional PK data with the 
current dosing regimen would impact conclusions about exposure adequacy for CAB or RPV. 
The similarity of CAB and RPV PK between adolescents and adults is independent of dosing 
regimen. Subsequently, in conjunction with the clinical experience in the adult population with 
Q8W dosing, similar modeling and simulation has been utilized to recommend a Q8W dosing 
regimen for adolescents for evaluation in IMPAACT 2017.  
 
1.3.7 
Rationale for Long-Term Safety and Washout PK Follow-up (LSFU) 
 
As earlier mentioned, the CAB LA and RPV LA formulations have a pharmacokinetic decay rate 
which exposes the injected individual to detectable levels of CAB and RPV for up to 52 or more 
weeks after an injection. Given this prolonged decay rate, clinical protocols to date using these 
LA agents have included a long-term follow-up to assess safety and potential viral rebound and 
development of resistance in the setting of declining study product levels following the last 
intramuscular injection of either or both CAB LA and RPV LA. Any participant discontinuing the 
intramuscular injections, will then be followed per the 48-week follow-up visit schedule.  
 
1.3.8 
Rationale for Acceptability and Tolerability Assessments including Qualitative Phone 
Interviews: Participants and Parent/caregiver 
 
Following enfuvirtide, an HIV fusion inhibitor, that was the first of a novel class of antiretroviral 
drugs proposed as twice-a-day subcutaneous injections as part of cART for the treatment of HIV-
1 infection, the intramuscular LA formulations will be the first injectable antiretroviral agents to 
be studied in adolescents. Acceptability and tolerability will be critical to understand from both 
the standpoint of the participants and their caregivers, who facilitate their access to healthcare. 
Soliciting feedback on the LA formulations from diverse groups of patients and their caregivers 
will help inform ways to further optimize the delivery of these agents and their acceptability in 
future clinical trials as well as their offering as part of standard of care when these agents are 
approved. To accomplish this important study aim, assessments will be administered by site staff 
to participants via questions covering topics on participant perceptions of the study product 
injections, reasons for switching from daily oral cART to long-acting study products, satisfaction 


 
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with treatment, and quality of life at multiple time points throughout the study. In addition, a 
single in-depth qualitative phone interview will be conducted with selected participants, and, 
separately, with selected parents or caregivers, to identify acceptability concerns unique to the 
participant population. The written assessments are similar to ones that have been utilized for 
adult studies of LA agents but have been adapted to be age appropriate. These assessments will 
allow comparisons of adolescent feedback to that from adults. Some assessments such as the 
feedback from the caregivers will be unique to pediatric and adolescent populations and 
IMPAACT 2017 will provide the first opportunity to get this information.  
 
1.3.9 
Rationale for Proposed Doses of Study Agents 
 
1.3.9.1 Oral CAB 
 
Oral CAB has been administered to HIV infected adults at doses of 5 mg to 60 mg once daily. 
Oral CAB 10 mg, 30 mg, and 60 mg once daily were administered safely to HIV infected 
participants for 2 years or longer (LAI116482, LATTE). Oral CAB 30 mg was the dose used in 
the lead-in phases in the successful efficacy trials investigating the Q4W and Q8W regimens [the 
ATLAS study, FLAIR and ATLAS-2M.  A geometric mean Cmax of 22.5 g/mL [median (range) 
21.9 (16.9-39.2) g/mL] has been observed for CAB in healthy adults at supratherapeutic doses 
following 150 mg q12h x 3 in the TQT study without any impact on the QT interval 
(LAI117009).  
 
A CAB POP PK model was built based on CAB plasma concentrations collected from 1,647 
healthy (28%) and HIV-infected (72%) adult participants (age 18 to 74 years) in 16 studies at 7 
dose levels (10 mg to 60 mg for the oral tablet; 100 mg to 800 mg for CAB LA). The CAB POP 
PK model was employed to recommend doses in adolescents after accounting for relevant factors 
related to this population e.g. body weight. The predicted exposures with the 30 mg daily dose are 
summarized by weight group in Table 2. For adolescents weighing 35 to <50kg, oral CAB 30mg 
once daily is predicted to achieve median exposures that are ~60-70% higher than that observed 
at 30mg in adults in LATTE and comparable to exposures observed at 60 mg in adults in LATTE, 
which has been administered safely in HIV infected adult participants. These slightly higher 
exposures predicted in adolescents are largely due to their relatively lower body weight and are 
not of clinical concern based on observed efficacy and safety data from adult clinical studies. The 
Cmax CAB exposures at the proposed dose regimen are expected to be below the 22.5 g/mL – the 
geometric mean Cmax exposure at 150 mg q12h x 3 f. 
 


 
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Table 2. Predicted Steady State CAB Exposures following Oral CAB 30mg and 60mg QD 
in Adolescents compared to Observed Adult Values 
Plasma CAB 
Parameter 
Observed Adult Data 
(LAI116482, LATTE) 
Median 
(range) 
Adolescent Weight Group 
35 to <50kg 
50kg 
30mg QD 
(54-105kg) 
60mg QD 
(69-106kg) 
Predicted 
Median 
[5th, 95th %] 
Predicted 
Median 
[5th, 95th %] 
Cmax 
(g/mL) 
8.5 
(4.9-10.8) 
13.1  
(7.3-18.5) 
13.3 
[8.4, 21.3] 
9.7  
[5.8, 15.8] 
C 
(g/mL) 
4.4 
(2.5-7.7) 
6.4 
(2.4-11.3) 
7.3  
[4.0, 13.1] 
5.6  
[3.0, 10.0] 
AUC(0-) 
(g•h/mL) 
144   
(79-208) 
209  
(103-334) 
237 
[142, 393] 
175 
[102, 299] 
 
1.3.9.2 Injectable Cabotegravir 
 
CAB LA has been administered intramuscularly to healthy and HIV infected adults at doses of 
100mg to 800mg. In HIV-infected participants, CAB LA has maintained virologic suppression on 
maintenance doses of 400mg and 600 mg IM given Q4W and Q8W respectively with RPV LA 
(LATTE-2), demonstrating noninferiority of the Q4W regimens in the Phase 3 Studies ATLAS 
and FLAIR. In Phase IIIb Study 207966 (ATLAS-2M) CAB LA demonstrated noninferiority of 
the Q8W regimen to the Q4W regimen). 
 
The previously developed POP PK model was updated with data from both a Q8W and Q4W 
CAB IM injection dosing scheme. Model performance was evaluated and deemed adequate with 
appropriate qualification and validation. Clinical trial simulations for adolescents were 
subsequently conducted with the updated CAB POP PK model to recommend a Q8W dosing 
regimen. The proposed dosing is the same as that in adults and listed in Section 5. 30 mg CAB 
once daily orally for at least four weeks in addition to cART (Step 1 oral phase), followed by a 
single intramuscular injection of CAB LA 600 mg as first injection and a second CAB LA 600 
mg injection 4 weeks later, in addition to continuing cART (Step 2 injection phase) is 
recommended for the remainder of Cohort 1C. Cohort 2 will employ the following dosing for 
CAB – 30 mg CAB once daily orally for at least four weeks (Step 3 oral Phase), followed by a 
single intramuscular injection of CAB LA 600 mg as first injection, a second CAB LA 600 mg 
injection 4 weeks later and followed by CAB LA 600mg every 8 weeks thereafter during Step 4 
injection phase. 
 
The expected CAB concentration time profile from the Q8W injections suggest that minimal 
CAB accumulation is expected with the Q8W injections, as also observed in adults with the CAB 
Q8W regimen. The shorter first dose interval (4 weeks in between 2 first injections) will lead to 
predicted steady-state concentrations almost immediately after the first injection with trough 
concentrations expected to be well above the minimum target threshold of 0.65 ug/mL. The 
predicted trough exposures (C) are listed in Table 3 below.  Exposures in adolescents are 
expected to be slightly higher largely due to their relatively lower body weight. These differences 
are not of clinical concern based on observed efficacy and safety data from adult clinical studies. 
In summary, the Q8W regimen has been demonstrated to be effective and have an acceptable 
safety profile in pivotal trials in adults and, as such, is suitable for investigating in HIV-infected 
adolescent participants. Pharmacokinetics and safety data following CAB PO and LA will be 
reviewed for participants in Cohort 1C of the study. 


 
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Table 3. Predicted Steady State CAB Parameters following CAB LA IM Q8W regimen 
compared with Observed and Estimated data in Adults  
 
 
Predicted C (g/mL)b 
Post First Injection 
Post Second Injectionc 
Adolescent Body weight 
35 to <50kg 
2.49 [0.98, 4.72] 
2.34 [0.84, 3.98] 
50kg 
1.76 [0.69, 3.49] 
1.76 [0.77, 3.05] 
Observed adult data 
1.50 [0.65, 2.90] a 
1.61 [0.80, 2.99]d 
a. 
Geometric mean [5th and 95th percentile] - Week 8 pre-dose concentrations were obtained following a 
CAB 600 mg IM dose. 
b. 
Median [90% prediction Interval] 
c. 
C after second injection is 8 weeks post injection 
d. 
Geometric mean [5th and 95th percentile] - C at Week 48 with Q8W dosing regimen 
 
 
1.3.9.3 Oral Rilpivirine (RPV) 
 
RPV 25-mg once daily (oral tablet) is approved for the treatment of HIV-1 infection in ART-
naïve patients 12 years of age and older in multiple countries including the US, the EU, Canada, 
and Japan as EDURANT®, and as part of ODEFSEY® (emtricitabine/rilpivirine/tenofovir 
alafenamide). This approved dose of oral rilpivirine will be used one component of the oral lead-
in in Cohort 1R and Cohort 2. 
 
1.3.9.4 Injectable Rilpivirine 
 
RPV LA (formulation G001) has been administered intramuscularly (IM) to healthy and HIV 
infected adults at doses of 300 mg to 1200 mg. In HIV-infected participants, RPV LA maintained 
virologic suppression on maintenance IM doses of 600 mg monthly (Q4W)), in conjunction with 
CAB LA monthly (ATLAS, FLAIR) or RPV 900 mg 2-monthly (Q8W) in conjunction with CAB 
LA bi-monthly (LATTE-2, ATLAS-2M).  
 
A POP PK model for RPV LA after IM administration was developed based on data in healthy 
and HIV-1 infected participants. Factors including BMI, bodyweight, gender, and race were not 
identified as significant covariates for the POP PK model of RPV LA. Only age was identified to 
be a statistically significant covariate for absorption rate. This, however, was not considered 
clinically relevant, as it has no discernable effect on the RPV AUC and C (C28D) for RPV LA, 
and only a limited effect on the RPV Cmax after IM administration. 
 
In order to assess what could occur in case bodyweight would become more important for the 
absorption of RPV LA in adolescents, a conservative approach using an allometric scaling term 
for absorption rate from the injection site was used (Table 4). The impact of making the 
absorption rate a function of bodyweight however had minimal effects on the RPV Cmax or C 
(C28D) values. Even with the added scaling factor, in adolescent participants weighing 
35 to <50kg or 50kg, a RPV LA regimen of 600mg IM Q4W (after loading dose of 900 mg IM) 
or 900 mg IM Q8W (with first 2 injections separated by 4 weeks) is predicted to achieve median 
steady state trough concentrations that are similar to those in adults with the same RPV LA 
regimen and to those with oral RPV 25mg once daily (Table 4). The first participants in Cohort 
1R (Step 2) received an initial injection of RPV LA 900 mg, followed by 2 RPV LA 600 mg 
monthly doses thereafter, in line with the available adult data at that time. In the remainder of 


 
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Cohort 1R, two injections of RPV LA 900mg will be given 4 weeks apart, in line with currently 
available data for the Q8W regimen from Study 207966 in adults.  
 
The proposed dosing is the same as that in adults and listed in Section 5. 25 mg RPV once daily 
orally for at least four weeks in addition to continuing cART (Step 1 oral phase), followed by a 
single intramuscular injection of RPV LA 900 mg as first injection and a second RPV LA 900 mg 
injection 4 weeks later in addition to continuing cART (Step 2 injection phase) is recommended 
for Cohort 1R. Cohort 2 will employ the following dosing for RPV (in combination with CAB) – 
25 mg RPV once daily orally for at least four weeks (Step 3 oral Phase) followed by a single 
intramuscular injections of RPV LA 900 mg as first injection and a second RPV LA 900 mg 
injection 4 weeks later followed by RPV LA 900mg every 8 weeks thereafter during Step 4 
injection phase. 
 
Table 4.  Predicted RPV Trough Concentrations following RPV LA IM Q8W in 
Adolescents, compared with Observed Data in Adults  
 
 
Predicted (Adolescents)a,c or Observed (Adults)b C (ng/mL) 
 
 
Week 8 
(4 Weeks After 
First Injection) 
Week 16 
(4 Weeks After 
Second Injection) 
Week 24 
(8 Weeks After 
Third Injection) 
Week 48 
(8 Weeks After 
Sixth Injection) 
Adolescents 
35 to <50kg 
41.0 (19.3-81.9) 
32.5 (16.3-62.1) 
40.4 (20.0-75.9) 
57.0 (28.7-107) 
50kg 
41.8 (19.7-85.3) 
32.7 (16.0-64.8) 
40.3 (20.1-75.1) 
56.9 (28.0-106) 
Adults 
 
49.1 (20.9-116) 
45.2 (23.0-92.4) 
50.1 (23.3-90.4) 
64.7 (33.0-120) 
a. 
Median (90% prediction Interval) 
b. 
Median (5th, 95th percentile) 
c. 
Simulations for 1000 adolescents aged 12-<18y and weighing 35-<50kg or ≥50kg, with allometric scaling.  
 
1.4 
Risk/Benefit Assessment 
 
1.4.1 
Cohort 1 
 
Cohort 1 participants will remain on the same cART regimen on which they have a previous 
history of sustained HIV virologic suppression throughout Cohort 1 participation. Additionally, 
assignment to Cohort 1C or Cohort 1R is based on their cART composition such that there are no 
drug interactions with study agents and avoiding redundancy of agents from the same class of 
antiretrovirals. Given all of this, there is no anticipated risk of loss of HIV virologic control 
specifically related to participation in Cohort 1.  
 
Oral rilpivirine is currently approved for use in HIV-infected patients 12 years and older and the 
side effect profile has been well described and outlined in the package insert. The safety profile of 
oral cabotegravir, CAB LA and RPV LA is summarized earlier in this section and detailed in the 
related investigator’s brochures. In order to help identify any safety concerns prior to 
administration of a non-dialyzable, non-removable depot injection of the CAB LA and RPV LA 
that have a slow pharmacokinetic decay, a 4-6 week lead-in period of daily oral (short acting) 
CAB or RPV is planned, followed by 2 injections, 4 weeks apart. By enrolling patients with a 
history of sustained virologic suppression on cART and maintaining this cART backbone 
throughout Cohort 1 follow-up, the likelihood of virologic failure and associated development of 
resistance to study agents is highly unlikely.  


 
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Injection site reactions reported to date have been relatively common but not significant, 
becoming less frequent over time, and not life threatening nor serious.  Despite occurrence of 
ISRs, there has been high acceptability of the long acting study agents amongst the adult study 
participants. 
 
Other than a potential for an improved understanding of, and engagement in, HIV care both from 
the standpoint of the patient and their caregiver through participating in a safety, PK and 
acceptability/tolerability study of novel antiretroviral study agents and interacting with study 
staff, there is no immediate benefit to participation in Cohort 1. However, there is the potential of 
early access of Cohort 1 participants to Cohort 2 and its related risk-benefits. Based on the results 
of the interim PK and safety analysis of Cohort 1, graduates of Cohort 1 are likely, as per the 
study design, to have earlier access to enrollment into Cohort 2 and with that an opportunity to 
stop oral cART and switch to an entirely IM LA regimen. 
 
1.4.2 
Cohort 2 
 
In addition to the study agents’ specific side effects, Cohort 2 participants run the risk of having 
loss of virologic suppression, and the potential development of resistance mutations, once 
switched off oral cART to the two study agents, first as daily oral therapy and followed by every 
eight week injections of the long-acting formulations. There is a growing body of evidence 
assessing the efficacy and safety of contemporary dual-drug antiretroviral regimens as first-line 
treatment or as a simplification strategy in HIV-infected patients. A systematic review and meta-
analysis on this topic concluded as a switch strategy, dual therapy was equally efficacious to 
standard cART and although the dual therapy tended to have lower rates of adverse events than 
standard cART be it in an initial treatment setting or a switch strategy, it was associated with a 
higher relative risk of selecting virus with drug resistance mutations at virological failure.(6) The 
overall assessment of this anticipated risk of development of resistance in Cohort 2 of IMPAACT 
2017 is judged to be low for several reasons. Results from pivotal efficacy studies in naïve and 
treatment-experienced HIV-infected adults show that the CAB LA plus RPV LA regimen is well 
tolerated, demonstrates durable virologic response and the rate of treatment emergent resistance is 
extremely low through week 96  for ATLAS and FLAIR and week 48 for ATLAS 2-M. (9, 11, 
12, 20) Secondly, the dose of study agents confirmed from Cohort 1 PK in adolescents is likely to 
be the same as that which has currently been shown to be efficacious in adults. Lastly, only 
patients with durable virologic suppression are enrolled in Cohort 2 and, in addition with an 
injectable only regimen for majority of the study period, will get directly observed therapy 
making the likelihood of unobserved poor adherence to medications much less likely.  
 
Injection site reactions reported to date in adults have been very common but not significant, 
becoming less frequently reported over time, and not life threatening nor serious. Despite 
occurrence of ISRs, there has been high acceptability of the long acting study agents amongst the 
adult study participants.  
 
The potential benefit of participating in Cohort 2 relates to the convenience of not having to take 
daily oral cART and avoiding any oral cART related toxicities, medication fatigue and adherence 
issues. Long-acting two class therapy consisting of CAB LA + RPV LA as an IM regimen has the 
benefit of being a NRTI-sparing regimen for long-term treatment of HIV infection which will 
avoid known NRTI-associated adverse drug reactions and associated long-term toxicities. 
Additionally, a two-drug combination therapy with CAB LA plus RPV LA may offer a better 
tolerability and resistance profile, as well as improved adherence (particularly with Q8W) and 


 
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treatment satisfaction in virologically suppressed participants improving the quality of life for 
patients living with HIV. 
 
Taking into account the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with CAB LA and RPV LA, and the study as a whole, are justified 
by the anticipated benefits that may be afforded to treatment-experienced adolescents with HIV-1 
infection. 
 
1.5 
Hypotheses 
 
Cohort 1: CAB (oral and LA) and RPV LA will be safe and will achieve pharmacokinetic targets 
through Week 16 in HIV-infected adolescents at the chosen dose to ultimately allow for a final 
dose to be selected.  
 
Cohort 2:  CAB LA and RPV LA, when given as dual therapy to stable, virologically suppressed 
adolescents will maintain viral suppression and will be safe through Week 24 in HIV-infected 
adolescents at the selected dose. 
 
 
2 
OBJECTIVES 
 
2.1 
Primary Objective: Cohort 1 (continuing a background cART regimen) 
 
The primary objective of this study is:  
 
2.1.1 
To confirm the doses for oral CAB followed by injectable CAB LA in HIV-infected, 
virologically suppressed adolescents by evaluating: 
2.1.1.1 Safety and multiple dose PK of oral CAB through Week 4;  
2.1.1.2 Safety and multiple dose PK of CAB LA through Week 16. 
 
2.1.2 
To confirm doses for injectable RPV LA in HIV-infected, virologically suppressed 
adolescents by evaluating safety and multiple dose PK of RPV LA through Week 16. 
 
2.2 
Primary Objective: Cohort 2 (discontinuing a background cART regimen) 
 
The primary objective of this study is:  
 
2.2.1 
To assess the safety of CAB LA + RPV LA through Week 24 in HIV-infected, 
virologically suppressed adolescents. 
 
2.3 
Secondary Objectives: Cohort 1 
 
The secondary objectives of this study are:  
 
2.3.1 
To monitor maintenance of viral suppression through Week 16 in HIV-infected, 
virologically suppressed adolescents. 
 


 
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2.3.2 
To evaluate the tolerability and acceptability of CAB LA through Week 16 in HIV-
infected, virologically suppressed adolescents. 
 
2.3.3 
To evaluate the tolerability and acceptability of RPV LA through Week 16 in HIV-
infected, virologically suppressed adolescents. 
 
2.4 
Secondary Objectives: Cohort 2 
 
The secondary objectives of this study are:  
 
2.4.1 
To assess safety of oral CAB + oral RPV followed by CAB LA + RPV LA through Week 
48 in HIV-infected, virologically suppressed adolescents. 
 
2.4.2 
To evaluate repeat-dose pharmacokinetics of CAB LA + RPV LA through Week 24, and 
through Week 48 in HIV-infected, virologically suppressed adolescents. 
 
2.4.3 
To assess antiviral activity of CAB LA + RPV LA through Week 24, and through Week 
48 in HIV-infected, virologically suppressed adolescents. 
 
2.5 
Other Objectives 
 
The other objectives of this study are:  
 
2.5.1 
To evaluate the tolerability and acceptability of CAB LA + RPV LA through Week 24, 
through Week 48, and through Week 96 in HIV‐infected, virologically suppressed 
adolescents (Cohort 2). 
 
2.5.2 
To evaluate the safety, antiviral and immunologic activity, and characterize PK of CAB 
LA + RPV LA through Week 96 in HIV-infected, virologically suppressed adolescents 
(Cohort 2). 
 
2.5.3 
To evaluate adolescent participant’s experience of CAB LA and/or RPV LA, and 
parent/caregiver’s experience and perceptions of adolescent acceptability and tolerability 
of CAB LA and/or RPV LA (Cohort 1 and Cohort 2). 
 
2.5.4 
To evaluate the tolerability and acceptability, and characterize long-term safety and 
washout PK through 48 weeks following permanent discontinuation of CAB LA or RPV 
LA (Cohort 1). 
 
2.5.5 
To evaluate the tolerability and acceptability, and characterize long-term safety and 
washout PK through 48 weeks following permanent discontinuation of CAB LA + RPV 
LA (Cohort 2). 
 
2.5.6 
To describe HIV-1 resistance in participants experiencing virologic failure (Cohort 1 and 
Cohort 2). 
 
 


 
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3 
STUDY DESIGN 
 
This is a Phase I/II, multi‐center, open‐label, non‐comparative study to confirm the dose and 
evaluate the safety, tolerability, acceptability, and PK of oral CAB, long-acting injectable CAB 
(CAB LA), and long-acting injectable RPV (RPV LA) among up to 155 virologically suppressed 
HIV‐1 infected children and adolescents aged 12 to <18 years.  
 
Up to 60 parents/caregivers of adolescent participants in the U.S. will also be enrolled to take part 
in in-depth qualitative interviews. Unless otherwise noted, the term ‘participant’ will refer to the 
adolescent participants. 
 
The study design includes two cohorts of participants and two steps of study participation in each 
cohort. Cohort 1, Step 1 and Cohort 2, Step 3 are both a lead-in phase in which participants will 
receive oral formulations of the study products for at least 4 weeks, and up to 6 weeks 
(maximum). In Cohort 1, Step 2 and Cohort 2, Step 4, participants will receive injectable 
formulations of the study products. In each cohort, participants will enter the study in the oral 
lead-in phase (Step 1, or Step 3) and then transition to the injectable phase (Step 2, or Step 4) if 
eligibility criteria for the injectable phase are met. Cohort 1 Step 2 and Cohort 2 Step 4 
participants, including those who prematurely permanently discontinue injectable study product, 
will continue on-study for an additional 48 weeks after their last study product injection, per the 
long-term safety and washout PK follow-up (LSFU) schedule. Any female participant who 
permanently discontinues study product (either oral or injectable study product) due to pregnancy 
will also be followed per the LSFU visit schedule, based on the date of the positive confirmatory 
pregnancy test result, for an additional 48 weeks. Expectations regarding the LSFU visit schedule 
for specific participants are described in further detail in Sections 3.3 and 6.5. 
 
The study will open to accrual in Cohort 1, in which participants, in addition to continuing their 
pre-study cART regimen, will receive either oral CAB or oral RPV (Step 1) followed by either 
CAB LA or RPV LA (Step 2). Cohort 1 participants will be assigned either CAB (Cohort 1C) or 
RPV (Cohort 1R) based on their pre-study cART regimen.  Interim analyses will be performed 
with a sub-set of participants in Cohort 1 to first determine whether to open Cohort 2 to Cohort 1 
participants who meet criteria to enter Cohort 2 and establish the doses for Cohort 2, and then to 
determine whether to open Cohort 2 to additional participants who were not previously enrolled 
in Cohort 1, and lastly a final analysis will be performed to confirm the final doses for Cohort 
2.  See Section 3.1 below for further details describing these Cohort 1 data analyses.  Upon 
Cohort 2 Entry (i.e. Cohort 2, Step 3), all Cohort 2 participants will discontinue their pre-study 
cART regimen and receive both study products — CAB and RPV — at the doses confirmed in 
Cohort 1. 
  
Safety and PK evaluations will be performed in each cohort, as well as during LSFU. Antiviral 
activity assessments will be performed in each cohort. Acceptability and tolerability will be 
assessed in each cohort and during LSFU, with all participants completing quantitative 
questionnaires and a sub-set of participants completing in-depth qualitative interviews.  
 
Further information describing the two cohorts is provided in Sections 3.1 and 3.2. Further 
information describing the LSFU visit schedule, for both Cohort 1 and Cohort 2 participants, is 
provided in Section 3.3. Refer to Figure 1, Figure 2, Figure 3, and Figure 4 Error! Reference 
source not found.for an overview of Cohort 1, Cohort 2, and the overall study design for the 
adolescent participants; Section 4 for the eligibility criteria relevant to each cohort and step; and 
Section 6 and Appendix I for the study visit and procedure schedules for each cohort. Details 
regarding the in-depth qualitative interviews are provided in Section 11.  


 
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Parent/caregiver eligibility criteria are provided in Section 4, with further details regarding the 
parent/caregiver in-depth qualitative interviews in Appendix V-A. 
 
3.1 
Cohort 1 
 
Up to 55 participants will be enrolled in Cohort 1 to achieve approximately 30-35 dose-evaluable 
(refer to Section 9.5.1.3 for the definition of dose-evaluable for this cohort). Within this cohort, 
participants will be assigned to either Cohort 1C (approximately 15-20 dose-evaluable), in which 
participants will receive CAB, or Cohort 1R, in which participants will receive RPV 
(approximately 15 dose-evaluable). Assignment to Cohort 1C or 1R will be based on each 
participant’s pre-study cART regimen:   
 
• 
Participants on a PI-based and/or NNRTI-based cART regimen will be assigned to Cohort 1C 
• 
Participants on a non-boosted INSTI-based cART regimen will be assigned to Cohort 1R 
 
All participants in Cohort 1 will remain on their pre-study cART regimen and will additionally 
receive either CAB (Cohort 1C) or RPV (Cohort 1R). 
 
Upon enrollment, Cohort 1 participants will receive oral CAB (Cohort 1C) or oral RPV (Cohort 
1R) for at least 4 weeks (and up to 6 weeks) in Step 1. An intensive PK visit will be conducted at 
the Week 2 visit. Data collected through the Week 4a study visit will be assessed to determine 
eligibility for each participant to enter Step 2 and receive injectable CAB LA or RPV LA, 
respectively. The Cohort 1 Week 4b visit serves as the Step 2 Entry visit. This visit should be 
scheduled to occur as soon as possible after Week 4a laboratory test results are available, to 
minimize the time between the Week 4a visit and initiation of the injectable study products in 
Step 2. Clinical assessments conducted at the Week 4b visit, and prior to administering the first 
injection, will also be used to confirm Step 2 eligibility.  
 
Cohort 1 participants who meet eligibility criteria for Step 2 are generally expected to receive 
their last oral dose of CAB or RPV on the same day as their first injection of CAB LA or RPV 
LA, at the Week 4b Step 2 Entry visit (see Section 6.3.4 for further details). See Section 4.3 for 
eligibility criteria to enter Step 2. Cohort 1 participants who do not meet eligibility criteria for 
Step 2 will discontinue use of oral CAB or RPV and exit the study 28 days after their last oral 
study product dosing.    
 
In Step 2, participants will receive CAB LA (Cohort 1C) or RPV LA (Cohort 1R) while 
continuing their cART regimen. A single intramuscular (IM) injection of CAB LA or RPV LA 
will be administered at the following visits: once at the Week 4b (Step 2 Entry) visit and once at 
the Week 8 visit. Cohort 1 Step 2 participants will be followed for safety and PK assessments 
through their Week 16 visit.  
 
In Step 2, Weeks 5 through 16 visits will be scheduled based on the date of first injection 
administration (Week 4b Step 2 Entry visit). Cohort 1 Step 2 participants will be followed for up 
to an additional 48 weeks, per the LSFU visit schedule, upon premature injectable study product 
discontinuation or upon completion of the Step 2 Week 16 visit. Cohort 1 participants who have 
completed all Step 2 visits may enroll to Cohort 2 (if eligible), prior to completing all LSFU 
visits. Further guidance on scheduling study visits are provided in the IMPAACT 2017 Manual of 
Procedures (MOP). 
 


 
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Interim Analysis #1 (conducted under protocol version 2.0; see protocol Section 1.3) 
Once seven dose-evaluable Cohort 1C participants and seven dose-evaluable Cohort 1R 
participants have completed Step 2 injectable study product dosing and safety and PK evaluations 
through the Cohort 1 Step 2 Week 16 visit, an interim analysis of safety and PK data will be 
performed to: 
 
• 
Determine whether criteria have been met to open Cohort 2 to accrual — limited to Cohort 1 
participants 
• 
Establish the dose of the oral and injectable CAB study products, and the injectable RPV 
study product to be provided in Cohort 2   
 
Interim Analysis #2 
Once approximately 15-20 Cohort 1C participants and approximately 15 Cohort 1R participants 
contributing to the dose-finding algorithm have enrolled, and 80% of these participants have 
completed the Step 2 Week 8 visit, an interim analysis of safety and PK evaluations will be 
performed to determine whether criteria have been sufficiently met to fully open Cohort 2 to 
accrual, including accrual of participants who were not previously enrolled in Cohort 1. 
 
Cohort 1 Final Analysis 
Once Cohort 2 is determined to be opened to accrual for new participants who were not 
previously enrolled in Cohort 1, accrual into Cohort 1 will stop. Once Cohort 1 participants have 
all completed safety and PK evaluations through the Cohort 1 Step 2 Week 16 visit, the final 
analysis of all Cohort 1 safety, PK and maintenance of viral suppression data will be performed to 
confirm the dose of the oral and injectable CAB study products, and the injectable RPV study 
product provided in Cohort 2. 
 
Refer to Section 9 for the definition of dose-evaluable, and detailed descriptions of all Cohort 1 
analyses and associated decision-making.  
 
Participant safety will be monitored throughout follow-up, and samples for antiviral activity and 
PK evaluations will be collected at visits as specified in Section 6, with blood volume ranges 
provided in Appendix I-A. Acceptability and tolerability will be assessed with all participants 
completing quantitative questionnaires, and a sub-set of participants also completing in-depth 
qualitative interviews.  
 
3.2 
Cohort 2 
 
Up to 155 participants may participate in Cohort 2: Up to 100 participants, who have not 
previously participated in Cohort 1, will be enrolled directly into Cohort 2 to achieve 
approximately 70 evaluable adolescents newly enrolling to the study.  
 
In addition to the up to 100 participants enrolling directly into Cohort 2, adolescents who 
participated in Cohort 1 Step 2 (up to 55 participants) may continue study participation in Cohort 
2 Step 3, if eligible. These participants may screen and enroll into Cohort 2 either prior to 
completing all scheduled LSFU study visits or resume study participation if after having already 
exited the study. See Section 6.2 for additional considerations regarding Cohort 1 Step 2 
participants screening and enrolling into Cohort 2 Step 3. 
 
Upon enrollment into Cohort 2, participants will discontinue their pre-study cART regimen and 
receive oral CAB + RPV for at least 4 weeks (and up to 6 weeks) in Step 3. A PK visit will be 
conducted at the Week 2 visit. Data collected through the Week 4a study visit will be assessed to 


 
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determine eligibility for each participant to enter Step 4 and receive injectable CAB LA + RPV 
LA. The Cohort 2 Week 4b visit serves as the Step 4 Entry visit. This visit should be scheduled to 
occur as soon as possible after Week 4a laboratory test results are available, to minimize the time 
between the Week 4a visit and initiation of the injectable study products in Step 4. Clinical 
assessments conducted at the Week 4b visit, and prior to administering the first injection, will 
also be used to confirm Step 4 eligibility. 
 
Cohort 2 participants who meet eligibility criteria for Step 4 are generally expected to receive 
their last oral dose of CAB + RPV on the same day as their first injection of CAB LA + RPV LA, 
at the Week 4b Step 4 Entry visit (see Section 6.4.4 for further details). See Section 4.4 for 
eligibility criteria to enter Step 4. Cohort 2 participants who do not meet eligibility criteria for 
Step 4 will discontinue use of oral CAB + RPV and exit the study 28 days after their last oral 
study product dosing. Cohort 1 Step 2 participants who continue in Cohort 2 Step 3 but are not 
eligible to progress to Cohort 2 Step 4 will be followed per the LSFU visit schedule.    
 
In Step 4, participants will receive injectable CAB LA + RPV LA. Two IM injections, a single 
injection of CAB LA and a single injection of RPV LA, will be administered at the Week 4b 
(Step 4 Entry) visit, at the Week 8 visit, and then continuing every eight weeks thereafter, over an 
88-week period, with the last injections administered at the Week 96 visit. Study visits during 
Step 4 will be scheduled based on the date of which the first CAB LA + RPV LA injections were 
administered (Week 4b Step 4 Entry). Upon premature discontinuation of injectable study 
products, Cohort 2 Step 4 participants will be followed for 48 weeks per the LSFU visit schedule. 
Further guidance on scheduling study visits are provided in Section 6.1 and the IMPAACT 2017 
MOP.  
 
At the Week 96 visit, Cohort 2 Step 4 participants continuing to receive injectable CAB LA + 
RPV LA external to the protocol will exit the study. See Section 14.11 for more information 
regarding post-trial access to study products. Participants who discontinue receiving the injectable 
CAB LA + RPV LA at the Week 96 visit will not exit the study and will be followed for 48 
weeks per the LSFU visit schedule. 
 
Participant safety will be monitored, and samples for antiviral activity and PK evaluations will be 
collected, at visits as specified in Section 6; blood volume ranges are provided in Appendix I-B. 
Acceptability and tolerability of CAB LA and RPV LA will be assessed with all participants 
completing quantitative questionnaires, and a sub-set of participants also completing in-depth 
qualitative interviews.  
 
3.3 
Long-term Safety and Washout PK Follow-up (LSFU) 
 
Specified participants who permanently discontinue injectable study product use will be followed 
for an additional 48 weeks to assess long-term safety and washout PK of the study products. 
Participants will enter into the LSFU visit schedule at different timepoints:  
• 
Premature permanent discontinuation of injectable study product during Step 2 or Step 4  
• 
Completion of the Cohort 1 Step 2 Week 16 visit 
• 
Completion of the Cohort 2 Step 4 Week 96 study visit but not continuing to receive 
injectable CAB LA + RPV LA external to the protocol 
• 
Female participants who discontinue study product use (either oral or injectable study 
product) due to pregnancy during Steps 1-4 
 


 
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LSFU visits will be scheduled approximately 8, 24, 36, and 48 weeks after the last injection, after 
which participants will exit the study.  For Cohort 1 Step 2 participants who complete their Week 
16 visit, their next scheduled visit will be the LSFU Week 24 Visit (i.e. their LSFU Week 8 visit 
is skipped). Cohort 1 Step 2 participants who enroll to Cohort 2 Step 3 but are then not eligible to 
progress to Cohort 2 Step 4 will be followed per the LSFU visit schedule, also based on the date 
of their last study product injection (i.e. their Cohort 1 Step 2 Week 8 visit). Cohort 2 Step 3 
participants will resume (non-study provided) oral cART within 4 weeks of discontinuing oral 
study product. 
 
At the Week 96 visit, Cohort 2, Step 4 participants not continuing to receive injectable CAB LA 
+ RPV LA (external to the protocol) will be followed per the LSFU visit schedule. All Cohort 2, 
Step 4 participants following the LSFU visit schedule will complete all LSFU study visits, 
including the LSFU Week 8 study visit.  Cohort 2 Step 4 participants will resume (non-study 
provided) oral cART at 8 weeks (±7 days) of discontinuing injectable study products. See Section 
8.8 for criteria for premature permanent discontinuation of study product. 
 
Female participants who permanently discontinue study product use (either oral or injectable 
study product) due to pregnancy during Steps 1-4 will be followed for an additional 48 weeks 
based on their confirmed positive pregnancy test result, per the LSFU visit schedule. For female 
participants who become pregnant during LSFU visits, the LSFU visits will continue as scheduled 
and not restart. Further details on participant management of contraception and pregnancy is 
located in Sections 6.13 and 8.3. 
 
Participant safety will be monitored, and samples for antiviral activity and PK will be collected, 
at visits as specified in Section 6; blood volume ranges are provided in Appendix I-C. 
Acceptability and tolerability will be assessed with all participants completing quantitative 
questionnaires, and a sub-set of participants also completing in-depth qualitative interviews.  
 
 
4 
STUDY POPULATION 
 
This study will be conducted among approximately 155 HIV-infected adolescents, and up to 60 
parents/caregivers of study participants. Inclusion and exclusion criteria for each of the study 
populations are provided in Sections 4.1- 4.5 below.  
 
Adolescents will be enrolled into either Cohort 1 Step 1 or Cohort 2 Step 3. Adolescents who 
previously participated in Cohort 1 Step 2 and are continuing study participation by enrolling into 
Cohort 2, must meet the same eligibility criteria as other participants enrolling directly into 
Cohort 2 Step 3, unless otherwise noted.  
 
The study-specific approach to recruitment, screening, and enrollment is described in Section 4.7. 
Considerations related to participant retention and withdrawal/termination from the study are 
provided in Sections 4.8 and 8.8, respectively. 
 
4.1 
Inclusion Criteria: Cohort 1 Step 1 and Cohort 2 Step 3 
 
All the following criteria must be met for inclusion of any adolescent participant in Step 1 of 
Cohort 1, or in Step 3 of Cohort 2, unless otherwise noted: 
 
4.1.1 
At enrollment, 12 to < 18 years of age 
 


 
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Note: For Cohort 1 Step 2 participants, age will not be exclusionary for enrollment into 
Cohort 2 Step 3, if otherwise eligible. 
 
4.1.2 
If not of legal age or otherwise not able to provide independent informed consent as 
determined by site SOPs and consistent with site institutional review board (IRB)/ ethics 
committee (EC) policies and procedures:  Parent or legal guardian is willing and able to 
provide written informed consent for study participation and potential participant is 
willing and able to provide written assent for study participation 
 
If of legal age or otherwise able to provide independent informed consent as determined 
by site SOPs and consistent with site IRB/EC policies and procedures:  Willing and able 
to provide written informed consent for study participation 
 
4.1.3 
At enrollment, body weight ≥ 35 kg (77 lbs.) 
 
Note: For Cohort 1 Step 2 participants, body weight will not be exclusionary for 
enrollment into Cohort 2 Step 3, if otherwise eligible. 
 
4.1.4 
For Cohort 1, at enrollment, body mass index (BMI) < 31.5 kg/m2 
 
4.1.5 
At enrollment, willing and able to comply with the study visit schedule and other study 
requirements, as determined by the site investigator or designee 
 
4.1.6 
Confirmed HIV-1-infection based on documented testing of two samples collected from 
two separate blood collection tubes per Sample #1 and Sample #2 requirements, at 
different time points. Test results may be obtained from medical records or from testing 
performed during the study screening period:  
 
• 
For results obtained from medical records, adequate source documentation, including 
the date of specimen collection, date of testing, name of test/assay performed, and 
test result, must be available in study records prior to study entry. Requirements 
related to laboratory operations (e.g., CLIA, GCLP, or VQA) and related to 
regulatory authority approvals (e.g., FDA) do not apply to results obtained from 
medical records.  
• 
If adequate source documentation is not available, Sample #1 and/or Sample #2 
should be collected during the study screening period and tested in the study site’s 
designated testing laboratory. At least one of the tests used to confirm infection must 
be performed in CLIA- certified or equivalent laboratory (for US sites) or in a 
DAIDS-monitored laboratory that is GCLP compliant and participates in an approved 
external quality assurance proficiency testing program (for non-US sites). 
 
Sample #1 may be tested using any of the following: 
• 
Two rapid antibody tests from different manufacturers or based on different 
principles and epitopes; combination antigen-antibody-based rapid tests may be used. 
• 
One enzyme immunoassay (EIA) OR Western Blot OR immunofluorescence OR 
chemiluminescence 
• 
One HIV DNA polymerase chain reaction (PCR) 
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay) 
• 
One qualitative HIV RNA PCR 
• 
One HIV total nucleic acid test 


 
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Sample #2 may be tested using any of the following: 
• 
Rapid antibody test. If this option is used in combination with two rapid tests for 
Sample #1, at least one of the three rapid tests must be FDA-approved, and the third 
rapid test must be from a third manufacturer or based on a third principle or epitope. 
• 
One EIA OR Western Blot OR immunofluorescence OR chemiluminescence 
• 
One HIV DNA PCR 
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay) 
• 
One qualitative HIV RNA PCR 
• 
One HIV total nucleic acid test 
 
All study-specific samples tested to determine HIV status must be whole blood, serum, or 
plasma. Testing methods and algorithms must be approved for each site by the 
IMPAACT Laboratory Center (for NIAID-funded sites) or Westat (for NICHD-funded 
sites). All testing methods should be FDA-approved, if available. If both samples are 
tested using antibody tests, at least one of the samples must be tested in a laboratory that 
operates according to Good Clinical Laboratory Practice (GCLP) guidelines and 
participates in an appropriate external quality assurance program. If nucleic acid testing is 
used, at least one test must be performed in a Clinical Laboratory Improvement 
Amendments CLIA-certified (US sites) laboratory or a VQA-certified laboratory (non-
US sites). For tests performed in other (non-GCLP-compliant) settings, adequate source 
documentation including the date of specimen collection, date of testing, name of 
test/assay performed, and test result must be available. 
 
4.1.7 
For at least 3 consecutive months (defined as 90 consecutive days) prior to screening, and 
prior to enrollment, has been on stable unchanged cART consisting of 2 or more drugs 
from 2 or more classes of antiretroviral drugs, ascertainment of this criterion may be 
based on parent or guardian report only, but available medical records should also be 
reviewed in relation to this criterion. 
 
Note: Participants undergoing dose modifications to their antiretroviral regimen for 
growth or who are switching medication formulation(s) are considered to be on a stable 
cART. 
 
4.1.8 
Has at least one documented plasma HIV-1 RNA result less than the lower limit of 
detection of the assay from a specimen collected in the 6 to 12 months (defined as 180 to 
365 days) prior to entry 
 
OR 
 
Has at least one documented plasma HIV-1 RNA result less than the lower limit of 
detection of the assay from a specimen less than 6 months (defined as within 179 days) 
prior to entry and at least one documented plasma HIV-1 RNA result less than the lower 
limit of detection of the assay from a specimen collected in the 12-18 months (defined as 
365 to 545 days) prior to entry. 
 


 
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4.1.9 
At screening, has Grade 2 or lower of all the following laboratory test results: 
• 
ALT (u/l) 
• 
Lipase (u/l) 
• 
Estimated creatinine clearance (CrCl; Schwartz formula mL/min/1.73m2)  
• 
Platelets (cells/mm3) 
• 
Hemoglobin (g/dL) 
 
See Section 7.3.3 for guidance on severity grading. Laboratory tests may be repeated 
during the study screening period, with the latest result used for eligibility determination. 
 
4.1.10 For participants enrolling into Cohort 1, Step 1 or Cohort 2, Step 3 and on an atazanavir-
containing (ATV) cART regimen, at screening, has total bilirubin ≤ 1.5 mg/dL or normal 
direct bilirubin 
 
4.1.11 At screening, has documented plasma HIV-1 RNA < 50 copies/mL 
 
4.1.12 At screening, mean value of QTc interval (automated machine readout or calculated 
using either Bazett or Fridericia) on ECG performed in triplicate, < 500 msec.  
 
4.1.13 For females, has a negative (blood or urine) hCG laboratory test result at entry 
 
 
4.1.14 For females of childbearing potential, at entry, currently using at least one allowable 
effective method of contraception, and agrees to use at least one allowable effective 
method of contraception throughout study participation, for at least 30 days after 
discontinuation of oral study product, and for at least 48 weeks after discontinuation of 
CAB LA and/or RPV LA, and intending to delay any planned pregnancies until 30 days 
after last oral study product use or until 48 weeks after last injectable study product use.   
 
Note: See Section 6.13 for details regarding contraceptive counseling, a list of the 
allowed effective contraceptive methods for this study, and the definition of a female of 
childbearing potential.  Hormonal-based contraceptives must have been initiated within 
the prescribed time, per the respective contraceptive method, to be considered effective at 
the time of Entry.  The site IoR or designee is responsible for ensuring that 
the contraceptive is used in accordance with the approved product label, and counseling 
participants on proper use of chosen methods of contraception, including barrier methods.  
 
4.1.15 For Cohort 1 participants enrolling to Cohort 2, have completed all scheduled product 
injections and completed Week 16 visit in Cohort 1 Step 2 
 
Note: Cohort 1 participants unable to receive study product injections or complete the 
Week 16 visit due to site limitations or restrictions in response to COVID-19 or 
circumstances beyond the control of the participant/participant’s family and not raising 
concerns of future adherence to protocol requirements are exempt from this inclusion 
criterion. 
 
4.2 
Exclusion Criteria: Cohort 1 Step 1, or Cohort 2 Step 3 
 
Adolescents will be excluded from the study if any of the following are identified during the 
screening period:  
 


 
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4.2.1 
Within 6 months (defined as within 179 days) prior to entry, two consecutive documented 
HIV-1 RNA values greater than the lower limit of detection of the assay 
 
Note: Unconfirmed virologic HIV-1 RNA value of greater than the lower limit of 
detection of the assay (transient detectable viremia, or “blip”) prior to screening is not 
exclusionary. 
 
4.2.2 
For Cohort 1 participants enrolling to Cohort 2, Step 3, occurrence of any Grade 3 or 
higher adverse event assessed as related to study product or permanent discontinuation of 
study product due to an adverse event of any grade assessed as related to study product, 
during participation in Cohort 1 (including any long-term safety and washout PK follow-
up visits).  
 
4.2.3 
For participants enrolling to Cohort 1 Step 1, based on available medical records, 
currently on either a cART regimen containing both a PI and an INSTI, or a cART 
regimen containing both an INSTI and a NNRTI. 
 
4.2.4 
As determined by the IoR or designee, and based on available medical records, known or 
suspected resistance to RPV 
 
4.2.5 
As determined by the IoR or designee based on available medical records, known or 
suspected resistance to INSTIs 
 
4.2.6 
History of congestive heart failure, symptomatic arrhythmia, or any clinically significant 
cardiac disease, as determined by the IoR or designee based on available medical records 
 
4.2.7 
At entry, known active tuberculosis infection, as determined by the Investigator of 
Record (IoR) or designee based on available medical records 
 
4.2.8 
Known hepatitis B or hepatitis C infection, as determined by the IoR or designee based 
on available medical records 
 
4.2.9 
Clinically significant hepatic disease, as determined by the IoR or designee based on 
available medical records 
 
4.2.10 Current or anticipated need for chronic anti-coagulation, as determined by the IoR or 
designee, based on available medical records 
 
4.2.11 History of sensitivity to heparin or heparin-induced thrombocytopenia, as determined by 
the IoR or designee, based on available medical records  
 
4.2.12 History of known or suspected bleeding disorder including history of prolonged bleeding, 
as determined by the IoR or designee, based on available medical records 
 
4.2.13 Known or suspected allergy to study product components 
 
4.2.14 More than one seizure within one year (defined as within 365 days) prior to entry, or 
unstable or poorly controlled seizure disorder, as determined by the IoR or designee, 
based on available medical records.  
 


 
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4.2.15 At entry, participant is receiving (or has received in the last 7 days) any disallowed 
medication listed in Section 5.7.  
 
4.2.16 Current inflammatory skin condition that compromises the safety of intramuscular 
injections as determined by the IoR or designee.  
 
4.2.17 Has a tattoo or other dermatological condition overlying the buttock region which, in the 
opinion of the IoR or designee, may interfere with interpretation of injection site 
reactions 
 
4.2.18 Surgically‐placed, or planned, buttock implants, per self‐report 
 
4.2.19 For females, lactating (per self-report and/or parent/guardian report) at entry 
 
4.2.20 Enrolled in another clinical trial of an investigational agent, device, or vaccine  
 
4.2.21 Any other condition or social circumstance situation that, in the opinion of the IoR or 
designee, would make study participation unsafe, complicate interpretation of study 
outcome data, or otherwise interfere with achieving the study objectives 
 
4.3 
Inclusion/Exclusion Criteria, Step 2 (Cohort 1 Progression Criteria, Step 1 to Step 2)  
 
Cohort 1 Step 1 participants will be assessed for eligibility to progress from the oral lead-in phase 
(Step 1) to the injection phase (Step 2) primarily based on the safety assessments from the Cohort 
1 Step 1 Week 4a study visit. Clinical assessments conducted prior to administering the first 
injection at the Week 4b visit will also be used to confirm eligibility to receive the injectable 
study product. See Sections 6.3.3and 6.3.4 for Week 4a and Week 4b visit scheduling, order of 
procedures, and visit windows, respectively. 
 
All of the following criteria must be met in order for participants to be included in Cohort 1 Step 
2: 
 
4.3.1 
Currently enrolled in Cohort 1, Step 1 
 
4.3.2 
At Cohort 1 Step 1 Week 4a study visit, or from confirmatory repeat testing of Cohort 1 
Step 1 Week 4a study visit laboratory tests, has Grade 2 or lower of all the following 
laboratory test results: 
• 
ALT (u/l) 
• 
Lipase (u/l)  
• 
Estimated creatinine clearance (CrCl; Schwartz formula mL/min/1.73m2)  
• 
Platelets (cells/mm3) 
• 
Hemoglobin (g/dL) 
 
Note: For a Grade 2 ALT test result from this visit, refer to Section 8.1.5 for required 
participant management. Abnormal laboratory test result values from the Week 4a visit 
may be repeated within the target visit window, and if confirmatory testing results in 
Grade 2 or lower, the participant may be eligible to continue onto the injection phase, 
should all other eligibility criteria be met. 
 


 
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4.3.3 
For females, at Cohort 1 Step 1 Week 4b study visit, has a negative hCG laboratory test 
result 
 
4.3.4 
Assessed by the IoR or designee as sufficiently adherent in Step 1 to permit an adequate 
evaluation of safety and tolerability as part of the oral lead-in phase prior to entry into the 
injection phase 
 
Participants who meet any of the following criteria will be excluded from Cohort 1 Step 2:  
 
4.3.5 
Has permanently discontinued oral study product 
 
4.3.6 
Occurrence of any grade 3 or higher adverse event assessed as related to study product 
during participation in Step 1 
 
4.3.7 
Any other condition or social circumstance that, in the opinion of the IoR or designee, 
would make study participation unsafe, complicate interpretation of study outcome data, 
or otherwise interfere with achieving the study objectives. 
 
4.4 
Inclusion/Exclusion Criteria, Step 4 (Cohort 2 Progression Criteria, Step 3 to Step 4)  
 
Cohort 2 Step 3 participants will be assessed for eligibility to progress from the oral lead-in phase 
(Step 3) to the injection phase (Step 4) primarily based on the safety assessments from the Cohort 
2 Step 3 Week 4a study visit. Clinical assessments conducted prior to administering the first 
injection at the Week 4b visit will also be used to confirm eligibility to receive the injectable 
study products. See Sections 6.4.3 and 6.4.4 for Week 4a and Week 4b visit scheduling, order of 
procedures, and target visit windows, respectively. 
 
All of the following criteria must be met in order for participants to be included in Cohort 2 Step 
4: 
 
4.4.1 
Currently enrolled in Cohort 2, Step 3 
 
4.4.2 
At Cohort 2 Step 3 Week 4a study visit, or from confirmatory repeat testing of Cohort 2 
Step 3 Week 4a study visit laboratory tests, has Grade 2 or lower of the following 
laboratory test results: 
• 
ALT (u/l) 
• 
Lipase (u/l)  
• 
Estimated creatinine clearance (CrCl; Schwartz formula mL/min/1.73m2)  
• 
Platelets (cells/mm3) 
• 
Hemoglobin (g/dL) 
 
Note: For a Grade 2 ALT test result from this visit, refer to Section 8.1.5 for required 
participant management. Abnormal laboratory test result values from the Week 4a visit 
may be repeated, within the target visit window, and if confirmatory testing results in 
Grade 2 or lower, the participant may be eligible to continue onto the injection phase, 
should all other eligibility criteria be met. 
 
4.4.3 
For females, at Cohort 2 Step 3 Week 4b study visit, has a negative hCG laboratory test 
result 
 


 
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4.4.4 
Assessed by the IoR or designee as sufficiently adherent in Step 3 to permit an adequate 
evaluation of safety and tolerability as part of the oral lead-in phase prior to entry into the 
injection phase 
 
Participants who meet any of the following criteria will be excluded from Cohort 2 Step 4:  
 
4.4.5 
Has permanently discontinued oral study products 
 
4.4.6 
Occurrence of any grade 3 or higher adverse event assessed as related to study product 
during participation in Cohort 2, Step 3 
 
4.4.7 
Any other condition or social circumstance that, in the opinion of the IoR or designee, 
would make study participation unsafe, complicate interpretation of study outcome data, 
or otherwise interfere with achieving the study objectives. 
 
4.5 
Inclusion/Exclusion Criteria: Parents/Caregivers 
 
For U.S. sites only, selected parents or caregivers of adolescents may be enrolled to complete 
qualitative phone interviews. See Appendix V-A for more information regarding the selection 
process, and coordination of scheduling the interviews. All of the following criteria must be met 
for the parent/caregiver to be enrolled: 
 
4.5.1 
Selected by the protocol team for participation in the study 
 
4.5.2 
Willing and able to provide informed (verbal or written) consent for study participation 
 
4.5.3 
Per the adolescent participant, has knowledge of how the adolescent participant tolerated 
the study product, and lives with or has regular supportive contact with the adolescent 
participant  
 
4.5.4 
Per parent/caregiver self-report, has knowledge of how the participant tolerated the study 
product, and lives with or has regular supportive contact with the adolescent participant 
 
4.5.5 
Willing and able to complete interview in English by phone 
 
Parents and/or caregivers of participants who meet the following criterion will be excluded from 
study participation:  
 
4.5.6 
Any condition or social circumstance that, in the opinion of the IoR or designee, would 
make study participation unsafe for either the parent/caregiver or the adolescent 
participant, complicate interpretation of study outcome data, or otherwise interfere with 
achieving the study objectives. 
 
4.6 
Co-Enrollment Considerations 
 
Co-enrollment in observational or other studies not involving an investigational agent, device, or 
vaccine may be permitted although careful consideration must be given to visit burden, blood 
draw volumes, and interpretation of outcome data across studies. Requests for co-enrollment must 
be approved in advance by both study teams. Requests for such approval or questions related to 
co-enrollment should be emailed to the IMPAACT 2017 Clinical Management Committee 
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4.7 
Recruitment, Screening, and Enrollment Process 
 
This section provides a description of the recruitment methods, screening and enrollment 
processes, and the definition of enrollment for the adolescent participants.  
 
See Appendix V-A for recruitment, eligibility confirmation, and enrollment processes, including 
the definition of enrollment, for parents/caregivers to take part in a single qualitative phone 
interview. 
 
4.7.1 
Recruitment and Screening of Cohort 1 (Step 1) and Cohort 2 (Step 3) Participants 
 
Recruitment methods for this study may vary across sites. All participants must be 12 to less than 
18 years of age at the time of enrollment (with the exception of adolescents who previously 
participated in Cohort 1 Step 2 and continuing into Cohort 2, as noted in Section 4.1.1 above). 
Recruitment of participants, for both Cohort 1 and Cohort 2, is expected to rely on current 
patients being seen at a study clinic or from active identification and referral of HIV-1-infected 
children and adolescents who are ART-experienced and virologically suppressed; participants 
may be perinatally or behaviorally infected. 
 
Any advertising materials must undergo approval by each participating site’s IRB/EC. Sites are 
encouraged to solicit input and feedback on recruitment materials from their local Community 
Advisory Board, particularly any adolescent Community Advisory Board members.  
 
Upon identification of a potentially eligible participant, study staff will provide information about 
the study to the parent or guardian and/or the potential participant (as applicable). Each parent or 
guardian and/or potential participant (as applicable) who expresses interest in learning more about 
the study will be provided additional information, education, and counseling as part of the study 
informed consent process. The process will include detailed review of the study informed consent 
and assent forms (as applicable), time to address any questions or concerns the potential 
participant, parent, or guardian may have, and an assessment of understanding, before proceeding 
to informed consent and assent decisions. Informed consent and assent processes will be fully 
documented, consistent with the DAIDS policies referenced in Section 12.2. Refer to Section 
14.3 for further information on informed consent procedures for this study.  
 
Each site must establish standard operating procedures (SOPs) for eligibility determination that 
describe where and when screening procedures will be performed; roles and responsibilities for 
performing the required procedures; roles and responsibilities for assessing and confirming 
eligibility; and procedures for documenting the process, taking into consideration the required 
timing of enrollment. Sites are encouraged to minimize the time from screening to enrollment.  
 
Eligibility screening will be initiated after written informed consent and assent (as applicable) is 
provided. See Section 4.7.2 below for use of the Subject Enrollment System (SES) to assist in 
tracking of the screening process and obtaining a study-specific screening number. Screening will 
include confirmatory HIV-1 testing (if needed) and assessment of other entry criteria. If at any 
time it is determined that an individual is not eligible for the study, or that study participation may 
not be feasible or in the participant’s best interest, the eligibility screening process will be 
discontinued; these individuals should be actively referred to non-study sources of care. 
Screening assessments, unless otherwise noted (see Section 6.2), must be completed within 28 
days prior to entry; re-screening is permitted one time per Cohort. For adolescents who are 
screened and found to be ineligible for the study, or who do not enroll in the study for any reason, 


 
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limited demographic information and reasons for non-enrollment will be entered into electronic 
case report forms (eCRFs). Refer to Section 9.5 for more information on monitoring participant 
accrual in this study. 
 
4.7.2 
Enrollment Process for Cohort 1 (Step 1) and Cohort 2 (Step 3) Participants 
 
Adolescents who are found to meet the study eligibility criteria will be enrolled into the 
applicable Cohort and Step. Screening procedures may be performed on the day of enrollment; 
however, all required screening laboratory test results must be available for eligibility 
determination prior to enrollment.  
 
The IMPAACT Data Management Center’s (DMC) SES will be used to assist with tracking the 
screening and enrollment process. When informed consent and assent (as applicable) are obtained 
for the adolescent, participant identification numbers (PIDs) will be assigned and a study-specific 
screening number will be obtained through the SES. For adolescents found to be eligible, 
enrollment into the study or into a subsequent step will occur upon successful entry of required 
eligibility data into the SES. Successful entry into the SES will generate a study identification 
number (SID) and the prescribing information for the Cohort and Step in which the participant 
has been enrolled.  
 
4.8 
Participant Retention 
 
Once a participant is enrolled in this study, study staff will make every effort to retain him or her 
for the protocol-specified duration of follow-up, thereby maximizing statistical power and 
minimizing potential biases associated with loss to follow-up. Each site must establish and 
implement SOPs that target retention rates that are sufficient to allow the primary study outcomes 
to be reliably estimated (a maximum 10% loss to follow-up is assumed in sample size 
calculations). Additional guidance regarding special considerations for retaining adolescents and 
particularly Cohort 2 participants no longer on pre-study cART regimen, are provided in the 
IMPAACT 2017 MOP. Refer to Section 9.5 for more information on monitoring participant 
retention in this study. 
 
 
5 
STUDY PRODUCT 
 
Site pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS Clinical 
Trials Networks for standard pharmacy operations. Refer to Figure 1, Figure 2, Figure 3, and 
Figure 4 for an overview of the cohorts, and study design, and to the package inserts and 
investigator’s brochures (IBs) for further information about the study products. 
 
5.1 
Study Product Regimen and Administration 
 
Study participants will be assigned to receive (open-label) either CAB (oral CAB followed by 
intramuscular CAB LA) or RPV (oral RPV followed by intramuscular RPV LA) in Cohort 1. 
Study arm assignments in Cohort 1 will be based on participants’ pre-study cART regimen (as 
described in Section 5.1.1 below). 
 
In Cohort 2, study participants will be assigned to receive (open-label) both CAB and RPV (oral 
CAB + oral RPV, followed by intramuscular CAB LA + intramuscular RPV LA). 
 


 
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5.1.1 
Cohort 1 
 
Participants in Cohort 1 will be assigned to Cohort 1C (oral CAB followed by intramuscular CAB 
LA) or Cohort 1R (oral RPV followed by intramuscular RPV LA) based on their pre-study cART 
regimen:   
 
• 
Participants on a PI-based and/or NNRTI-based cART regimen will be assigned to Cohort 1C 
• 
Participants on a non-boosted INSTI-based cART regimen will be assigned to Cohort 1R 
 
All participants in Cohort 1 will continue their pre-study cART regimen and receive either CAB 
(Cohort 1C) or RPV (Cohort 1R) as shown in Table 5. Participants enrolled under protocol 
Version 2.0 received the Q4W dosing regimen presented in that version; refer to Section 1.3 for 
additional details regarding protocol version history. 
 
Table 5. Cohort 1: Study Product Regimen and Administration 
Cohort 
Step 
Study Product Regimen and Administration (with non-study provided 
cART regimen) 
1C 
1 
CAB administered orally as one 30 mg tablet once daily, beginning at 
the Entry visit, for 4-6 weeks (up to 43 doses), with or without food.  
2 
CAB LA administered as one IM injection in the gluteus medius at 
Week 4b (Step 2 Entry) study visit (600 mg/3 mL), and at Week 8 
(600 mg/3 mL). 
1R 
 
1 
RPV administered orally as one 25 mg tablet once daily, beginning at 
the Entry visit, for 4-6 weeks (up to 43 doses), with a meal. 
2 
RPV LA administered as one IM injection in the gluteus medius at 
Week 4b (Step 2 Entry) study visit (900 mg/3 mL), and at Week 8 
(900 mg/3 mL). 
 
Study participants are generally expected to receive the first dose of intramuscular CAB LA 
(Cohort 1C) or intramuscular RPV LA (Cohort 1R) on the same day as the last dose of oral CAB 
dose or oral RPV, respectively (at the Week 4b Step 2 Entry visit). 
 
5.1.2 
Cohort 2 
 
All participants in Cohort 2 will discontinue their pre-study cART regimen and receive both CAB 
and RPV as shown in Table 6. Cohort 2 doses may change based on experience in Cohort 1, in 
which case, the new doses will be specified in a letter of amendment or full amendment. 
 


 
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Table 6. Cohort 2: Study Product Regimen and Administration 
Cohort 
Step 
Study Product Regimen and Administration (without cART regimen) 
2 
3 
CAB administered orally as one 30 mg tablet once daily AND RPV 
administered orally as one 25 mg tablet once daily, taken together and 
with a meal, beginning at the Entry visit for 4-6 weeks (up to 43 doses 
of each). 
4 
 
First and second set of injections: CAB LA administered as one 600 
mg (3 mL) IM injection in the gluteus medius AND RPV LA 
administered as one 900 mg (3 mL) IM injection in the gluteus 
medius, at Week 4b (Step 4 Entry) and at Week 8.  
 
Subsequent injections: starting at the Week 16 visit, CAB LA 
administered as a 600 mg (3 mL) IM injection in the gluteus medius 
muscle AND RPV LA administered as a 900 mg (3 mL) IM injection 
in the gluteus medius, every eight weeks through Week 96. 
 
 
Study participants are generally expected to receive the first doses of intramuscular CAB LA and 
intramuscular RPV LA on the same day as the last doses of oral CAB and oral RPV (at the Week 
4b Step 4 Entry visit).  
 
5.1.3 
Dispensing of Oral Study Product (Cohort 1 Step 1, or Cohort 2 Step 3) 
 
A 30-day supply of oral study product will be provided at the Entry visit (Cohort 1 and Cohort 2). 
Cohort 1 participants will be provided a 30-day supply of only the oral study product to which 
they are assigned, whereas Cohort 2 participants will be provided a 30-day supply of each oral 
study product. 
 
An additional 30-day supply of oral study product may be dispensed at the Week 2 or Week 4a 
visits (Cohort 1 and Cohort 2) to ensure sufficient coverage for daily use through the participant’s 
scheduled Week 4b visit and their first study product injection. See Sections 6.3.4 and 6.4.4 for 
more details on the Cohort 1 Step 2 Week 4b visit, and Cohort 2 Step 4 Week 4b visit, 
respectively. 
 
5.1.4 
Short-term Oral Bridging for Cohort 2 Step 4 Participants 
 
In exceptional circumstances and following consultation with the CMC, to address planned 
missed CAB LA + RPV LA injection visits, sites may provide daily oral CAB 30 mg + 
RPV 25 mg as a short-term bridging strategy for Cohort 2 Step 4 participants who will miss a 
scheduled injection.  Daily oral CAB 30 mg + RPV 25 mg for short-term oral bridging may be 
dispensed to study staff for providing to a participant off-site.  Supply of oral study product for 
short-term oral bridging should ensure sufficient coverage for daily use until the participant can 
resume study product injections. The daily oral CAB 30 mg + RPV 25 mg bridging regimen is 
ideally to begin on the same target visit date (or within the same target visit window) as that of 
the missed injection visit.  The last dose of the daily oral bridging regimen should be taken on the 
same day and prior to resuming injectable study product.   
 
The CMC must be consulted prior to resuming study product injections.  Cohort 2 Step 4 
participants may be required to have interim injection visits upon resuming the study product 


 
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injections to appropriately reinitiate the dosing regimen or to realign to the original injection visit 
dosing schedule. 
  
See Section 6.9 for required procedures prior to dispensing oral study products or administering 
study product injections. See Section 6.1 for further guidance on scheduling study visits, and 
Section 6.4.14 for interim injection visits. 
 
5.1.5 
Preparation and Administration of Injections 
 
The Pharmacist of Record must be proficient in the preparation of products requiring aseptic 
technique under a pharmacy biological safety cabinet/isolator. Local regulations and site 
institutional policies and procedures for use of protective equipment, such as gloves, gowns, and 
masks, and safety glasses, must be followed.  
 
All injections will be administered using standard IM injection technique in the gluteus medius. 
The following information must be source documented and entered into eCRFs with each 
injection of study product (e.g. Cohort 2 Step 4 participants will have information entered for 
CAB LA, and information entered for RPV LA): 
• 
Location (which side) of administration 
• 
Needle length and needle gauge used  
• 
Volume of injectable study product administered  
 
Whenever possible, for Cohort 2 Step 4 participants, CAB LA is to be administered in the 
contralateral gluteus medius muscle from the RPV LA. However, if the participant prefers, 
injections can both be administered on the same side with the injection sites at least 2cm apart. In 
these instances, site staff must source document where on the gluteus medius muscle each 
injection has been administered for assessing adverse reactions to the injections.  
 
Injectable study product must be administered within the respective study visit windows or per 
CMC guidance (for Cohort 2 Step 4 participants resuming injections following short-term oral 
bridging); see Section 6.1 for visit window requirements.  
 
Refer to Appendix VI for detailed instructions on the preparation of injectable study products, 
and to the IMPAACT 2017 MOP for instructions on the administration of the study products. 
 
5.2 
Study Product Formulation 
 
5.2.1 
Oral CAB 
 
CAB 30 mg tablets are formulated as white to almost white oval-shaped film-coated tablets for 
oral administration. Cabotegravir 30 mg tablets may also be debossed with the code “SV CTV” 
on one face. The tablets are packaged in high density polyethylene (HDPE) bottles with child-
resistant closures that include induction seal liners. The bottles contain 30 tablets and a desiccant. 
The tablets should be stored up to 30° C (86° F), in the original container with the desiccant, and 
protected from moisture. 
 
5.2.2 
Oral RPV 
 
RPV 25 mg tablets are formulated as white to off-white, film-coated, round, biconvex tablets for 
oral administration. Each tablet is debossed with “TMC” on one side and “25” on the other side. 


 
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Tablets are packaged in bottles containing 30 tablets. Tablets should be stored in their original 
bottles to protect from light. The tablets should be stored at 25° C (77° F) with excursions 
permitted to 15°-30°C (59°-86°F). Further information on the study product is available in the 
EDURANT® Prescribing Information. 
 
5.2.3 
Injectable CAB LA 
 
CAB LA is formulated as a sterile white to slightly pink suspension containing 200mg/mL of 
cabotegravir free acid for administration by IM injection. The product is packaged in a glass vial 
with a grey stopper and aluminum seal with a plastic flip-off lid. Each vial is for single use and 
contains a nominal fill volume of 2 mL (400 mg of CAB LA) or 3 mL (600 mg of CAB LA). 
Dilution is not required prior to administration. Vials should be stored up to 30° C (86° F); do not 
freeze.  
 
5.2.4 
Injectable RPV LA 
 
RPV LA is formulated as a sterile white suspension containing 300 mg/mL of RPV free base for 
administration by IM injection. The product is packaged in single-use vials, containing a nominal 
fill volume of 2 mL (600 mg of RPV LA) or 3 mL (900 mg of RPV LA). Dilution is not required 
prior to administration. Vials should be stored refrigerated at 2° to 8° C (36° to 46° F); protect 
from light and do not freeze. 
 
5.2.5 
Study Product Regulatory Approval Status 
 
The following study products being tested in this study are investigational and not yet approved 
by the US FDA for the treatment or prevention of HIV-1 infection: oral cabotegravir, injectable 
cabotegravir long-acting, injectable rilpivirine long-acting. Further information on the study 
product is available in the Investigator’s Brochure, which will be provided by the DAIDS 
Regulatory Support Center (RSC). 
The oral rilpivirine study product being used in this study is approved by the US FDA for the 
treatment of HIV-1 infection in patients ages 12 years and older. Further information on the study 
product is available in the EDURANT® Prescribing Information. 
 
5.3 
Study Product Supply 
 
CAB and CAB LA (oral and injectable formulations), and RPV and RPV LA (oral and injectable 
formulations) will be supplied by ViiV Healthcare. 
 
The above-listed study products will be made available to study sites through the National 
Institute of Allergy and Infectious Diseases (NIAID) Clinical Research Products Management 
Center (CRPMC). Upon successful completion of protocol registration procedures, these study 
products may be obtained by the site pharmacist by following instructions provided in the 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks.  
 
5.4 
Study Product Accountability 
 
Site pharmacists must maintain complete records of all study products received from the CRPMC 
and subsequently dispensed to study participants. All study products must be stored in the 
pharmacy.  
 


 
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5.5 
Final Disposition of Study Product 
 
 
Participants who temporarily or permanently discontinue oral study product during Step 1 or Step 
3, or during oral bridging in Step 4, will be instructed to return all oral study products to the site 
clinic as soon as possible. 
 
All unused study products remaining at US sites after the study is completed or terminated will be 
returned to the CRPMC (unless otherwise directed by DAIDS). At non-US sites, any remaining 
unused study products will be quarantined for destruction. Study products may also be returned to 
the CRPMC for other reasons, as requested by DAIDS. Site pharmacists will follow the relevant 
instructions for return or destruction of unused study products provided in the Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks.  
 
5.6 
Concomitant Medications 
 
All concomitant medications received by enrolled participants must be source documented as part 
of the medical and medication histories obtained at each study visit. This includes prescription 
and non-prescription (over-the-counter) medications; vaccines and other preventive medications; 
therapeutic foods and nutritional supplements; and alternative, complementary, and traditional 
medications and preparations. All concomitant medications (except herbal or traditional) are to be 
entered into eCRFs, per Section 6.10.  
 
cART, other than CAB and RPV (oral and injectable formulations), will not be provided through  
the study. 
 
5.7 
Prohibited Medications  
 
Any study participant who requires a medication considered prohibited while on study product 
must have the study product held or permanently discontinued. A list of prohibited medications 
may be found on the IMPAACT 2017 protocol-specific website 
(http://impaactnetwork.org/studies/IMPAACT2017.asp). Upon identification of the need for a 
prohibited medication, the site investigator should consult the CMC for further guidance on study 
product management, and per Section 8.  
 
5.8 
Precautionary Medications  
 
A list of medications that should be used with caution while on study product may be found on 
the IMPAACT 2017 protocol-specific website. 
 
 
6 
STUDY VISITS AND PROCEDURES 
 
All visits and procedures must be performed at the approved clinical research site or approved 
associated facilities unless otherwise noted (specified visits or visit procedures may be conducted 
off-site; see Section 6.1.3). All visits and procedures must be documented in accordance with 
DAIDS policies for source documentation; refer to Section 12 for more information on data 
handling and record keeping. Refer to Section 7 for information on expedited adverse event 
(EAE) reporting, which may be required at any time during follow-up.  
 


 
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In addition to the protocol-specified procedures listed in this section, study staff may complete 
other tasks including but not limited to collecting, reviewing, and updating demographic and 
locator information; reviewing elements of informed consent and/or assent; scheduling telephone 
contacts and visits; providing instructions for contacting study staff between visits; providing visit 
reminders; and following up on missed visits. All such tasks should be conducted and 
documented consistent with site SOPs. Study staff should inform participants (or 
parents/guardians, if applicable) of clinically meaningful physical exam findings and laboratory 
test results, when available. See Section 14.9 for additional considerations of disclosing test 
results to the parents/guardians of adolescent participants.  
 
Information relating to study visit windows, split and interim visits, and off-site visits is described 
in Section 6.1, including additional considerations for scheduling injection visits. See Section 
6.4.14 for additional considerations for scheduling and conducting interim injection visits for 
Cohort 2 Step 4 participants following short-term oral bridging. Detailed information related to 
specific visits, such as target visit dates, individual visit windows, required procedures per 
scheduled visits, and further guidance for select procedures are presented in Sections 6.2-6.16. 
See Section 5.1.5 for source documentation and eCRF requirements for any study product 
injection. Procedures required to continue oral and injectable study product administration at 
scheduled follow-up visits are described in Section 6.9.  
 
PK sample collections are required at visits throughout Cohort 1, Cohort 2, and LSFU. All pre-
dose PK sample collections should be performed prior to and on the same day as administration 
of the specified study product. The date and time of each PK sample collection must be source 
documented and entered into eCRFs for all PK samples. Additional source documentation, eCRF 
requirements, and scheduling considerations for PK sample collections during Weeks 2, and 4b 
(for both Cohorts 1 and 2) are provided in the relevant visit sections below.    
 
Site staff collecting specimens for PK evaluations must prepare workspace and supplies with 
regards to protecting all PK specimens from light, as specified in the laboratory processing chart 
(LPC). As Cohort 2 participants will receive both CAB and RPV, the PK sample collection must 
be sufficient for the number of aliquots specified in the LPC for CAB and for RPV. Albumin 
(g/dL) will be obtained as part of blood collection for chemistries, but only at visits in which both 
chemistries and a PK sample are collected. See Section 6.16 for details on specimen collection 
considerations and processing, and Appendix I-A, Appendix I-B, and Appendix I-C for required 
blood volumes.  
 
For sites experiencing disruptions or limitations of usual operations due to COVID-19, 
operational guidance is provided in Appendix VII. All sites should follow applicable government, 
health authority, and institutional policies with respect to conduct of study visits and procedures, 
with utmost importance placed on the health and well-being of study participants and study staff. 
 
6.1 
Study Visit Windows, Split and Interim Visits, and Off-site Visits 
 
6.1.1 
Study Visit Windows and Injection Visit Spacing Requirements 
 
For follow-up study visits, a target visit date and a target visit window are specified. Study visits 
should be scheduled to occur on the respective target visit date. If it is not possible to conduct a 
visit on the respective target visit date, the visit may be scheduled within the target visit window.  
 


 
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For select non-injection visits, broader allowable visit windows are provided. If the participant is 
unable to attend the scheduled non-injection study visit on the target visit date or within the target 
window, the non-injection study visit may be conducted within the allowable window.  
 
For study product injection visits, target visit dates and target visit windows are provided and 
established based on the participant’s first study product injection administered for the applicable 
Step (the Step 2 Week 4b visit for Cohort 1, or the Step 4 Week 4b visit for Cohort 2). In addition 
to scheduling study product injection visits per the above, Cohort 2 Step 4 study product 
injections should be scheduled to occur and administered within each respective target visit 
window as follows: 
• 
For the Step 4 Week 8 injection, a minimum of 3 weeks (21 days) and a maximum of 4 
weeks and 3 days (31 days) from the Step 4 Week 4b injection. 
• 
For the Step 4 Week 16 injection, a minimum of 7 weeks (49 days) and a maximum of 8 
weeks and 3 days (59 days) from the Step 4 Week 8 injection. 
• 
For the Week 24 and all subsequent injections, a minimum of 7 weeks (49 days) and a 
maximum of 9 weeks (63 days) from the previous regularly scheduled injection. 
 
Depending on when the previous injection was administered within the previous target visit 
window, the minimum and maximum spacing requirements may impact the availability of a 
target visit window (including the target visit date).  Scheduled injection visits which do not occur 
within the target window are considered missed, and the CMC must be consulted regarding 
clinical considerations and study product management.  
 
Sites are expected to make every effort to schedule and conduct each study visit on the respective 
target visit date, or, when necessary, within the target visit window. Further guidance on 
scheduling study visits are provided in the IMPAACT 2017 MOP. 
 
6.1.2 
Split and Interim Visits 
 
All visit procedures specified to be performed at scheduled visits should ideally be performed on 
the same day. Unless otherwise noted, if it is not possible to conduct all visit procedures on the 
same day (e.g., if a participant must leave the clinical research site before all procedures can be 
performed), visits may be split, with procedures performed on more than one day within the 
target visit window or allowable visit window (if applicable). See Section 6.9 for required study 
visit procedures to be performed on the same day as and prior to administration of study product. 
 
Interim contacts and visits (those between regularly scheduled follow-up visits) may be 
performed at participant request or as deemed necessary by the site investigator or designee at 
any time during the study, and without prior approval from the CMC. Some interim visits may 
occur for administrative reasons or retention purposes. Interim visits at which no data are 
collected should be source documented but not entered into eCRFs. Other interim contacts and 
visits may occur in response to AEs experienced by study participants. When interim contacts or 
visits are completed in response to participant reports of adverse events, study staff will assess the 
reported event clinically, enter the event into eCRFs per Section 7.2, and provide or refer the 
participant to appropriate medical care. See Section 8 for participant management and specified 
AE management. 
 
For Cohort 2 Step 4 participants initiating short-term oral bridging, an interim visit may be 
conducted to dispense oral study products and conduct required procedures per Section 6.9.  See 
Section 5.1.4 for details regarding initiating short-term oral bridging and Section 6.1.3 below 
regarding conducting non-injection study visits at an off-site location. See Section 6.4.14 for 


 
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interim injection visit scheduling and considerations for Cohort 2 Step 4 participants resuming 
study product injections following short-term oral bridging. 
 
6.1.3 
Off-Site Visit Considerations for Non-Injection Study Visits 
 
Sites are expected to make every effort to conduct each study visit at the clinical research site.  
However, if allowed per local law and regulations and/or institutional policies, participants may 
have non-injection follow-up study visits or non-injection interim visits conducted in their home 
or in other off-site locations. Off-site visits must be completed within the respective visit’s target 
window or allowable window.  Additionally, off-site visits should only be conducted if sites are 
able to collect and transport any PK samples required for the applicable non-injection follow-up 
study visit; see further guidelines below regarding off-site specimen collection. 
 
At sites where off-site visits are permitted, study staff will discuss this option with participants 
(and parent or legal guardian, as applicable) in advance and agree on where and when such visits 
may take place, with adequate protections for participant privacy and confidentiality. Prior to 
each off-site visit, study staff will again confirm the date, location, and time of each visit with the 
participant (and parent or legal guardian, as applicable) to indicate permission for this activity and 
record any special instructions for the study staff. 
 
At off-site visits when specimen collection is required, the procedures specified in Section 6.16 
must be followed. Off-site visits may only be conducted by designated study staff who are 
qualified to perform all protocol-specified procedures and have undergone study-specific and all 
other applicable training relevant to the procedures they will perform off-site (e.g., Human 
Subject Protection [HSP], Good Clinical Practices [GCP], International Air Transport Association 
[IATA]). These staff should also be adequately trained and qualified to immediately manage any 
adverse events and/or social impacts that may occur during off-site visits (e.g., fainting during 
phlebotomy, family dispute in the home). If adverse events requiring further evaluation or 
management are identified during an off-site visit, study staff conducting the visit will arrange for 
the participant to return to the study site as soon as possible.   
 
6.2 
Cohort 1 Step 1, and Cohort 2 Step 3 Screening Visit  
 
Refer to Section 4.7 for a description of the study recruitment, screening, and enrollment process. 
 
Screening may be initiated after written informed consent/assent is obtained. All screening 
procedures must be performed within 28 days prior to study entry. Hematology, chemistries, 
HIV-1 RNA, pregnancy testing, and confirmation of HIV infection (if necessary) are required, in 
relation to the eligibility criterion in Sections 4.1-4.2; as soon as the required laboratory screening 
test results are obtained, all results should be graded for severity as specified in Section 7.3.3. 
Multiple visits may be conducted within the 28-day time frame to complete all required 
procedures and to repeat laboratory tests for confirmation, if necessary. 
 
Potential Cohort 2 Step 3 participants should be counseled to continue their pre-study cART 
regimen during the screening window, with their last pre-study cART regimen dose(s) 
administered on the day prior to the scheduled Cohort 2 Step 3 Entry visit.  Cohort 1 Step 1 
participants will continue their pre-study cART regimen throughout Cohort 1 participation.  


 
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Cohort 1 Step 1, and Cohort 2 Step 3, Screening Visit Procedures 
Administrative 
and Regulatory 
• Obtain written informed consent/assent 
• Assign PID to adolescent 
• Obtain screening number from SES 
• Obtain available documentation of participant’s HIV status  
• Collect demographic and locator information 
Behavioral and 
Counseling 
• Provide HIV pre-/post-test counseling, if indicated 
• Provide contraceptive counseling 
Clinical 
• Obtain available medical records and medical and medications history  
• Assess documentation of HIV infection 
• Assess ARV history 
• Assess HIV-1 RNA test result history 
• Perform complete physical exam 
• Perform Sexual Maturity Rating 
• Perform an electrocardiogram (ECG) in triplicate 
• For Cohort 1 participants screening for Cohort 2, confirm completion of all 
study product injections and the Week 16 visit in Cohort 1 Step 2  
Laboratory 
Blood  
Collect blood for: 
• Confirmatory HIV testing, if needed per Section 4.1.6 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN) 
• HIV-1 RNA 
 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test 
 
For potential participants who do not meet the eligibility criteria, screening should be 
discontinued once ineligibility is determined and these individuals should be actively referred to 
non-study sources of care. See Section 4.7.1 for documentation requirements for adolescents who 
are found to be ineligible. 
 
Participants may rescreen once per Cohort (i.e. total of two screening attempts for Cohort 1 and 
two screening attempts for Cohort 2 are allowed). If any participant is re-screened, all screening 
procedures listed above must be repeated, with the exception that: 
 
• 
A new PID should not be assigned (Note: Obtain new screening number from SES for second 
screening attempt) 
• 
Confirmatory HIV testing, if conducted during first screening attempt, need not be repeated 
• 
Previously documented medical and medications history information should be reviewed and 
updated through the date of re-screening (it is not necessary to re-record history information 
that was previously documented) 
 
The Cohort 1 Entry Visit (Step 1 – oral phase) is described in Section 6.3.1. The Cohort 2 Entry 
Visit (Step 3 – oral phase) is described in Section 6.4.1.  
 


 
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Additional Considerations for Cohort 1 Step 2 Participants Screening for Cohort 2 Step 3 
 
Cohort 2, Step 3 will initially open to accrual limited to Cohort 1 participants. These participants 
must undergo screening procedures to determine Cohort 2, Step 3 eligibility, should they wish to 
participate in Cohort 2. The timing of screening and, if eligible, enrolling into Cohort 2 Step 3 
may occur prior to completing all scheduled LSFU study visits. In the event Cohort 1 Step 2 
participants complete all scheduled LSFU study visits and exit the study (as described in Section 
6.5 below), these former Cohort 1 Step 2 participants may undergo screening procedures to 
determine eligibility for resuming study participation in Cohort 2 Step 3. 
 
Any adolescent screening for Cohort 2, Step 3 is required to meet eligibility criteria per Sections 
4.1-4.2, regardless of previous Cohort 1 study participation. Clinical assessments, evaluations, 
and laboratory values obtained during Cohort 1 Step 2 or LSFU study visits may be used to 
screen for Cohort 2 eligibility, if obtained within 28 days of the Cohort 2 Entry Visit. Otherwise, 
all screening visit procedures as described above must be completed for Cohort 2 Step 3 
eligibility determination. For previous Cohort 1 Step 2 participants, a new screening number will 
not be obtained from SES for the Cohort 2 Step 3 screening attempt. 
 
Any adolescent found to meet the applicable eligibility criteria will be enrolled into Cohort 2 Step 
3, per Section 4.7 and Section 6.4.1. Previous Cohort 1 Step 2 participants will retain their PID as 
assigned during Cohort 1 procedures and a new SID will be assigned upon successful enrollment 
using the SES. 
 
Additional guidance and eCRF completion processes for (former) Cohort 1 Step 2 participants 
enrolling into Cohort 2 Step 3 may be found in the IMPAACT 2017 MOP. 
 
6.3 
Cohort 1  
 
6.3.1 
Cohort 1 Entry Visit (Step 1 – oral phase) 
 
Refer to Section 4.7 for a description of the study recruitment, screening, and enrollment 
processes. The Cohort 1 Step 1 Entry visit must occur within 28 days (inclusive) from the Cohort 
1 Screening Visit. Cohort 1 Step 1 Entry visit procedures that may provide information relevant 
to study eligibility should be performed first, prior to final eligibility determination and 
enrollment. In the event a participant is found to be ineligible on the day of enrollment, 
enrollment should not occur.  
 
The Cohort 1 Step 1 Entry visit may not be conducted over a multi-day split visit, and the 
following visit procedures must be conducted in the sequence specified below:  
• 
Complete final eligibility determination and confirmation (medical and medications history 
including ARV history assessment, symptom-directed physical exam, an ECG if indicated, 
and, for females, pregnancy testing); for females, pregnancy test results must be available for 
eligibility confirmation 
• 
Complete a paper-based Step 1 eligibility checklist  
• 
Enroll the participant on Cohort 1 Step 1 and obtain SID 
• 
Prescribe assigned oral study product  
• 
Dispense assigned oral study product 
• 
Facilitate and observe administration of assigned oral study product 
 


 
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Cohort 1R participants should be provided a meal with the observed oral study product dose; see 
Section 5.1 regarding RPV oral dosing regimen and food intake requirements 
 
Note that acceptability and tolerability questionnaires must be administered relative to other Entry 
visit procedures as specified in the IMPAACT 2017 MOP. Visit procedures not otherwise 
specified may be conducted at any timepoint during the Cohort 1 Step 1 Entry visit. Operational 
guidance on the order of Entry visit procedures may be found in the IMPAACT 2017 MOP. 
 
Cohort 1 Step 1 Entry Visit Procedures 
Administrative 
and Regulatory 
• Complete final eligibility determination and confirmation* 
• Complete paper-based eligibility checklist*, enter checklist data into SES to 
enroll the participant and generate SID; print and file a copy of the 
confirmation file 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires 
Clinical 
• Update medical and medications history since last visit* 
• Perform symptom-directed physical exam*  
• Assess ARV history* 
• Perform an ECG, if indicated* 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN)  
• CD4 count and percentage 
• HIV-1 RNA 
• Store whole blood for genotypic resistance testing 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test* 
Study Product 
• Prescribe, dispense, facilitate and observe administration of the assigned oral 
study product, see Section 5.1 
*Perform prior to enrollment 
 
6.3.2 
Cohort 1 Week 2 Visit (Step 1 – oral phase) 
 
The Cohort 1 Week 2 visit is targeted to be conducted on day 14, counted from the day of entry, 
with a target window of +7 days from the target date. If necessary, this visit may be conducted 
within the allowable window of +14 days from the target date and the CMC notified. 
 
PK samples will be collected at the Week 2 visit (intensive PK); Cohort 1C and Cohort 1R will 
have different PK sample collection timepoints at the Week 2 visit only. The pre-dose PK sample 
collection should be performed prior to and on the same day as the oral study product dose 
observed at the site. See the procedural table below for the specific PK collection time points and 
collection windows.  
 
After the Entry visit and through the Week 2 visit, participants should be recommended to take 
the oral study product at the same time of day (morning or evening) as the Week 2 visit pre-dose 
PK collection time point. At minimum, for the three days prior to the Week 2 visit, participants 
should take their oral study product at the same time of day (morning or evening) as the 


 
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scheduled pre-dose PK collection time point and be fully adherent to their assigned daily oral 
study product regimen. In preparation for the Week 2 visit, sites may contact participants or 
parents and guardians, to reinforce adherence within the three days prior to the scheduled PK 
evaluation using retention methods as described in Section 4.8, as well as to remind the 
participant to hold the oral study product dose due on the day of the Week 2 visit. For example, 
sites may call or visit the participant and/or parent/guardian prior to the scheduled PK evaluation 
to reinforce adherence.  
 
If, for the three days prior to the Week 2 visit, either a missed dose is reported or the participant 
has not adjusted the timing of their oral study product dosing to align with the pre-dose PK 
collection time point, the Week 2 visit should be rescheduled. Additional guidelines for 
scheduling and conducting the Cohort 1 Week 2 visit are below.  
• 
Participants and their parents/guardians should be reminded to hold administration of the 
daily oral study product due on the day of the Week 2 visit, to allow for a pre-dose PK 
sample collection and for the dose to be observed at the site. The Week 2 visit should be 
rescheduled if the oral study product dose was already taken and not observed at the site. 
• 
Participants and their parents/guardians should also be reminded to return all oral study 
product at the Week 2 visit, such that the adherence assessment may be performed. 
• 
Height and weight must be obtained on the same day as initiating the Week 2 PK evaluation.  
• 
Cohort 1R participants should be provided a meal with the observed oral study product dose; 
see Section 5.1 regarding RPV oral dosing regimen and food intake requirements 
• 
The oral study product dose dates, times, dose amounts, and food intake around the oral doses 
must be source documented and entered into eCRFs for the oral doses observed at the Week 2 
visit in addition to the previous three doses.  
• 
For participants who report intercurrent illness immediately prior to or on the day of the 
scheduled PK visit that may have interfered with study product administration or resulted in 
malabsorption of study product (e.g., fever, vomiting, diarrhea), the Week 2 visit should be 
rescheduled. 
• 
If the observed oral study product dose is not retained within 30 minutes (inclusive) of 
administration (e.g., vomiting), the Week 2 visit should be rescheduled.  
• 
Depending on site capacity and participant preferences, participants and their parents or 
guardians may stay at the clinical research facility overnight for the intensive PK sampling. 
 
Additional oral study product, as assigned per Cohort 1C or Cohort 1R, may be dispensed at this 
visit if needed to provide coverage until the Week 4a visit, per Section 5.1.3. Pregnancy test 
results must be obtained prior to any dispensing of additional oral study product. 
 
Following the Week 2 visit, timing of taking the oral study product may be changed, if desired. 
However, participants should be encouraged to maintain the timing of taking their oral study 
product (morning or evening) through the Week 4b visit. Additional guidance regarding the 
timing of oral study product dosing prior to the Week 2 visit is provided in the IMPAACT 2017 
MOP. 


 
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Cohort 1 Week 2 Visit Procedures (Step 1 – oral phase) 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam (including height and weight) 
• Perform adherence assessment 
• Identify/review/update adverse events  
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance 
(CrCl; Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
Blood 
(Intensive 
PK 
evaluation) 
Collect blood for: 
• Cohort 1C: Pre-dose, 1, 2, 3, 4, and 8 hours post-dose (6 PK collection 
timepoints) 
• Cohort 1R: Pre-dose, 4, and 8 hours post-dose (3 PK collection timepoints) 
± 30 minutes window is allowed for the 4-hours post-dose; ± 1 hour window 
is allowed for the 8 hours post-dose 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be 
obtained before observed dose of oral study product 
Study Product 
• Facilitate and observe administration of the assigned study product 
following pre-dose blood collection 
• Prescribe and dispense assigned oral study product, if indicated, see Section 
5.1 
 
6.3.3 
Cohort 1 Week 4a Visit (Step 1 – oral phase) 
 
The Cohort 1 Week 4a visit is targeted to be conducted on day 28, counted from the day of entry, 
with a target window of +7 days from the target date, and an allowable window of -7 days/+10 
days from the target date.    
 
Participants and their parents/guardians should be reminded to return all oral study product at the 
Week 4a visit, such that the adherence assessment may be performed. Additional oral study 
product, as assigned per Cohort 1C or Cohort 1R, may be dispensed at this visit if needed to 
provide coverage until the Week 4b visit, per Section 5.1.3. Pregnancy test results must be 
obtained prior to any dispensing of additional oral study product. 
 
Data collected through the Week 4a study visit will be assessed to determine eligibility to enter 
Step 2 and receive injectable CAB LA or RPV LA, per Cohort 1C or Cohort 1R, respectively. 
Week 4a visit laboratory test results should be reviewed as soon as they are available, for 
determining Step 2 eligibility and scheduling the Week 4b visit. Abnormal laboratory test result 
values from the Week 4a visit may be repeated prior to scheduling the Week 4b visit. If repeat 
laboratory test results confirm Step 2 eligibility, and all other eligibility criteria are met, the Week 
4b visit may be scheduled within the target visit window (see Section 6.3.4 below) for Step 2 
Entry and injectable study product administration, and may be combined with the Week 4a visit. 
See Section 4.3 for Cohort 1 Step 2 eligibility criteria.  
 


 
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If Cohort 1 participants are ineligible to receive injectable study product in Step 2, they will 
permanently discontinue oral study product use and complete an Early Termination visit 28 days 
after their last oral study product dose (see Section 6.5.4). 
 
Cohort 1 Week 4a Visit Procedures (Step 1 – oral phase) 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Perform adherence assessment 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN) 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be obtained 
before dispensing oral study product, if dispensing is indicated at this visit 
Study product 
• Prescribe, dispense, and facilitate administration of the assigned oral study 
product, if indicated, see Section 5.1 
 
6.3.4 
Cohort 1 Week 4b Visit (Step 2 Entry – injection phase) 
 
The Week 4b visit must take place after Week 4a laboratory test results are available, and with 
the target visit window of day 21-42, counted from the day of Step 1 entry. This visit should be 
scheduled to minimize the time between the Week 4a visit and initiation of the injectable study 
products in Step 2. Additionally, the Week 4b visit must occur within 42 days (inclusive) of Step 
1 entry so as not to exceed the intended maximum of 6 weeks on oral study product (up to 43 
doses).  
 
Cohort 1 participants who meet eligibility criteria to progress to Step 2, per Section 4.3, are 
generally expected to receive their last oral dose of CAB or RPV on the same day as their first 
injection of CAB LA or RPV LA at the Week 4b study visit, which also serves as the Step 2 
Entry visit.  PK samples will be collected at the Week 4b visit.  Participants who report taking an 
oral study product dose within 12 hours (inclusive) of the scheduled Week 4b pre-dose sample 
collection will not take the oral study product dose during the Week 4b study visit; see below for 
further details regarding PK sampling and flexibility in study visit scheduling. Note that HIV-1 
RNA test results collected at the Week 4b visit are not required to be obtained or reviewed prior 
to administering injectable study product.  
 
After the Week 2 visit and through the Week 4b visit, participants should be recommended to 
take the oral study product at the same time of day (morning or evening) as the Week 4b visit pre-
dose PK collection time point. For the three days prior to the Week 4b visit, participants should 
ideally take their oral study product at the same time of day (morning or evening) as the 
scheduled pre-dose PK collection time point, and be fully adherent to their assigned daily oral 
study product regimen. However, the Week 4b visit may continue as scheduled if a missed dose is 
reported, or the participant has not adjusted the timing of their oral study product dosing to align 
with the pre-dose PK collection time point. 
 


 
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In preparation for the Week 4b visit, sites may contact participants or parents and guardians, to 
reinforce adherence and oral study product dose timing within the three days prior to the 
scheduled PK evaluation using retention methods as described in Section 4.8. For example, sites 
may call or visit the participant and/or parent/guardian prior to the scheduled PK evaluation to 
reinforce adherence. Participants and their parents/guardians should be reminded to hold 
administration of the daily oral study product due on the day of the Week 4b visit, to allow for a 
pre-dose PK sample collection and for the dose to be observed at the site. Participants and their 
parents/guardians should also be reminded to return all oral study product at the Week 4b visit, 
such that the adherence assessment may be performed. 
 
Prior to initiating the pre-dose PK sample collection, study staff should ascertain when the 
participant’s most recent oral study product dose was administered to determine whether oral 
study product should be administered during Week 4b visit:   
• 
If the participant’s most recent oral study product dose was taken more than 12 hours from 
the Week 4b pre-dose PK sample collection, the pre-dose PK sample should be collected 
prior to observing the participant’s last oral study product dose administered (and observed) 
at the site. Sites should provide Cohort 1R participants a meal with the observed oral study 
product dose; see Section 5.1 regarding RPV oral dosing regimen and food intake 
requirements. 
 
• 
If the participant’s most recent oral study product dose was taken within 12 hours (inclusive) 
of the Week 4b pre-dose PK sample collection, an oral study product dose may not be 
administered during Week 4b visit. The Week 4b visit may still occur as scheduled and the 
pre-dose PK sample collection will be prior to the participant’s first study product injection. 
 
The Cohort 1 Week 4b visit may not be conducted over a multi-day split visit with the following 
procedures conducted as specified below: 
• 
Contraceptive and adherence counseling must be provided prior to enrolling the participant 
into Step 2 to confirm the participant is willing to receive the injectable study product. 
• 
Final eligibility determination and confirmation must be completed prior to completing the 
Step 2 eligibility checklist: medical and medications history, symptom-directed physical 
exam (must include height and weight), adherence assessment, and, for females, pregnancy 
testing; for females, pregnancy test results must be available for eligibility confirmation. 
• 
The pre-dose PK sample must be collected prior to the participant’s first study product 
injection. See guidance above regarding whether the pre-dose PK sample is collected prior to 
an oral study product dose administered (and observed) at the site, or whether no oral study 
product dose is administered at this visit. 
• 
The Step 2 paper-based eligibility checklist must be completed prior to enrolling the 
participant to Step 2. 
• 
Enrollment to Step 2 must occur prior to prescribing the assigned injectable study product.  
• 
Prescribing must occur prior to dispense assigned injectable study product. 
• 
Administration of the assigned injectable study product must occur after enrollment into Step 
2, and after prescribing and dispensing the participant’s assigned injectable study product. 
• 
The post-dose PK sample must be collected after administration of both the oral study 
product and the injectable study product. 
 
Note that acceptability and tolerability questionnaires must be administered relative to other 
Week 4b visit procedures as specified in the IMPAACT 2017 MOP.  Visit procedures not 
otherwise specified may be conducted at any timepoint during the Week 4b visit. Operational 
guidance on the order of Week 4b visit procedures may be found in the IMPAACT 2017 MOP. 


 
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Cohort 1 Week 4b Visit Procedures (Step 2 Entry - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling* 
• Provide adherence counseling* 
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Administrative 
and Regulatory 
• Complete final eligibility confirmation for Step 2 Entry, see Section 4.3* 
• Complete paper-based eligibility checklist*, enter checklist data into SES to 
enroll the participant and generate SID; print and file a copy of the 
confirmation file 
Clinical 
• Update medical and medications history since last visit* 
• Perform symptom-directed physical exam* 
• Identify/review/update adverse events* 
• Perform adherence assessment* 
Laboratory 
Blood 
 
Collect blood for: 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Pre-dose and 2 hours post-dose (2 PK collection timepoints), 
± 30 minutes window is allowed for the 2-hours post-dose  
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test* 
Study product 
• Facilitate and observe administration of the assigned oral study product, if 
indicated, see above 
• Prescribe, prepare, and administer assigned injectable study product, see 
Section 5.1 
*Perform prior to completing the Step 2 eligibility checklist and prior to prescribing injectable study 
product. 
 
6.3.5 
Cohort 1 Week 5 Visit (Step 2 – injection phase) 
 
The Week 5 visit is targeted to be conducted 3 days after completion of the Week 4b Step 2 Entry 
visit (the first administration of injectable study product), with a target window of +4 days from 
the target date, and an allowable window of -1 day/+5 days from the target date. 
 
Cohort 1 Week 5 Visit Procedures (Step 2 - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• PK evaluation: Single sample  
 


 
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6.3.6 
Cohort 1 Week 8 Visit (Step 2 – injection phase) 
 
The Week 8 visit is targeted to be conducted 28 days after the Week 4b Step 2 Entry visit (the 
first administration of injectable study product), with a target window of -7 days/+3 days from the 
target date.     
 
Cohort 1 Week 8 Visit Procedures (Step 2 - injection phase) 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be obtained 
before administering injectable study product 
Study product 
• Prescribe, prepare, and administer assigned injectable study product, see 
Section 5.1 
 
6.3.7 
Cohort 1 Week 9 Visit (Step 2 – injection phase) 
 
The Week 9 visit is targeted to be conducted 3 days after completion of the Week 8 visit, with a 
target window of +7 days from the target date, and an allowable window of -1 day/+10 days from 
the target date. 
 
Cohort 1 Week 9 Visit Procedures (Step 2 - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
• Perform an ECG 
Laboratory 
Blood 
Collect blood for: 
• PK evaluation: Single sample 
 
6.3.8 
Cohort 1 Week 12 Visit (Step 2 – injection phase) 
 
The Week 12 visit is targeted to be conducted 28 days after completion of the Week 8 visit, with 
a target window of +4 days from the target date, and an allowable window of -1 day/+5 days from 
the target date. 
 


 
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Cohort 1 Week 12 Visit Procedures (Step 2 - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• PK evaluation: Single sample 
 
6.3.9 
Cohort 1 Week 16 Visit (Step 2 – injection phase) 
 
The Week 16 visit is targeted to be conducted 56 days after completion of the Week 8 visit, with 
a target window of ±7 days from the target date, and an allowable window of ±14 days from the 
target date. 
 
Cohort 1 Week 16 Visit Procedures (Step 2 - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling 
• Perform acceptability/tolerability assessment questionnaires 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Identify/review/update adverse events 
• Perform Sexual Maturity Rating 
• Perform an ECG 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• CD4 count and percentage 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation:  Single sample 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test 
 
Participants completing the Cohort 1 Week 16 visit will be followed according to the LSFU visit 
schedule beginning with the LSFU Week 24 Visit (see Section 6.5 and Appendix I-C), or may 
screen for Cohort 2 eligibility if Cohort 2 has been opened to accrual. 
 
6.4 
Cohort 2 
 
6.4.1 
Cohort 2 Step 3 Entry Visit (Step 3 – oral phase) 
 
Refer to Section 4.7 for a description of the study recruitment, screening, and enrollment 
processes. The Cohort 2 Step 3 Entry visit must occur within 28 days (inclusive) from the Cohort 
2 Screening Visit. Potential Cohort 2 Step 3 participants should be counseled to continue their 
pre-study cART regimen during the screening window, with their last dose administered on the 
day prior to the scheduled Cohort 2 Step 3 Entry visit.  Cohort 2 Step 3 Entry visit procedures that 
may provide information relevant to eligibility for the study should be performed first, prior to 


 
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final eligibility determination and enrollment. In the event a participant is found to be ineligible 
on the day of enrollment, enrollment should not occur.  
 
The Cohort 2 Step 3 Entry visit may not be conducted over a multi-day split visit, and the 
following visit procedures must be conducted in the sequence specified below: 
• 
Complete final eligibility determination and confirmation (medical and medications history, 
symptom-directed physical exam, an ECG if indicated, and, for females, pregnancy testing); 
for females, pregnancy test results must be available for eligibility confirmation 
• 
Complete a paper-based Step 3 eligibility checklist  
• 
Enroll the participant on Cohort 2 Step 3 and obtain SID 
• 
Prescribe oral study product  
• 
Dispense oral study product 
• 
Facilitate and observe administration of oral study product 
 
Participants should be provided a meal with the observed oral study product doses; see Section 
5.1 regarding RPV oral dosing regimen and food intake requirements. 
 
Note that acceptability and tolerability questionnaires must be administered relative to other Entry 
visit procedures as specified in the IMPAACT 2017 MOP. Visit procedures not otherwise 
specified may be conducted at any timepoint during the Cohort 2 Step 3 Entry visit. Operational 
guidance on the order of Entry visit procedures may be found in the IMPAACT 2017 MOP. Upon 
enrolling into Cohort 2, Step 3, study participants will discontinue their pre-study oral cART 
regimen.  
 
Cohort 2 Step 3 Entry Visit Procedures 
Administrative 
and Regulatory 
• Complete final eligibility determination and confirmation* 
• Complete paper-based eligibility checklist*, enter checklist data into SES to 
enroll the participant and generate SID; print and file a copy of the 
confirmation file 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires 
Clinical 
• Update medical and medications history since last visit* 
• Perform symptom-directed physical exam*  
• Perform an ECG, if indicated* 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN) 
• CD4 count and percentage 
• HIV-1 RNA 
• Store whole blood for genotypic resistance testing 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test* 
Study Product 
• Prescribe, dispense, facilitate, and observe administration of oral study 
products, see Section 5.1 
*Perform prior to enrollment 
 


 
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6.4.2 
Cohort 2 Week 2 Visit (Step 3 – oral phase) 
 
The Cohort 2 Week 2 visit is targeted to be conducted on day 14, counted from the day of entry, 
with a target window of +7 days from the target date, and an allowable window of +14 days from 
the target date. 
 
PK samples will be collected at the Week 2 visit. The pre-dose PK sample collection should be 
performed prior to and on the same day as the oral study product dose observed at the site.      
 
After the Entry visit and through the Week 2 visit, participants should be recommended to take 
the oral study product at the same time of day (morning or evening) as the Week 2 visit pre-dose 
PK collection time point. At minimum, for the three days prior to the Week 2 visit, participants 
should take their oral study product at the same time of day (morning or evening) as the 
scheduled pre-dose PK collection time point and be fully adherent to the daily oral study product 
regimen. In preparation for the Week 2 visit, sites may contact participants or parents and 
guardians, to reinforce adherence within the three days prior to the scheduled PK evaluation using 
retention methods as described in Section 4.8, as well as to remind the participant to hold the oral 
study product dose due on the day of the Week 2 visit. For example, sites may call or visit the 
participant and/or parent/guardian prior to the scheduled PK evaluation to reinforce adherence.  
 
If, for the three days prior to the Week 2 visit, either a missed dose is reported or the participant 
has not adjusted the timing of their oral study product dosing to align with the pre-dose PK 
collection time point, the Week 2 visit should be rescheduled. Additional guidelines for 
scheduling and conducting the Cohort 2 Week 2 visit are below.  
• 
Participants and their parents/guardians should be reminded to hold administration of the 
daily oral study product due on the day of the Week 2 visit, to allow for a pre-dose PK 
sample collection and for the dose to be observed at the site. The Week 2 visit should be 
rescheduled if the oral study product dose was already taken and not observed at the site. 
• 
Participants and their parents/guardians should also be reminded to return all oral study 
product at the Week 2 visit, such that the adherence assessment may be performed. 
• 
Height and weight must be obtained on the same day as initiating the Week 2 PK evaluation. 
• 
Participants should be provided a meal with the observed oral study product doses; see 
Section 5.1 regarding RPV oral dosing regimen and food intake requirements. 
• 
The oral study product dose dates, times, dose amounts, and food intake around the oral doses 
must be source documented and entered into eCRFs for the oral doses observed at the Week 2 
visit in addition to the previous three doses.  
• 
For participants who report intercurrent illness immediately prior to or on the day of the 
scheduled PK visit that may have interfered with study product administration or resulted in 
malabsorption of study product (e.g., fever, vomiting, diarrhea), the PK evaluation should be 
rescheduled.  
• 
If the observed oral study product dose is not retained within 30 minutes (inclusive) of 
administration (e.g., the vomiting), the Week 2 visit should be rescheduled.  
• 
Depending on site capacity and participant preferences, participants and their parents or 
guardians may stay at the clinical research facility overnight for the PK sampling. 
 
Additional oral study product may be dispensed at this visit if needed to provide coverage until 
the Week 4a visit, per Section 5.1.3. Pregnancy test results must be obtained prior to any 
dispensing of additional oral study product. 
 


 
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Following the Week 2 visit, timing of taking the oral study product may be changed, if desired. 
However, participants should be encouraged to maintain the timing of taking their oral study 
product (morning or evening) through the Week 4b visit. Additional guidance regarding the 
timing of oral study product dosing prior to the Week 2 visit is provided in the IMPAACT 2017 
MOP. 
 
Cohort 2 Week 2 Visit Procedures (Step 3 – oral phase) 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam (including height and weight) 
• Perform adherence assessment 
• Identify/review/update adverse events  
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Pre-dose and 3 hours post-dose (2 PK collection timepoints), 
± 1 hour window is allowed for the 3 hours post-dose 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be obtained 
before observed dose of oral study product 
Study Product 
• Facilitate and observe administration of oral study products following pre-
dose blood collection 
• Prescribe and dispense oral study products, if indicated, see Section 5.1 
 
6.4.3 
Cohort 2 Week 4a Visit (Step 3 – oral phase) 
 
The Cohort 2 Week 4a visit is targeted to be conducted on day 28, counted from the day of entry, 
with a target window of +7 days from the target date, and an allowable window of -7 days/+10 
days from the target date.    
 
Participants and their parents/guardians should also be reminded to return all oral study product at 
the Week 4a visit, such that the adherence assessment may be performed. Additional oral study 
products may be dispensed if needed to provide coverage until the Week 4b visit, per Section 
5.1.3. Pregnancy test results must be obtained prior to any dispensing of additional oral study 
products. 
 
Data collected through the Week 4a study visit will be assessed to determine eligibility to enter 
Step 4 and receive injectable CAB LA + RPV LA. Week 4a visit laboratory test results should be 
reviewed as soon as they are available, for determining Step 4 eligibility and scheduling the Week 
4b visit. See Section 4.4 for Cohort 2 Step 4 eligibility criteria. Abnormal laboratory test result 
values from the Week 4a visit may be repeated prior to scheduling the Week 4b visit. If repeat 
laboratory test results confirm Step 4 eligibility, and all other eligibility criteria are met, the Week 
4b visit may be scheduled within the target visit window (see Section 6.4.4 below) for Step 4 
Entry and injectable study products administration, and may be combined with the Week 4a visit.    
 


 
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If Cohort 2 participants (who had not previously participated in Cohort 1 Step 2) are ineligible to 
receive injectable study products in Step 4, they will permanently discontinue oral study product 
use and complete an Early Termination visit 28 days after their last oral study product dose (see 
Section 6.5.4).  Cohort 1 Step 2 participants who continue in Cohort 2 Step 3 but are not eligible 
to progress to Cohort 2 Step 4 will be followed per the LSFU visit schedule (see Section 6.5).  
 
Cohort 2 Week 4a Visit Procedures (Step 3 – oral phase) 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Identify/review/update adverse events 
• Perform adherence assessment 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN) 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be obtained 
before dispensing oral study product, if dispensing is indicated at this visit 
Study product 
• Prescribe, dispense, and facilitate administration of oral study products, if 
indicated, see Section 5.1 
 
6.4.4 
Cohort 2 Week 4b Visit (Step 4 Entry – injection phase) 
 
The Week 4b visit must take place after Week 4a laboratory test results are available, and with 
the target visit window of day 21-42, counted from the day of Step 3 entry. This visit should be 
scheduled to minimize the time between the Week 4a visit and initiation of the injectable study 
products in Step 4. Additionally, the Week 4b visit must occur within 42 days (inclusive) of Step 
3 entry so as not to exceed the intended maximum of 6 weeks on oral study product (up to 43 
doses of each oral study product).  
 
Cohort 2 participants who meet eligibility criteria to progress to Step 4, per Section 4.4, are 
generally expected to receive their last oral dose of CAB + RPV on the same day as their first 
injection of CAB LA + RPV LA at the Week 4b study visit, which also serves as the Step 4 Entry 
visit. PK samples will be collected at the Week 4b visit.  Participants who report taking oral study 
product doses within 12 hours (inclusive) of the scheduled Week 4b pre-dose sample collection 
will not take the oral study product doses during the Week 4b study visit; see below for further 
details regarding PK sampling and flexibility in study visit scheduling. Note that HIV-1 RNA test 
results collected at the Week 4b visit are not required to be obtained or reviewed prior to 
administering injectable study products.  
 
After the Week 2 visit and through the Week 4b visit, participants should be recommended to 
take the oral study product at the same time of day (morning or evening) as the Week 4b visit pre-
dose PK collection time point. For the three days prior to the Week 4b visit, participants should 
ideally take their oral study product at the same time of day (morning or evening) as the 
scheduled pre-dose PK collection time point and be fully adherent to the daily oral study product 
regimen. However, the Week 4b visit may continue as scheduled if a missed dose is reported, or 


 
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the participant has not adjusted the timing of their oral study product dosing to align with the pre-
dose PK collection time point. 
 
In preparation for the Week 4b visit, sites may contact participants or parents and guardians, to 
reinforce adherence and oral study product dose timing within the three days prior to the 
scheduled PK evaluation using retention methods as described in Section 4.8. For example, sites 
may call or visit the participant and/or parent/guardian prior to the scheduled PK evaluation to 
reinforce adherence. Participants and their parents/guardians should be reminded to hold 
administration of the daily oral study product due on the day of the Week 4b visit, to allow for a 
pre-dose PK sample collection and for the dose to be observed at the site. Participants and their 
parents/guardians should also be reminded to return all oral study product at the Week 4b visit, 
such that the adherence assessment may be performed. 
 
Prior to initiating the pre-dose PK sample collection, study staff should ascertain when the 
participant’s most recent oral study product dose was administered to determine whether oral 
study product should be administered during Week 4b visit:   
• 
If the participant’s most recent oral study product dose was taken more than 12 hours from 
the Week 4b pre-dose PK sample collection, the pre-dose PK sample should be collected 
prior to observing the participant’s last oral study product dose administered (and observed) 
at the site. Sites should provide participants a meal with the observed oral study product dose; 
see Section 5.1 regarding RPV oral dosing regimen and food intake requirements. 
 
• 
If the participant’s most recent oral study product dose was taken within 12 hours (inclusive) 
of the Week 4b pre-dose PK sample collection, an oral study product dose may not be 
administered during Week 4b visit. The Week 4b visit may still occur as scheduled and the 
pre-dose PK sample collection will be prior to the participant’s first study product injection. 
 
The Cohort 2 Week 4b visit may not be conducted over a multi-day split visit with the following 
procedures conducted as specified below: 
• 
Contraceptive and adherence counseling must be provided prior to enrolling the participant 
into Step 4 to confirm the participant is willing to receive the injectable study products. 
• 
Final eligibility determination and confirmation must be completed prior to completing the 
Step 4 eligibility checklist: medical and medications history, symptom-directed physical 
exam (must include height and weight), adherence assessment, and, for females, pregnancy 
testing; for females, pregnancy test results must be available for eligibility confirmation. 
• 
The pre-dose PK sample must be collected prior to the participant’s first study product 
injection. See guidance above regarding whether the pre-dose PK sample is collected prior to 
an oral study product dose administered (and observed) at the site, or whether no oral study 
product dose is administered at this visit. 
• 
The Step 4 paper-based eligibility checklist must be completed prior to enrolling the 
participant to Step 4. 
• 
Enrollment to Step 4 must occur prior to prescribing injectable study products.  
• 
Prescribing must occur prior to dispensing injectable study products. 
• 
Administration of injectable study products must occur after enrollment into Step 4, and after 
prescribing and dispensing the injectable study products. 
• 
The post-dose PK sample must be collected after administration of both the oral study 
product and the injectable study products. 
 
Note that acceptability and tolerability questionnaires must be administered relative to other 
Week 4b visit procedures as specified in the IMPAACT 2017 MOP. Visit procedures not 


 
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otherwise specified may be conducted at any timepoint during the Week 4b visit. Operational 
guidance on the order of Week 4b visit procedures may be found in the IMPAACT 2017 MOP. 
 
Cohort 2 Week 4b Visit Procedures (Step 4 Entry - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling* 
• Provide adherence counseling* 
• Perform acceptability/tolerability assessment questionnaires 
Administrative 
and Regulatory 
• Complete final eligibility confirmation for Step 4 Entry, see Section 4.4* 
• Complete paper-based eligibility checklist*, enter checklist data into SES to 
enroll the participant and generate SID; print and file a copy of the 
confirmation file 
Clinical 
• Update medical and medications history since last visit* 
• Perform symptom-directed physical exam* 
• Identify/review/update adverse events* 
• Perform adherence assessment* 
• Perform ECG: 2 hours post-injection dose, ± 1 hour window is allowed 
Laboratory 
Blood 
 
Collect blood for: 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Pre-dose and 2 hours post-injection dose (2 PK collection 
timepoints), ± 30 minutes window is allowed for the 2-hours post-dose 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test* 
Study product 
• Facilitate and observe administration of oral study products, if indicated, see 
above 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
*Perform prior to completing the Step 4 eligibility checklist and prior to prescribing injectable study 
products. 
 
6.4.5 
Cohort 2 Week 5 Visit (Step 4 – injection phase) 
 
The Week 5 visit is targeted to be conducted 3 days after completion of the Week 4b Step 4 Entry 
visit (the first administration of injectable study products), with a target window of +4 days from 
the target date, and an allowable window of -1 day/+5 days from the target date. 
 
Cohort 2 Week 5 Visit Procedures (Step 4 - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• PK evaluation: Single sample 
 


 
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6.4.6 
Cohort 2 Weeks 8 Visit (Step 4 – injection phase) 
 
The Week 8 visit is targeted to be conducted 28 days after the Week 4b Step 4 Entry visit (the 
first administration of injectable study products), with a target window of -7 days/+3 days from 
the target date.   
 
Cohort 2 Week 8 Visit Procedures (Step 4 - injection phase) 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be obtained 
before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 
6.4.7 
Cohort 2 Weeks 16 Visit (Step 4 – injection phase) 
 
The Week 16 visit target date is 84 days after completion of the Week 4b visit with a target 
window of -7 days/+3 days from the target date. Additionally, the Week 16 visit and the third 
injection of study product should be scheduled a minimum of 7 weeks (49 days) and a maximum 
of 8 weeks and 3 days (59 days) from the previous injection.   
 


 
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Cohort 2 Weeks 16 Visit Procedures (Step 4 – injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
•  Perform acceptability/tolerability assessment questionnaires, if indicated 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam  
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be obtained 
before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 
6.4.8 
Cohort 2 Week 24 Visit (Step 4 – injection phase) 
 
The Week 24 visit target date is 140 days after completion of the Week 4b visit, with a target 
window of ±7 days.  Additionally, the Week 24 visit should occur a minimum of 7 weeks (49 
days) and a maximum of 9 weeks (63 days) from the previous injection. 
 
Cohort 2 Week 24 Visit Procedures (Step 4 – injection phase) 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Identify/review/update adverse events 
• Sexual Maturity Rating assessment 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• CD4 count and percentage 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation:  Single pre-dose sample 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be obtained 
before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 


 
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6.4.9 
Cohort 2 Week 25 Visit (Step 4 – injection phase) 
 
The Week 25 visit is targeted to be conducted 3 days after completion of the Week 24 visit, with 
a target window of +4 days from the target date, and an allowable window of -1 day/+5 days from 
the target date. 
 
Cohort 2 Week 25 Visit Procedures (Step 4 – injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• PK evaluation: Single sample 
 
6.4.10 Cohort 2 Weeks 32 and 40 Visits (Step 4 – injection phase) 
 
The Week 32 study visit is targeted to occur 196 days after the Week 4b visit, with a target 
window of ±7 days from the target date.  The Week 40 study visit is targeted to occur 252 days 
after the Week 4b visit, with a target window of ±7 days from the target date.  Additionally, the 
Week 32 and 40 visits should occur a minimum of 7 weeks (49 days) and a maximum of 9 weeks 
(63 days) from the previous injection  
 
Cohort 2 Weeks 32 and 40 Visit Procedures (Step 4 – injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be obtained 
before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 
6.4.11 Cohort 2 Week 48 Visit (Step 4 – injection phase) 
 
The Week 48 study visit is targeted to occur 308 days after the Week 4b visit, with a target 
window of ±7 days from the target date.  Additionally, the Week 48 visit should occur a 
minimum of 7 weeks (49 days) and a maximum of 9 weeks (63 days) from the previous injection. 
 


 
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Cohort 2 Week 48 Visit Procedures (Step 4 – injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling 
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• CD4 count and percentage 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be obtained 
before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 
6.4.12 Cohort 2 Weeks 56, 64, 72, 80, 88 Visits (Step 4 – injection phase) 
 
Weeks 56, 64, 72, 80, and 88 study visits have the following target dates as counted from 
completion of the Week 4b visit: 
• 
Week 56 visit target date is 364 days after Week 4b  
• 
Week 64 visit target date is 420 days after Week 4b  
• 
Week 72 visit target date is 476 days after Week 4b  
• 
Week 80 visit target date is 532 days after Week 4b 
• 
Week 88 visit target date is 588 days after Week 4b 
 
These visits each have a target window of ±7 days from the respective target date. Additionally, 
each visit should occur a minimum of 7 weeks (49 days) and a maximum of 9 weeks (63 days) 
from the previous injection. 
 


 
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Cohort 2 Weeks 56, 64, 72, 80, 88 Visit Procedures (Step 4 – injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling (Week 72 only) 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• CD4 count and percentage (Week 72 only) 
• HIV-1 RNA (Weeks 64 and 80 only) 
• Store plasma for genotypic and phenotypic resistance testing (Weeks 64 and 
80 only) 
• PK evaluation (Weeks 64, 80, and 88 only): Single pre-dose sample 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be 
obtained before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 
6.4.13 Cohort 2 Week 96 Visit (Step 4 – injection phase) 
 
The Week 96 visit target date is 644 days after completion of the Week 4b visit, with a target 
window of ±7 days from the target date. Additionally, the Week 96 visit should occur a minimum 
of 7 weeks (49 days) and a maximum of 9 weeks (63 days) from the previous injection. 
 
At the Week 96 visit, Cohort 2 Step 4 participants who will continue to receive injectable CAB 
LA + RPV LA external to the protocol will exit the study. See Section 6.8 for more information 
on post-study contacts, and Section 14.11 for more information regarding post-trial access to 
study products. Participants who discontinue receiving the injectable CAB LA + RPV LA beyond 
the Week 96 visit will not exit the study but will be followed per the LSFU visit schedule as 
described in Section 6.5 below. 
 


 
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Cohort 2 Week 96 Visit Procedures (Step 4 – injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling  
• Provide instructions for cART administration and adherence counseling to the 
participant, parent or guardian, (Week 96 as study exit visit only)  
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam  
• Identify/review/update adverse events 
• Sexual Maturity Rating assessment 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• CD4 count and percentage  
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be obtained 
before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 
6.4.14 Interim Injection Visit Following Short-Term Oral Bridging (Step 4 – injection phase) 
 
For Cohort 2 Step 4 participants resuming injectable study products following short-term oral 
bridging, in consultation with and per CMC guidance, an interim injection visit may be required 
to administer study product injections outside of a regularly scheduled injection visit window.  In 
consultation with the CMC, one or more interim injection visits may be necessary to 
appropriately reinitiate a participant on the dosing regimen or to realign to the original injection 
visit dosing schedule (as established based on the Cohort 2 Step 4 Week 4b visit).  Regularly 
scheduled visits may be missed to maintain adequate spacing requirements between interim 
injection visits.  The CMC must be consulted prior to initiating short-term oral bridging and prior 
resuming study product injections regarding clinical considerations, and injectable study product 
management and scheduling.  It is generally expected that, in consultation with the CMC, the 
following guidelines will apply when resuming injectable study products following short-term 
oral bridging: 
• 
If a participant will be on short-term oral bridging for ≤ 8 weeks (56 days) and is able to 
receive their study product injections with ≥ 3 weeks (21 days) before the next regularly 
scheduled injection visit, then an interim injection visit may be conducted; the next regularly 
scheduled injection visit will be conducted as originally scheduled. 
• 
If a participant will be on short-term oral bridging for ≤ 8 weeks (56 days) but there are < 3 
weeks (21 days) until the next regularly scheduled injection visit, then oral bridging should 
continue until the next regularly scheduled injection visit.  No interim injection visit will be 
conducted; and the regularly scheduled injection visit should occur early within the window 
to facilitate the shortest course of oral bridging necessary. 


 
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• 
If a participant will be on short-term oral bridging for more than 8 weeks (56 days), the CMC 
must be consulted for guidance on resuming the injections versus premature discontinuation 
of study products. 
 
Interim injection visit procedures are provided below, and study data will be entered into eCRFs 
per Section 5.1.5 and Section 7.2  Section 6.9 must also be followed prior to administering any 
study product injection.  Further details and guidance on scheduling and conducting study 
injection visits, including interim injection visits, are provided in the IMPAACT 2017 MOP. 
 
Cohort 2 Step 4 Interim Injection Visit Procedures (Step 4 - injection phase) 
Behavioral and 
Counseling 
• Provide adherence counseling* 
• Provide contraceptive counseling* 
Clinical 
• Update medical and medications history since last visit* 
• Perform symptom-directed physical exam* 
• Identify/review/update adverse events* 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample* 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test; result must be obtained 
before administering injectable study product* 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
*Perform prior to administration of injectable study products 
 
6.5 
Long-Term Safety and Washout PK Follow-Up (LSFU) Visits  
 
As noted in Section 3, the below specified participants will be followed according to the long-
term safety and washout PK follow-up (LSFU) visit schedule:  
• 
For Cohort 1 Step 2 participants: upon premature permanent discontinuation of injectable 
study product, or completion of the Cohort 1 Step 2 Week 16 visit 
 
• 
For Cohort 1 Step 2 participants who enroll to Cohort 2 Step 3 but are ineligible for Step 4: 
upon premature permanent discontinuation of oral study product in Cohort 2 Step 3 (the 
LSFU visit schedule will be based on the date of their last study product injection, i.e. their 
Cohort 1 Step 2 Week 8 visit) 
 
• 
For Cohort 2 Step 4 participants: upon premature permanent discontinuation of injectable 
study products, or completion of the Cohort 2 Step 4 Week 96 study visit but not continuing 
to receive injectable CAB LA + RPV LA external to the protocol (see Section 6.4.13 above)  
 
• 
Female participants who discontinue study product use (either oral or injectable study 
product) due to pregnancy during Steps 1-4 
 
For participants permanently discontinuing injectable study product (not due to pregnancy), the 
LSFU visit schedule is based on the date of the participant’s last study product injection. For 


 
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Cohort 1 Step 2 participants who complete their Week 16 visit, their next scheduled visit will be 
the LSFU Week 24 Visit (and the LSFU Week 8 Visit is skipped).  
 
Female participants who permanently discontinue study product (either oral or injectable study 
product and during Steps 1 through 4) due to pregnancy will be followed for 48 weeks, based on 
the date of the positive confirmatory pregnancy test result, per the LSFU visit schedule. For 
female participants who become pregnant during LSFU visits, the LSFU visits will continue as 
scheduled and not restart. All LSFU visit procedures will be conducted, with the exception that 
pregnancy testing will not be required for participants who are currently pregnant. See Section 8.3 
for further details on management of pregnant participants and pregnancy outcome.  
 
Cohort 2 Step 3 participants should resume (non-study provided) cART as soon as possible and 
within 4 weeks from their last oral study product use. Cohort 2 Step 4 participants should resume 
(non-study provided) cART at 8 weeks (±7 days) after their last study product injections. See the 
IMPAACT 2017 MOP for further guidance on scheduling LSFU study visits. 
 
During LSFU, a single random PK sample will be collected at each visit as shown in the 
procedural tables below. Participants must have sufficient blood volume collection for their 
assigned study product(s), as specified in the LPC. See Section 6.16 for additional considerations 
for laboratory procedures, and Appendix I-C for blood volume ranges during LSFU visits. 
 
6.5.1 
LSFU Week 8 Visit 
 
The LSFU Week 8 visit is targeted to be conducted 56 days after the last administration of 
injectable study product (or confirmatory positive pregnancy test result), with a target window of 
-14 days/+28 days from the target visit date. For Cohort 1 Step 2 participants completing the 
Week 16 visit, the LSFU Week 8 Visit will be skipped. Cohort 2 participants will resume (non-
study provided) oral cART at 8 weeks (±7 days) of discontinuing study product.  
 
LSFU Week 8 Visit Procedures (LSFU) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling 
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: single sample 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test (unless currently 
pregnant) 
 


 
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Sites may conduct interim safety visits between the LSFU Week 8 and LSFU Week 24 visits to 
clinically assess participants as they initiate their cART regimen, per standard of care or site 
SOPs. 
 
6.5.2 
LSFU Week 24 Visit 
 
The LSFU Week 24 Visit is targeted to take place 168 days after the last administration of 
injectable study product (or confirmatory positive pregnancy test result), with a target window of 
±42 days from the target visit date. 
 
LSFU Week 24 Visit Procedures (LSFU) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: single sample 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test (unless currently 
pregnant) 
 
6.5.3 
LSFU Week 36 Visit 
 
The LSFU Week 36 Visit is targeted to take place 252 days after the last administration of 
injectable study product (or confirmatory positive pregnancy test result), with a target window of 
±42 days from the target visit date. 
 


 
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LSFU Week 36 Visit Procedures (LSFU) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: single sample 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test (unless currently 
pregnant) 
 
6.5.4 
LSFU Week 48 /Study Exit/Early Termination Visit 
 
The LSFU Week 48 Visit is targeted to take place 336 days after the last administration of 
injectable study product (or confirmatory positive pregnancy test result), with a target window of 
±42 days from the target visit date. These same visit procedures will be conducted as an Early 
Termination visit for participants withdrawing or terminating from the study prior to scheduled 
completion of study follow-up, instead of their regularly scheduled study visit, for a final series of 
evaluations. All participants completing this visit, whether as the LSFU Week 48 Visit (per the 
LSFU visit schedule) or as an Early Termination visit, will exit the study.  
 
Scheduling and completion of Early Termination visits will be in consideration of participant 
withdrawal or termination; visit procedures may be combined with an ongoing study visit. Any 
procedures conducted within 14 days of an Early Termination visit need not be repeated, with the 
following target dates for completing the Early Termination visit:   
• 
For Cohort 1 Step 1 and Cohort 2 Step 3 participants not progressing to the injection phase, 
an Early Termination visit is targeted to be completed 28 days after the participant’s last oral 
study product use; the Early Termination visit may be completed sooner, if necessary. For 
these participants, a PK evaluation will not be performed at this visit.  Cohort 2 Step 3 
participants should resume (non-study provided) cART as soon as possible and within 4 
weeks from their last oral study product use. 
 
• 
For Cohort 1 Step 2, Cohort 2 Step 4, and any participant being followed per the LSFU visit 
schedule, an Early Termination visit is targeted to be completed within 28 days (inclusive) of 
the previous study visit.  Cohort 2 Step 4 participants should resume (non-study provided) 
cART at 8 weeks (±7 days) after their last study product injections.    
 
Participants completing an Early Termination visit will be followed until resolution (return to 
baseline) or stabilization of any adverse events per Section 8.  
 
Refer to Section 6.7 for the definition of scheduled completion of follow-up, and additional 
considerations for participants exiting the study (whether scheduled completion of follow-up or 
an early termination visit). Refer to Section 8.8 for criteria for participant withdrawal or 


 
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premature termination from the study. The IMPAACT 2017 MOP provides further guidance on 
Early Termination visit scheduling considerations. 
 
LSFU Week 48 /Early Termination Visit Procedures  
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling 
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC if indicated) 
• Sexual Maturity Rating assessment 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (only if PK is also collected at this 
visit, g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing (LSFU Week 48 
visit only) 
• Store whole blood for genotypic resistance testing (Early Termination visit 
only) 
• PK evaluation: single sample, (except for participants completing an Early 
Termination visit during Cohort 1 Step 1 or Cohort 2 Step 3) 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test (unless currently 
pregnant) 
 
6.6 
Confirmation of Virologic Failure Visit 
 
Virologic failure is defined as two consecutive plasma HIV-1 RNA test results ≥200 copies/mL, 
from two separate specimens. Any participant with a plasma HIV-1 RNA level ≥200 copies/mL 
after enrollment should be recalled to the clinic for confirmatory testing 2-4 weeks after specimen 
collection for the initial test. Refer to Section 8.4 for more information on monitoring HIV-1 viral 
load, definitions of virologic failure, and managing virologic failure  
 
Scheduling of confirmatory testing should be in consideration of potential causes for virologic 
failure such as intercurrent illness, recent immunizations, inadequate adherence or interruptions to 
cART (for Cohort 1 or LSFU participants), interruptions of study product due to toxicity 
management, or other extenuating circumstances. For Cohort 1 Step 2 or Cohort 2 Step 4 
participants (i.e. participants receiving injectable study product), confirmatory test results should 
ideally be obtained and reviewed prior to the next scheduled administration of injectable study 
product. While injection study visits for these participants may be delayed within the respective 
target visit window, injectable study product must not be withheld for pending confirmatory 
testing or results. 
  
Confirmation of Virologic Failure visit procedures may be combined with regularly scheduled 
visit procedures if they are performed within the target window of a regularly scheduled visit. In 
addition to the protocol-specific procedures listed in this section, study staff may complete other 


 
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tasks and assessments consistent with local standards of care and site SOPs. Viral load results 
should be provided to participants and may be used to guide adherence counseling. See Section 
6.14 for additional details on adherence counseling. 
 
Confirmation of Virologic Failure Visit Procedures 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling, if indicated 
• Provide instructions for cART administration and adherence counseling to the 
participant, parent or guardian, if indicated 
Clinical 
• Obtain interval medical and medications history  
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC if indicated) 
Laboratory 
Blood 
Collect blood for: 
• HIV-1 RNA 
• Plasma for genotypic and phenotypic resistance testing 
• PK evaluation: single sample 
 
Blood or 
Urine 
• For females, collect blood or urine for pregnancy test (unless currently 
pregnant) 
 
6.7 
Study Exit 
 
Participants may exit the study at different timepoints, with the following considered as scheduled 
study completion of follow-up: 
• 
Upon permanently discontinuing injectable study product, Cohort 1 Step 2 and Cohort 2 
Step 4 participants will be followed per the LSFU visit schedule, and will exit the study 
at their LSFU Week 48 study visit (see Section 6.5 above) 
 
• 
Cohort 2 participants continuing to receive the study product after their Step 4 Week 96 
visit (as external to the protocol; see Section 14.11) will not be followed per the LSFU 
visit schedule, and will exit the study at their Week 96 visit (See Section 6.4.13 above) 
 
Any participant withdrawing or terminating from the study prior to these timepoints is considered 
as prematurely terminating from the study and the LSFU Week 48 study visit will be conducted 
as an Early Termination visit, instead of their regularly scheduled study visit, for a final series of 
evaluations. All visit procedures as described in and applicable to Section 6.5.4 will be completed 
for an Early Termination visit, with additional procedures and exceptions as noted.  
 
At any study exit visit (scheduled completion of follow-up or an early termination visit), 
arrangements should be made to provide all clinically meaningful results to the participant and 
the participant’s parent or guardian. The participant and parent or guardian should be provided 
information on how to remain in contact with study staff (if desired) and how to learn about the 
results of the study when available. The participant and the participant’s parent or guardian 
should also be provided information, counseling, and referrals to non-study sources of care and 
treatment for the participant, as applicable. Cohort 2 Step 3 participants should resume (non-study 
provided) cART as soon as possible and within 4 weeks from their last oral study product use.  
Cohort 2 Step 4 participants should resume (non-study provided) cART at 8 weeks (±7 days) 
after their last study product injections. See Section 8.1 regarding management of adverse events 
at study exit, and Section 8.8 for additional considerations regarding participant withdrawal or 
termination. 


 
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6.8 
Post-Study Contacts 
 
Planning for transition to non-study care and treatment for participants exiting the study should 
begin prior to the participant’s scheduled study exit visit, and the transition should be 
implemented at the participant’s scheduled study exit visit. Study staff will complete a final study 
contact, with the participant and the participant’s parent or guardian, if applicable, within 4 to 8 
weeks of the participant’s study exit visit to confirm the transition and should be documented in 
each participant’s study chart. These contacts are not expected to be entered into eCRFs. 
However, eCRF data collection is required after the participant’s study exit visit in the following 
scenarios:  
• 
If a participant becomes pregnant while on study:  Refer to Section 8.3; the pregnancy 
outcome must be ascertained and the relevant eCRFs entered after the participant exits the 
study to record the pregnancy outcome. 
 
• 
If confirmation of virologic failure is pending after the LSFU Week 48 visit:  Refer to Section 
6.5; in this scenario, the confirmatory HIV-1 RNA PCR assay must be performed and the 
relevant eCRFs entered to record the result of the assay. 
 
• 
If the participant has any Grade 3 or higher adverse event at the study exit visit: participants 
should be asked to be continued on study for up to 56 days or until resolution (return to 
baseline) or stabilization (i.e. Grade 2 or lower), whichever is sooner, with the frequency of 
visits determined by the site investigator. 
 
6.9 
Procedures for Continued Oral and Injectable Study Product Administration 
 
The following procedures must be performed on the same day as and prior to administering study 
product (i.e. either dispensing oral study product or administering study product injection), to 
assess for any indication of study product hold or permanent discontinuation: 
• 
Clinical evaluations per the respective study visit (see Section 6 and Appendix I) 
• 
Laboratory test results from the previous study visit obtained and reviewed for indication of 
study product hold or permanent discontinuation (see Section 8) 
• 
For females, a negative pregnancy test result 
• 
For females of childbearing potential, confirmation (per participant report) of effective 
contraception, per Section 6.13 
 
See Section 8.1 for details regarding participant management. See Section 8.6 for details 
regarding deferring study product due to managing adverse events and other indications.  
 
6.10 
Medical and Medications History  
 
Collection of medical and medication history information is required at each scheduled visit. A 
baseline history is established at Screening and Entry, and interval (since the last visit) histories 
are obtained at subsequent follow-up visits. All history information may be obtained based on 
participant self-report or as reported by the parent or guardian, but available medical records 
should be obtained when possible to supplement self-reported information. Refer to the 
IMPAACT 2017 MOP for additional guidance regarding establishing baseline history. 
 
Documented medical conditions will be assessed for severity as described in Section 7.3.3, and 
new conditions occurring during follow-up will also be assessed for relationship to study product 


 
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as described in Section 8.1. Relevant dates will be recorded for all conditions and medications; 
see Section 5.6 for more information on concomitant medications.  
 
Table 7 specifies the baseline and interval medical and medications history elements that must be 
source documented for participants, as well as associated eCRF entry requirements.  
 
Table 7. Documentation Requirements for Medical and Medication Histories 
Assess for and Source Document 
Enter into eCRFs or SES 
Baseline Medical and Medication History Elements 
Age, sex at birth, and other socio-
demographics 
 
Yes (all) 
HIV diagnosis, mode of transmission, and 
ARV treatment history (including all prior 
ARV use) 
Yes (all, including start/stop dates, dates and 
values of results, as applicable) 
History of allergy and/or hypersensitivity 
(including to ARVs) 
Yes (all) 
Medical conditions (including malignancies) 
occurring during the 28 days prior to entry, 
ongoing at entry, as well as all prior 
significant central nervous system disorders 
(including seizures and migraines/headaches), 
mood disorders (such as depression), and 
significant liver disease resulting in 
hospitalization or interfering with daily 
activities.  
Yes (all, including start/stop dates, and dates 
of diagnosis, as applicable) 
Medications, (other than ARVs, see above) 
taken within the 28 days prior to enrollment 
and/or ongoing at enrollment 
Yes (all, except herbal or traditional 
medications are not be captured on eCRFs) 
Assessment of sexual activity 
Yes 
Contraceptives ongoing at enrollment, 
including start date and most recent date of 
administration of current contraceptive 
method. 
 
Note:  Hormonal-based contraceptives must 
have been initiated within the prescribed time, 
per the respective contraceptive method, to be 
considered effective at the time of Entry. The 
site IoR or designee is responsible for 
ensuring that the contraceptive is used in 
accordance with the approved product label 
Yes 
Any other information needed to determine 
eligibility for the study 
— 
Interval Medical and Medication History Elements 
Current status of conditions that were ongoing 
at the previous visit 
Any updates of previous entries 
(e.g., resolution dates) 
Occurrence of any new conditions since the 
last visit 
Any newly identified adverse events that meet 
criteria in Section 7.2 


 
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Assess for and Source Document 
Enter into eCRFs or SES 
Current status of medications (including 
contraceptives) that were ongoing at the 
previous visit 
Any updates of previous entries  
(e.g., stop dates) 
Use of any new medications since the last 
visit (see Section 5.6 for more information on 
concomitant medications) 
 
Note: For participants in Cohort 1 and LSFU, 
ARVs would be considered concomitant 
medications.  
 
 
• Any concomitant ARVs taken 
• Any new use of concomitant medications, 
including contraceptives  
• All medications taken at onset of or in 
response to adverse events that are specified 
to be entered into eCRFs per Section 7.2 
 
Note: herbal or traditional medications taken 
during follow-up should not be captured on 
eCRFs. 
Oral Study Product since the last visit (for 
Cohort 1 Step 1, Cohort 2 Step 3 participants, 
and any Cohort 1 or Cohort 2 participants on 
oral bridging)   
 
Note: Injectable study product information is 
not considered as part of medical and 
medications history since last visit, and will 
be collected as per Section 5. See Section 6 
above for details regarding study product 
dosing documentation requirements for PK 
evaluations. 
• Oral study product doses taken from time of 
enrollment through completion of follow-up 
Assessment of sexual activity since the last 
visit 
— 
 
6.11 
Physical Examinations 
 
A physical examination is required at each scheduled visit, either as a complete physical exam or 
as a symptom-directed physical exam, per the specified procedures for each visit. Table 8 below 
outlines the visits when a complete physical exam is required; symptom-directed exams are 
required at all other scheduled visits. 
 
Table 8. Visits Requiring Complete Physical Examination 
Cohort 1 
Screening, Week 4a, and Week 16 Visits 
Cohort 2 
Screening, Week 4a, Week 24, Week 48,  
and Week 96 
LSFU 
LSFU Week 4, and LSFU Week 48/Early 
Termination Visit 
 
Complete exams should include the following: 
• 
Height and weight 
• 
Vital signs, including heart rate, temperature and blood pressure 
• 
Examination of: 
– General appearance 
– Head 


 
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– Eyes  
– Ears  
– Nose  
– Neck 
– Mouth and throat 
– Lymph nodes 
– Lungs 
– Heart 
– Abdomen 
– Musculoskeletal system 
– Skin 
– Neuro 
– Sexual Maturity Rating (SMR) (at Screening for both Cohort 1 and Cohort 2, Cohort 1 
Week 16, Cohort 2 Week 24 and 96, and LSFU Week 48/Early Termination visits)  
• 
Examination of other body systems driven by other identified signs or symptoms 
 
Symptom-directed exam should include the following:  
• 
Height and weight 
• 
Vital signs, including heart rate, temperature and blood pressure 
• 
Examination of body systems driven by identified signs or symptoms 
 
At all visits, additional assessments may be performed at the discretion of the examining site 
investigator. All exam findings should be source documented, with vital signs and any abnormal 
findings entered into eCRFs, as specified in Section 7.2. Additionally, height and weight must be 
obtained on the same day as any PK sample collection, and source documented and entered into 
eCRFs, even if a physical exam was already conducted as part of that visit.  
 
6.12 
Performing an Electrocardiogram (ECG/EKG)  
 
Electrocardiogram (ECG) readings are required at Screening (for both Cohort 1 and Cohort 2), 
Cohort 1 Weeks 9 and 16, and Cohort 2 Week 4b. For all ECG readings, a 12-lead ECG should 
be performed with the participant in a semi-supine position. An ECG machine that automatically 
calculates the heart rate and measures QTc intervals is preferred, and the automated calculations 
can be used for reporting purposes. Otherwise, an appropriately qualified ECG reader must 
interpret the results.  
 
At the Cohort 1 Screening and Cohort 2 Screening visits, the ECG reading should be done in 
triplicate such that three, single automated QTc readings will be done, each separated by at least 2 
minutes, with the mean value establishing baseline. The triplicate ECG reading must be 
conducted within 2 weeks (14 days) of the participant’s Entry visit; the triplicate ECG conducted 
at the Screening may be repeated to maintain this timeframe. During follow-up, single automated 
readings will be compared to the baseline value, with a result of > 500 msec requiring two repeat 
readings (for a total of three readings - as performed at the respective Screening visit). See 
Section 8.2 for Monitoring and Management of QTc Prolongation. 
 
All ECG readings should be source documented, and baseline (i.e. mean value of triplicate 
readings) and follow-up values entered into eCRFs. Abnormal findings identified after 
administration of first dose of oral study product will be entered into eCRFs as specified in 
Section 7.2. 
 


 
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6.13 
Pregnancy Testing and Contraceptive Counseling 
 
Pregnancy testing is required for all female participants, at specified study visits and prior to 
administration of study product, regardless of self-reported sexual activity or childbearing 
potential. See Section 8.3 for details on participant and study product management relating to 
Management of Contraception and Pregnancy.  
 
As stated in Section 4.1.14, females of childbearing potential are required to use at least one 
allowable effective method of contraception to enroll to the study. For any female participant who 
becomes of childbearing potential during the study, an allowable effective contraceptive method 
must be initiated prior to administration of study product (oral or injectable study product). A 
female born participant is considered of childbearing potential following the initiation of puberty 
(Tanner stage 2) until becoming post-menopausal, unless permanently sterile or with medically 
documented ovarian failure. Women are considered to be in a postmenopausal state when they 
are > 54 years of age with cessation of previously occurring menses for > 12 months without an 
alternative cause. Permanent sterilization includes hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy in a female participant of any age. 
 
The effective methods of contraception allowed for this study are listed below.  
• 
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the participant’s preferred and usual 
lifestyle 
 
OR 
 
• 
Consistent and correct use of 1 of the following methods of birth control listed below.  
o Intrauterine device (IUD) with a failure rate of < 1% per year  
o Intrauterine hormone-releasing system (IUS) with a failure rate of < 1% per year  
o Tubal sterilization  
o Essure micro-insert system (provided confirmation of success 3 months after procedure)  
o Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)  
 
OR 
 
• 
Consistent and correct use of one hormonal method AND one barrier method  
o Barrier methods  
▪ 
Diaphragm with spermicide  
▪ 
Cervical cap with spermicide  
▪ 
Male condom (with or without spermicide)  
o Hormonal methods  
▪ 
Oral contraceptives (either combined or progesterone only)  
▪ 
Injectable progesterone  
▪ 
Implants of levonorgestrel  
▪ 
Transdermal contraceptive patch  
▪ 
Contraceptive vaginal ring  
 
For any methods of contraception not included in the listing which have a < 1% failure rate, per 
the product label, may be allowed in consultation with the CMC. 
 


 
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Study staff will provide contraception counseling to all male and female participants, regardless 
of self-reported sexual activity or childbearing potential, at all study visits. Counseling will 
include maintaining contraceptive use for 30 days after the last oral study product use and for 48 
weeks after any single injection of study product. Female participants should also be encouraged 
to delay pregnancy for at least 30 days following oral study product use, or 48 weeks following 
any single injection of study product. 
 
At any point during study participation, additional counseling on correct use of chosen 
contraceptive methods should also be offered according to site SOPs; this will include 
information on correct use of barrier methods. For Cohort 1 and all LSFU participants, 
contraceptive counseling will also reflect the ARVs which participants are currently taking for the 
potential interactions between these ARVs and available contraceptive methods. Contraceptive 
counseling may be tailored to be age-appropriate and will be provided by clinic and/or pharmacy 
staff consistent with local standards of care and site SOPs. Study sites should ideally integrate 
provision of contraceptive methods with other services offered to study participants and should 
provide referrals to non-study sources of methods that cannot be provided at the study site. Study 
staff should confirm (per participant report) effective contraception with one of the study-required 
contraceptive methods for all female participants of childbearing potential at each visit in which 
study product is administered.  
 
Pregnancy test results will be disclosed to participants and their parent/guardians consistent with 
local standards of care; local standard procedures will be noted in site-specific informed consent 
and assent forms. 
 
6.14 
Study Product Adherence Assessment and Adherence Counseling (Study Product, cART 
Regimen, Study Visits) 
 
Prior to progressing to the injection phase, participants should be assessed for adherence to oral 
study product and whether sufficient evaluations of safety and tolerability were permitted to be 
conducted during the oral lead-in phase. Pill counts will be conducted at the Week 2, Week 4a 
and Week 4b visits (for both Cohorts 1 and 2) but will not be used as a basis for counseling 
participants on oral study product adherence. Information obtained through the pill counts, 
participant self-report, and adherence counseling discussions should be used in combination as a 
broader adherence assessment evaluation when assessing each participant for eligibility to receive 
injectable study product. The IoR, or designee, should source document all contributing 
information leading to and final determination of Step 2 or Step 4 eligibility with regards to 
Sections 4.3.4 and 4.4.4.  
 
Adherence counseling will be provided to all study participants and parents/guardians throughout 
study participation at specified study visits, and as needed based on IoR discretion. Topics 
discussed during adherence counseling will vary depending on the Cohort, Step and whether 
participants are also taking a (non-study provided) cART regimen: 
• 
For Cohort 1 participants, adhering to the (non-study provided) cART regimen and 
instructions on cART administration will be provided. These topics will also be discussed 
prior to participants transitioning to the LSFU visit schedule (if permanently 
discontinuing injectable study product), during specified LSFU visits, and at Early 
Termination visits. 
• 
For Cohort 1 Step 1 and Cohort 2 Step 3 participants, counseling on adhering to the oral 
study product will be provided in relation to the purpose of the oral lead-in phase and 
allowing for sufficient evaluations of safety and tolerability. 


 
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• 
For Cohort 1 Step 2 and Cohort 2 Step 4 participants, counseling will include discussion 
with participants regarding the importance of adhering to the intended injectable study 
product dosing regimen, and adhering to the study visit schedule. 
• 
For all Cohort 2 participants, counseling will include discussion on the importance of 
adhering to the study visit schedule as these participants are no longer receiving a (non-
study provided) cART regimen. 
• 
For participants exiting the study at the Cohort 2 Week 96 visit (to continue injectable 
CAB LA + RPV LA external to the protocol), counseling will include the importance of 
adhering to the intended injectable dosing regimen and schedule. 
 
Counseling may be provided by clinic and/or pharmacy staff consistent with local standards of 
care and site SOPs. Counseling should be provided in a client-centered manner, tailored as 
needed to the information, skills building, and support needs of each participant. Information on 
correct use of oral study products will be provided. Counseling will also address challenges to 
consistent use of oral study product or attending injectable study visits over time, with the aim of 
supporting participants in identifying strategies to address any such challenges. 
 
6.15 
Acceptability and Tolerability Assessments 
 
Acceptability and tolerability of the study products will be assessed at specified study visits, and 
at visits during which permanent study product discontinuation is initiated. These assessments 
will be administered to participants by site staff via questionnaires covering topics on participant 
perceptions of the study product injections, reasons for switching from daily oral cART to long-
acting study products, satisfaction with treatment, quality of life, and treatment preferences. A 
shortened assessment battery will be utilized for individuals who are unable to complete the 
questionnaires in English or Spanish. Prior to the participant leaving the clinic, questionnaires 
should be reviewed, and any potential adverse events reported in the participant’s responses 
should be clinically assessed. Further guidance and considerations for conducting and reviewing 
the acceptability and tolerability assessments, the timing of administering the assessments relative 
to other visit procedures, as well as guidance regarding the appropriate site staff to administer 
specified assessments is provided in the study-specific MOP. 
 
6.16 
Additional Considerations for Laboratory Procedures 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy on 
Requirements for DAIDS Funded and/or Sponsored Laboratories in Clinical Trials Policy, which 
is available at: https://www.niaid.nih.gov/research/daids-clinical-research-laboratory-specimens-
management. 
 
6.16.1 Specimen Collection 
 
Specimens will be collected for this study as indicated in the Schedule of Evaluations and per 
detailed guidance provided in the LPC, which will be posted on the study-specific webpage: 
http://impaactnetwork.org/studies/IMPAACT2017.asp. Site staff collecting specimens for PK 
evaluations must prepare the workspace and supplies with regards to protecting all specimens 
from light, as specified in the LPC.  
 
In accordance with US National Institutes of Health (NIH) recommendations, pediatric (less than 
18 years) blood collection will not exceed 5 mL/kg in a single day or 9.5 mL/kg over any eight-


 
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week period. Adult (18 years and older) blood collection will not exceed 10.5 mL/kg or 550 mL, 
whichever is smaller, over any eight-week period.  
 
In the event blood collection must be limited, available specimens will be prioritized for use in 
the following order: (1) safety (chemistries, hematology, pregnancy testing), (2) PK, (3) HIV-1 
viral load, and (4) genotypic and phenotypic resistance storage sample.  
 
6.16.2 Specimen Preparation, Testing, Storage, and Shipping 
 
All specimens collected for this study will be labeled, transported, processed, tested, stored and/or 
shipped in accordance with the DAIDS policy referenced above, site and local laboratory SOPs, 
and the LPC. The frequency of specimen collection and testing will be directed by the Schedules 
of Evaluations in Appendix I-A, Appendix I-B, and Appendix I-C and specifications for clinical 
management provided in Section 8. The Laboratory Data Management System (LDMS) will be 
used to document specimen collection, testing, storage, and shipping as specified in the LPC. Any 
specimens stored at the Screening Visit for participants who do not subsequently enroll in the 
study will be destroyed. 
 
The following will be performed in real time at local laboratories that are CLIA-certified or 
equivalent (for US sites) or VQA-certified (for non-US sites) for the tests performed: 
• 
Pregnancy tests 
• 
Hematology laboratory testing: complete blood counts, with platelets (cells/mm3) and 
hemoglobin (g/dL) 
• 
Chemistry laboratory testing:  Creatinine, Creatine kinase (CPK), Creatinine Clearance 
(CrCl; Schwartz formula mL/min/1.73m2), Total bilirubin, ALT (u/l), Lipase (u/l), Blood 
Urea Nitrogen (BUN), Albumin (g/dL) 
• 
CD4 count and percentage tests 
• 
Plasma HIV-1 RNA assays 
 
HIV genotypic and phenotypic resistance samples for storage (collected at study visits other than 
the Confirmation of Virologic Failure visit) must be processed and stored per the LPC.  
 
HIV genotypic and phenotypic resistance samples collected at the Confirmation of Virologic 
Failure visit must be processed with plasma retained at the site laboratory, as specified in the 
LPC, pending HIV-1 RNA test results to confirm virologic failure. For participants with 
confirmed virologic failure, aliquots of plasma stored for resistance testing collected during the 
Confirmation of Virologic Failure visit, the visit in which the participant had an initial elevated 
viral load test result, the whole blood sample stored at the Entry visit, and any other study visits 
as requested by the CMC, will be shipped with testing performed in real time at a designated 
CLIA-certified or equivalent testing laboratory, as specified in the LPC. If failure is not 
confirmed, resistance samples collected during the Confirmation of Virologic Failure visit will 
remain stored at the site laboratory. 
 
Specimens collected, processed, and stored at site laboratories for PK evaluations are generally 
expected to be shipped to the designated testing laboratory as follows, or as otherwise requested 
by the protocol team:   
• 
Cohort 1 PK samples from Week 2 through Week 8 visits should be shipped upon completion 
of the Week 8 visit.  Cohort 1 PK samples from Week 9 through Week 16 visits should be 
shipped upon completion of the Week 16 visit. 


 
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• 
Cohort 2 PK samples from Week 2 through Week 16 should be shipped upon completion of 
the Week 16 visit.  Cohort 2 PK samples from the Week 24 visit should be shipped in real 
time and upon completion of the Week 24 visit.  Cohort 2 samples from Week 25 through 
Week 48 visits should be shipped upon completion of the Week 48 visit. 
• 
Cohort 2 PK samples from Week 56 through Week 96 visits, all LSFU visits (from both 
Cohorts 1 and 2), and all Confirmation of Virologic Failure visits (from both Cohorts 1 and 2) 
should be batched and shipped quarterly. 
 
After all protocol-specified laboratory testing has been performed, residual specimens may be of 
interest for future research use. Participants and participants’ parents or guardians (if applicable) 
will be asked to provide written informed consent/assent for future research use of these 
specimens, if permitted by site IRBs/ECs and other applicable review bodies. Parents or 
guardians (or participants) may choose to provide or to decline informed consent for future 
research use of residual specimens with no impact on other aspects of participation in the study. If 
informed consent for future research use of residual specimens is initially provided but if 
participants or their parent/guardian subsequently change their mind and withdraw that consent, 
all remaining residual samples will be destroyed.  
 
6.16.3 Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study as currently recommended by the US Centers for Disease Control and 
Prevention, NIH, and other applicable agencies. All specimens will be shipped using packaging 
that meets requirements specified by the International Air Transport Association Dangerous 
Goods Regulations for UN 3373, Biological Substance, Category B, and Packing Instruction 650. 
Culture isolates, if obtained in this study, are to be shipped as specified for UN 2814 Category A 
Infectious Substances. 
 
 
7 
SAFETY ASSESSMENT, MONITORING, AND REPORTING 
 
Participant safety will be carefully assessed, monitored, and reported at multiple levels 
throughout this study. Sections 7.1-7.3 describe safety-related roles, responsibilities, and 
procedures for site investigators. The safety monitoring roles of the Clinical Management 
Committee (CMC) and the IMPAACT Study Monitoring Committee (SMC) are briefly 
referenced in Section 7.1 and described in greater detail in Sections 9.5.1 and 9.5.2. 
 
Unless otherwise noted, the specifications of this section only apply to adolescent participants in 
Cohort 1, Cohort 2, and LSFU. 
 
7.1 
Safety-Related Roles and Responsibilities 
 
7.1.1 
Site Investigators 
 
Site investigators are responsible for continuous monitoring of all study participants and for 
alerting the CMC if unexpected concerns arise. Site investigators will enter safety-related data 
into eCRFs as indicated in Section 7.2 and complete expedited adverse event (EAE) reporting as 
indicated in Section 7.3. Site investigators are also responsible for prompt reporting to their 


 
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IRBs/ECs and other applicable review bodies of any unanticipated problems involving risks to 
any study participants or others. 
 
Importantly, site investigators must inform the CMC of any of the following:  
• 
New onset seizure  
• 
Grade 3 or higher alanine aminotransferase (ALT), creatine kinase (CPK), total bilirubin 
(unless isolated atazanavir related hyperbilirubinemia with normal direct bilirubin), or lipase  
• 
Grade 3 or higher adverse events assessed as related to study product 
• 
For Cohort 1, Step 2 and Cohort 2, Step 4 participants, a missed scheduled study product 
injection visit 
 
For creatine kinase (CPK), total bilirubin and lipase elevations, and Grade 3 or higher adverse 
events assessed as related to study product, the CMC should be informed as soon as possible and 
within 48 hours of awareness of the event. For new onset of seizure, the CMC should be informed 
within 24 hours of awareness of the event.  
 
For Cohort 1, Step 2 and Cohort 2, Step 4 participants who miss a scheduled study product 
injection, or who have a temporary hold which will cause the participant to miss a scheduled 
study product injection, the CMC should be consulted as soon as possible and within 48 hours of 
site awareness.  
 
7.1.2 
Clinical Management Committee (CMC) 
 
The following Protocol Team members comprise the CMC: Co-Chairs, Medical Officers, 
Statisticians, Data Managers, Clinical Trial Specialists, Laboratory Center Representatives, 
protocol Pharmacologists, at least one protocol Investigator, at least one Statistician 
representative from ViiV, at least one medical (or designee) representative from each ViiV and 
Janssen, and at least one Pharmacologist representative from each ViiV and Janssen. The CMC 
will provide guidance as needed to site investigators regarding all aspects of participant 
management, including but not limited to questions of participant eligibility, management of 
adverse events, study product administration, cART regimens, and other concomitant 
medications. Refer to Section 8 for more information on participant management. 
 
On behalf of the full Protocol Team, the CMC will monitor participant safety through routine 
review of study data reports as described in Section 9.5.1.  
 
Detailed toxicity management algorithms including criteria for discontinuation of study product 
can be found in Section 8 below. 
 
7.1.3 
Study Monitoring Committee (SMC) 
 
An independent IMPAACT Study Monitoring Committee (SMC) will monitor participant safety 
through routine and as needed reviews of study data. Refer to Section 9.5.2 for more information 
on the composition and role of the SMC in monitoring of this study.  
 
7.2 
Safety-Related Data Collection 
 
This section describes eCRF data collection for pre-existing conditions and adverse events. 
Criteria for expedited reporting of specified adverse events are further detailed in Sections 7.3.2 
and 7.3.3 below.  


 
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The definition of the term adverse event provided in Version 2.0 of the Manual for Expedited 
Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) will be used in this study. This 
definition will be applied only to the adolescent participants, beginning at the time of enrollment 
(as defined in Section 4.7), regardless of subsequent administration of or exposure to study 
product. Any untoward medical conditions (including abnormal laboratory test results, signs, 
symptoms, or diseases) identified prior to enrollment will be considered pre-existing conditions. 
 
Pre-Existing Conditions  
 
The following pre-existing conditions will be entered into medical history eCRFs: 
• 
All conditions identified during the 28 days prior to study entry  
• 
All conditions ongoing at the time of enrollment 
• 
All prior significant central nervous system disorders (including seizures and 
migraines/headaches), mood disorders (such as depression), and significant liver disease 
resulting in hospitalization or interfering with daily activities  
 
Adverse Events  
 
The following adverse events will be entered into the adverse events eCRFs: 
• 
Grade 1 and higher clinical adverse events (including all signs, symptoms, and associated 
laboratory test results of the clinical adverse event) 
• 
Grade 3 or higher laboratory-only adverse events 
• 
All adverse events that result in temporary study product hold or permanent discontinuation 
of study product 
• 
All adverse events that meet criteria for expedited reporting per protocol Section 7.3.2 
 
Laboratory Test Results  
 
All protocol-required laboratory test results will be entered into laboratory eCRFs. 
 
7.3 
Expedited Adverse Event (EAE) Reporting 
 
7.3.1 
EAE Reporting to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of adverse events are outlined in 
Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE 
Manual), which is available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-
research-sites/manual-expedited-reporting-adverse-events-daids. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system, must be used for EAE reporting to DAIDS. In the event of system outages or technical 
difficulties, EAEs may be submitted using the DAIDS EAE Form. This form is available on the 
DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. 
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Queries may also be sent from within the DAERS application 
itself.  
 
For questions about expedited reporting, please contact the DAIDS RSC Safety Office at 
DAIDSRSCSafetyOffice@tech-res.com. 


 
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7.3.2 
EAE Reporting Requirements for this Study 
 
The SAE (serious adverse event) reporting category, as defined in Version 2.0 of the DAIDS 
EAE Manual, will be used for this study. In addition, the following must also be reported in an 
expedited manner (i.e., as EAEs), regardless of severity or relationship to study product:   
• 
ALT ≥ 3x ULN with total bilirubin ≥ 2x ULN 
• 
ALT ≥8x ULN  
• 
ALT ≥3x baseline ALT with signs/symptoms of acute hepatitis  
• 
ALT ≥5x ULN that persists >2 weeks   
• 
Any seizure event 
 
The study agents for which expedited reporting are required are oral cabotegravir (CAB), long-
acting injectable cabotegravir (CAB LA), and oral rilpivirine (RPV), and long-acting injectable 
rilpivirine (RPV LA). 
 
Information on AEs will be included in reports to the US FDA, and other government and 
regulatory authorities, as applicable. 
 
7.3.3 
Grading Severity of Events (applies to EAEs and all other adverse events) 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017, will be used in this study. 
This table is available on the RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables. 
 
7.3.4 
EAE Reporting Period 
 
The EAE reporting period for this study is the protocol-specific period of follow-up, beginning at 
the time of study entry and ending on the date of the final follow-up visit. For all participants who 
continue per the LSFU visit schedule, EAE reporting requirements continue throughout LSFU 
follow-up. For Cohort 1 participants who may enter Cohort 2 after having exited the study, EAE 
reporting requirements resume upon re-entry into the study. 
 
After this reporting period, unless otherwise noted, only Suspected, Unexpected Serious Adverse 
Reactions (SUSARs) as defined in Version 2.0 of the EAE Manual will be reported to DAIDS if 
the study staff become aware of the events on a passive basis (from publicly available 
information). 
 
 
8 
PARTICIPANT MANAGEMENT 
 
8.1 
Management of Adverse Events 
 
All adverse events identified in this study will be source documented in participant research 
records, consistent with the policies and procedures referenced in Section 12. Among other 
details, source documentation will include the severity of each event (graded as described in 
Section 7.3.3) and its relationship to study product, assessed by the site clinician according to the 
following categories and definitions: 
 


 
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Related 
There is a reasonable possibility that the adverse event may be related to the 
study agents: oral cabotegravir (CAB), long-acting injectable cabotegravir (CAB 
LA), and oral rilpivirine (RPV), and long-acting injectable rilpivirine (RPV LA) 
 
Not related 
There is not a reasonable possibility that the adverse event may be related to the 
study agents: oral cabotegravir (CAB), long-acting injectable cabotegravir (CAB 
LA), and oral rilpivirine (RPV), and long-acting injectable rilpivirine (RPV LA) 
 
Further standardized guidance on determining whether there is a reasonable possibility of a 
relationship is available in the DAIDS EAE Manual, referenced in Section 7.3.1 above. 
  
Adverse events identified in enrolled participants will be managed based on their severity and 
assessed relationship to study product, as described in greater detail below. Unless otherwise 
specified below, AEs (clinical as well as abnormal laboratory values) should be managed per 
general management guidelines in Section 8.1.1. 
 
Individual dose adjustments or reductions of study products for management of toxicity-related 
AEs are not allowed. For Cohort 2 participants, in the event of a temporary study product hold or 
a permanent discontinuation of study product, both study products will always be held (or 
discontinued). For additional considerations regarding Cohort 2 participants and resuming (non-
study provided) cART, see Section 8.6 regarding temporary product holds, and Section 8.7 
regarding permanent discontinuation of study product.  
 
All adverse events must be followed to resolution (return to baseline) or stabilization, with the 
frequency of repeat evaluations determined by the clinical significance of each event. Additional 
evaluations beyond those listed in the Schedules of Evaluations (see Appendix I) may be 
performed at the discretion of the site investigator to determine the etiology of a given event 
and/or further assess its severity or relationship to study product. Clinical management of all 
adverse events should be provided consistent with the best medical judgment of the site 
investigator and local clinical practice standards.  
 
Adverse events that are ongoing at the time of the final study visit, particularly those of Grade 3 
or higher severity, should generally be followed to resolution or stabilization by the site 
investigator; if this is not possible, the site investigator should actively facilitate referral to local 
non-study sources of appropriate medical care and treatment. Unless otherwise specified, when 
management of an adverse event requires consultation with the CMC, the CMC should be 
contacted as soon as possible and within two business days of site awareness of the event. 
 
8.1.1 
General Management of Adverse Events 
 
Sections 8.1.2–8.1.9 provide detailed participant and study product management on specified 
adverse events and abnormal laboratory test result values. If an observed adverse event or 
abnormal laboratory test result value is not listed in those sections below, the guidance in this 
section (General Management of Adverse Events) should be followed.  
 
In general, the IoR or designee has the discretion to temporarily hold study product at any time if 
s/he feels that continued product use would be harmful to the participant or interfere with 
treatment deemed clinically necessary. See Sections 8.6 and 8.7 below. 
 
• 
Grade 1 or Grade 2, regardless of relationship to study product:  continue study product 
and manage participant according to standard of care practice at the site. 


 
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• 
Grade 3 assessed as not related:  continue study product and re-evaluate participant at least 
weekly until improvement to Grade 2 or lower. If improvement to Grade 2 or lower cannot be 
documented in 2 weeks, consult the CMC. 
 
• 
Grade 3 assessed as related:  temporarily hold study product use, notify the CMC, and re-
evaluate the participant at least weekly until improvement to Grade 2 or lower. If within 2 
weeks the AE has improved to Grade 2 or lower, study product may be resumed. Consult the 
CMC if improvement to Grade 2 or lower cannot be documented within 2 weeks 
o If study product use is resumed and the same Grade 3 AE deemed related to study 
product, recurs at any time, the IoR/designee must temporarily hold study product and 
consult the CMC for further guidance on continuing the temporary hold or progressing 
to permanent discontinuation of the study product. 
 
• 
Grade 4 regardless of relationship to study product:  temporarily hold study product, re-
evaluate the participant as soon as possible or within 2 business days, and consult the CMC.  
Continue the temporary product hold until a recommendation is obtained from the CMC 
  
8.1.2 
Injection Site Reactions (ISRs)  
 
An ISR is defined as an adverse event which, in the opinion of the IoR or designee, results in pain 
out of proportion of what would be expected when a person gets an intramuscular injection, 
tenderness, erythema, redness, induration or swelling, or pruritis, regardless of when it occurs 
after administration of an injection. ISRs should be assessed and reported per the Site Reactions 
to Injections and Infusions section of the DAIDS toxicity tables. 
 
Participants with ISRs should be managed as follows, regardless of relationship to study product: 
• 
Grade 1 or Grade 2:  continue study product, and manage the participant symptomatically 
(e.g. cold/warm compress, acetaminophen, ibuprofen)  
 
• 
Grade 3 or 4:  consult the CMC to determine etiology and study product management  
 
8.1.3 
Creatine Kinase (CK/CPK) Elevation  
 
All participants with elevated CPK results from baseline should be assessed for a history of use of 
drugs known to cause increase of CPK (such as statins), and/or physical activity or exercise 
preceding the CPK sample collection. Participants should abstain from exercise for more than 24 
hours and be well hydrated prior to any repeat sample collection. 
 
• 
Grade 1 or 2:  continue study product. 
 
• 
Grade 3:  continue study product and repeat testing from a new sample within 14 days. If the 
repeat test result is Grade 3 or higher, consult the CMC within 48 hours. 
 
• 
Grade 4, with no signs/symptoms of rhabdomyolysis:  continue study product and repeat 
testing from a new sample within 7 days, and after the participant has abstained from exercise 
for >24 hours. If the repeat test result is Grade 2 or lower, manage per grade. If the repeat test 
result is Grade 3 or higher, consult the CMC within 48 hours for further guidance on study 
product and participant management.  
 


 
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• 
Grade 4, with signs/symptoms of rhabdomyolysis: For Grade 4 CPK elevations that are in 
the opinion of the IoR associated with signs/symptoms of rhabdomyolysis (such as myalgias, 
muscle pain, dark urine, or clinically significant changes in creatinine clearance), temporarily 
hold study product, repeat testing from a new sample within 7 days, and consult the CMC 
within 48 hours for further guidance on study product and participant management.  
 
8.1.4 
Lipase Elevations and Pancreatitis  
 
Participants with asymptomatic elevations in lipase should be managed as follows, regardless of 
relationship to study product: 
 
• 
Grade 1 or 2:  continue study product, and be followed for development of symptoms (i.e. 
pancreatitis) according to standard of care practice at the site.  
 
• 
Grade 3 or higher:  temporarily hold study product, and repeat testing on a newly obtained 
sample within 2 weeks. If the repeat test result is Grade 2 or lower, resume study product. If 
upon resuming study product lipase elevation is Grade 3 or higher, permanently discontinue 
study product. If the repeat test result is Grade 3 or higher, and in the absence of other 
diagnoses, permanently discontinue study product.  
 
Participants with a confirmed diagnosis of clinical pancreatitis (i.e. symptomatic elevations in 
lipase) should be managed as follows:  
 
• 
Grade 2 or higher assessed as not related:  temporarily hold study product, notify the CMC 
within 48 hours, and re-evaluate the participant weekly until complete resolution (i.e. return 
to baseline). Upon returning to baseline, resume study product and re-evaluate the participant 
every 2 weeks for at least 6 weeks. If after resuming study product, any elevation of lipase of 
Grade 2 or higher, or any recurrence of symptoms, then permanently discontinue study 
product. 
 
• 
Grade 2 or higher assessed as related:  permanently discontinue study product, and notify 
the CMC.  
 
8.1.5 
Elevations in ALT, Bilirubin 
 
This section provides guidance on study product and participant management due to elevations in 
ALT, including considerations of accompanying bilirubin test results. Participants with an 
abnormal total bilirubin test result should have serum bilirubin fractionation (i.e. direct bilirubin) 
testing requested (ideally from the same sample - i.e. automatic fractionation - if raised bilirubin 
results), regardless of whether they are on an atazanavir-containing regimen.  Confirmatory repeat 
testing should be performed, at the timepoints indicated below (if ALT is also elevated) or per 
CMC consultation (if ALT is normal).  
 
In all cases of elevated ALT and/or elevated bilirubin (total or direct), possible alternative 
etiology should be assessed, and the underlying illness treated, or the likely causative agent 
removed. 
 
As noted in Section 7.1.1, the CMC must be informed of any Grade 3 or higher total bilirubin, 
unless isolated atazanavir related hyperbilirubinemia with normal direct bilirubin. Note that to 
assess total hyperbilirubinemia as atazanavir-related, demonstration of a normal direct bilirubin is 


 
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needed. Asymptomatic Cohort 1 participants on an atazanavir-containing cART regimen, who 
present with hyperbilirubinemia (any grade) with a normal direct bilirubin, normal ALT, and no 
other alternate etiology for the unconjugated hyperbilirubinemia, may continue study product use 
in consultation with the CMC.  
 
ALT SEVERITY GRADE WITH 
ACCOMPANYING BILIRUBIN SEVERITY 
GRADE (TOTAL OR DIRECT) 
PARTICIPANT AND STUDY PRODUCT 
MANAGEMENT 
Grade 1 ALT, and/or Grade 1 bilirubin 
Continue study product use, and repeat testing at 
the next scheduled study visit, or more frequently 
at the discretion of site investigator. 
 
 
Grade 2 ALT 
 
• 
With ≤ Grade 1 bilirubin (at the Week 4a 
visit): Continue study product use, and repeat 
testing within 72 hours. If repeat test results 
return to baseline, continue per study visit 
schedule (see Sections 6.3.3, and 6.4.3). If 
repeat test results in Grade 2, consult the 
CMC immediately and manage per CMC 
guidance. 
 
• 
With ≤ Grade 1 bilirubin (all visits except the 
Week 4a visit):  Continue study product use, 
and repeat testing weekly. If still Grade 2 
ALT after 4 weeks, consult the CMC. 
 
• 
With Grade 2 or higher bilirubin:  Hold study 
product, and repeat testing weekly. If repeat 
test results of both ALT and bilirubin return to 
baseline, resume study product use, inform the 
CMC, and continue to monitor per applicable 
Schedule of Evaluations. If after 4 weeks 
repeat test results of ALT is still ≥ Grade 2, 
and/or bilirubin is still ≥ Grade 1, continue to 
hold study product and consult the CMC. 
 
• 
If baseline ALT was ≤ ULN and participant is 
symptomatic (i.e. has nausea, abdominal 
discomfort or anorexia), regardless of 
accompanying bilirubin test results:  Hold 
study product, and repeat testing weekly. If 
repeat test results of ALT return to baseline, 
resume study product use, inform the CMC, 
and continue to monitor per applicable 
Schedule of Evaluations. If after 4 weeks 
repeat test results are still Grade 2 ALT, 
continue to hold study product and consult the 
CMC. 
 


 
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ALT SEVERITY GRADE WITH 
ACCOMPANYING BILIRUBIN SEVERITY 
GRADE (TOTAL OR DIRECT) 
PARTICIPANT AND STUDY PRODUCT 
MANAGEMENT 
Grade 3 ALT, regardless of 
accompanying bilirubin test result 
Hold study product, inform the CMC within 24 
hours, and repeat testing within 72 hours.  
 
Reinforce participant awareness and knowledge 
about signs and symptoms of hepatotoxicity. 
Participants should be advised to notify the study 
site immediately if they develop any concerning 
signs or symptoms: new or worsening nausea, 
vomiting, unexplained loss of appetite; yellowing 
of the skin or eyes; increased weakness or fatigue; 
pain in the upper abdomen (liver tenderness or 
hepatomegaly); pale or clay-colored stools; and/or 
unexplained weight loss. Participants should be 
advised to seek immediate medical attention and 
contact the site as soon as possible. 
 
• 
If repeat test results in ≤ Grade 2 without 
addressing possible alternative etiology, 
manage as per Grade 2 above.  
 
• 
If upon addressing possible alternative 
etiology repeat test results in ≤ Grade 2, 
consult CMC. If CMC agrees, resume study 
product. If event recurs at ≥ Grade 3, 
permanently discontinue study product and 
inform CMC. 
 
• 
If repeat test results in ≥ Grade 3, continue to 
hold study product and consult the CMC. If no 
possible alternative cause identified, 
permanently discontinue study product. 
 


 
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ALT SEVERITY GRADE WITH 
ACCOMPANYING BILIRUBIN SEVERITY 
GRADE (TOTAL OR DIRECT) 
PARTICIPANT AND STUDY PRODUCT 
MANAGEMENT 
Grade 4 ALT, regardless of 
accompanying bilirubin test result 
Hold study product, inform the CMC within 24 
hours, and repeat testing within 72 hours.  
 
Reinforce participant awareness and knowledge 
about signs and symptoms of hepatotoxicity. 
Participants should be advised to notify the study 
site immediately if they develop any concerning 
signs or symptoms: new or worsening nausea, 
vomiting, unexplained loss of appetite; yellowing 
of the skin or eyes; increased weakness or fatigue; 
pain in the upper abdomen (liver tenderness or 
hepatomegaly); pale or clay-colored stools; and/or 
unexplained weight loss. Participants should be 
advised to seek immediate medical attention and 
contact the site as soon as possible. 
 
• 
If repeat test results in ≤ Grade 2, manage as 
per Grade 2 above. 
 
• 
If repeat test results in Grade 3, manage as per 
Grade 3 above. 
 
• 
If repeat test result is still Grade 4, inform 
CMC and permanently discontinue study 
product. 
 
 
8.1.6 
Hypersensitivity Reaction 
 
Hypersensitivity includes a constellation of symptoms such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia. 
 
If the IoR or designee suspects hypersensitivity reaction, regardless of relationship to study 
product, the participant should be managed as follows: 
 
• 
Grade 1 or higher:  temporarily hold study product, and within 24 hours of site awareness 
repeat hematology and chemistries testing on newly obtained samples, and notify the CMC. 
Continue to re-evaluate the participant, and repeat testing on newly obtained samples at least 
twice weekly until the abnormal laboratory test results return to baseline values, or stabilize. 
Refer participant to a specialist or hepatology consultation, at the discretion of the site 
investigator, and in consultation with the CMC. 
 
8.1.7 
Allergic Reaction  
 
Participants with allergic reactions should be managed as follows: 
 


 
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• 
Grade 1 or higher assessed as not related, and Grades 1 or 2 assessed as related:  
continue study product, and antihistamines, topical corticosteroids, or antipruritic agents may 
be prescribed at the discretion of the IoR or designee. The participant should be advised to 
contact the site immediately if there is any worsening of symptoms or if further systemic 
signs or symptoms develop.  
 
• 
Grade 3 or higher assessed as related:  permanently discontinue study product, and notify 
the CMC within 24 hours. Manage as clinically appropriate including antihistamines, topical 
corticosteroids, or antipruritic agents. Admission to hospital may be required for severe 
allergic reactions. Following clinical stabilization, re-evaluate the participant weekly, and 
manage according to standard of care practice at the site until resolution to baseline. 
  
8.1.8 
Skin Rash 
 
All participants experiencing a rash should be assessed for systemic symptoms, laboratory 
abnormalities, or mucosal involvement.  
 
Participants with skin rash should be managed as follows, regardless of relationship to study 
product: 
 
• 
Grade 1 (regardless of systemic involvement), or Grade 2 without evidence of systemic 
involvement:  continue study product use at the discretion of the site investigator.  
 
• 
Grade 2 with evidence of systemic involvement, or Grade 3 or higher (regardless of 
systemic involvement):  permanently discontinue study product, and consult the CMC 
within 48 hours. Re-evaluate daily for at least 5 days for systemic symptoms, laboratory 
abnormalities, mucosal involvement, and for any progression of the rash or increase in 
severity. Cohort 1 participants should also discontinue their cART regimen, at the discretion 
of the site investigator and in consultation of the CMC. Participants may be referred to a 
dermatologist, at the discretion of the site investigator. 
 
Additionally, for any rash determined to be related to study product and presenting prior to the 
Week 4b visit (for both Cohort 1 and Cohort 2 participants), the CMC must be consulted prior to 
administering injectable study product at the Week 4b visit.  
 
8.1.9 
Depression, Suicidal Ideation or Attempt 
 
Participants with HIV infection may occasionally present with symptoms of depression and/or 
suicidal ideation or behavior. Participants who experience symptoms of depression and/or 
suicidal ideation or behavior, or report delusions and inappropriate behavior, regardless of 
relationship to study product, should be managed and re-evaluated according to standard of care 
practice at the site, or more frequently, or referred for specialist evaluation and treatment, at the 
discretion of the site investigator. Refer to the IMPAACT 2017 MOP for additional guidance 
regarding establishing a baseline screening assessment for depression. Participants reporting new 
symptoms of depression will be asked to contact the study IoR or designee immediately if 
symptoms of severe acute depression (including suicidal ideation/attempts) develop. All sites 
should have a plan in place for managing possible risks for suicide related events.  
 
• 
Grades 1 or 2: manage per site standard of care and SOPs.  


 
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• 
Grade 3 or higher: manage per site standard of care and SOPs, and consult the CMC within 
24 hours 
 
8.2 
Monitoring and Management of QTc Prolongation 
 
Monitoring 
 
An ECG machine that automatically calculates the heart rate and measures QTc intervals is 
preferred, and these calculated numbers can be used for reporting purposes. The IoR or designee 
can review the ECG reading and a cardiologist reading is not required. Otherwise, an 
appropriately qualified ECG reader must interpret the results. At the Screening visit, three single 
automated QTc readings will be done separated by at least 2 minutes, with the mean value of 
these readings being used to establish baseline. During follow-up, single automated readings will 
be compared to the baseline value, with a result of > 500 msec or > 60 msec increase from 
baseline averaged value requiring a repeat reading in triplicate and averaged QTc calculation (as 
performed at the Screening visit). 
 
The same QT correction formula (for e.g. Bazett’s or Fridericia's) must be used for each 
individual participant to determine eligibility for and discontinuation from the study. This 
formula may not be changed or substituted once the participant has been enrolled. For example, if 
a participant is eligible for the protocol based on QTcB (calculated using Bazett’s formula), then 
QTcB must be used for discontinuation of this individual participant as well. Once the QT 
correction formula has been chosen for a participant’s eligibility, the same formula must continue 
to be used for that participant for all QTc data being collected for data analysis. 
 
Management of QTc Prolongation 
 
During follow-up, if a single automated reading results in a QTc interval > 500 msec, or a >60 
msec increase from baseline averaged value, repeat the reading in triplicate (i.e. three tracings 
separated by at least 2 minutes).  
• 
If any one of the repeated readings confirm a QTc interval > 500 msec, or a > 60 msec 
increase from baseline, temporarily hold study product and assess participant for concomitant 
medications known to cause prolonged QT or Torsades de pointes.  
• 
Study product may be resumed in consultation with the CMC, and if the prolonged QTc is 
assessed as not related to study product. 
• 
If the prolonged QTc is assessed as related, or no other likely cause identified, permanently 
discontinue study product.  
 
For any other abnormality or irregularity reported by the automated read during follow-up that is 
considered clinically significant by the qualified site clinician, a cardiologist should be consulted, 
and the CMC notified. 
 
8.3 
Management of Contraception and Pregnancy 
 
Any female participant of childbearing potential must agree to maintain use of an allowable 
effective contraceptive method throughout study participation, in addition to: 
 
• 
at least 30 days after discontinuation of oral study products (if terminating early from the 
study during Cohort 1 Step 1 or Cohort 2 Step 3), and  
• 
at least 48 weeks after discontinuation of injectable study products.    


 
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Counseling should begin during the screening visit and continue for each participant throughout 
their participation in the study.  See Section 6.13 for more details on pregnancy testing, 
contraceptive counseling, and a list of the allowable effective contraception methods.  
 
For all female participants, a negative pregnancy test result must be obtained on the same day and 
prior to administration of study product. For females of childbearing potential, confirmation of 
contraceptive use (per participant report) must also be obtained on the same day and prior to 
administration of study product. If effective contraception cannot be confirmed, and in the 
opinion of the investigator early pregnancy cannot be excluded, then study product should be 
temporarily held, and the CMC consulted for further guidance on study product use and 
participant management.  
 
Female participants with a positive pregnancy test result will temporarily discontinue study 
product, with confirmatory testing conducted within 48 hours. Upon a confirmatory positive 
pregnancy test result, study product will be permanently discontinued. Cohort 2 female 
participants will resume an oral cART regimen. The choice of cART regimen is at the site 
investigator’s discretion and in accordance with the local standard of care and available resistance 
profiles, and appropriate for use in pregnancy. Sites should actively refer pregnant participants to 
antenatal standard of care, and to engage in antenatal care as early in the pregnancy as possible. 
Additionally, the CMC should be notified within 2 weeks of obtaining the initial positive 
pregnancy test result. 
 
Pregnant participants in Steps 1 through 4 will be followed per the LSFU visit schedule based on 
the date of the positive confirmatory test result. Pregnant participants already being followed per 
the LSFU visit schedule will continue their scheduled visits, however any pregnancy outcome 
occurring after study exit will be entered into eCRFs, as further described below.    
 
Pregnancy test results and pregnancy outcomes will be ascertained and entered into eCRFs. 
Pregnancy outcomes should be ascertained based on medical records; when medical records are 
unavailable, maternal report may be used. For participants who are pregnant at the time of study 
exit, or early study termination, additional post-study contacts should be completed to ascertain 
their pregnancy outcomes (see Section 6.8). If the site becomes aware of a pregnancy 
complication occurring after the participant has exited the study, and the pregnancy complication 
is assessed as related to study product, the CMC should be notified within 2 weeks of site 
awareness. 
 
Study sites will also be encouraged to prospectively register the participant’s pregnancy in the 
Antiretroviral Pregnancy Registry: http://www.apregistry.com/ (in US: 1-800-258-4263).  
 
8.4 
Monitoring and Management of HIV Viral Load 
 
Monitoring 
 
HIV-1 RNA (viral load) will be monitored closely with frequent testing as specified in the 
Schedules of Evaluations in Appendix I. All HIV-1 RNA assays must be performed in a CLIA-
certified or equivalent (US sites) or VQA-certified (non-US) laboratory using the testing platform 
specified in the LPC.  
 
Site investigators should review the results of each test as well as trends over time and consult 
with the CMC regarding any individual test results or trends of concern. As noted in Section 6.5, 


 
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viral load results should be provided to participants and may be used to guide adherence 
counseling. 
 
Definition and Confirmation of Virologic Failure 
 
Virologic failure is defined as two successive plasma HIV-1 RNA test results ≥200 copies/mL. 
 
Any participant with a plasma HIV-1 RNA level ≥200 copies/mL after enrollment should be 
recalled to the clinic for confirmatory testing 2-4 weeks after specimen collection for the initial 
test. Specimen collection for antiretroviral resistance testing and other procedures will also be 
performed at the time of specimen collection for confirmatory HIV-1 RNA testing. Refer to 
Section 6.6 for more details regarding the visit procedure and scheduling of the Confirmation of 
Virologic Failure visit. 
 
Management of Confirmed Virologic Failure 
 
The CMC should be consulted regarding any participant with confirmed virologic failure. All 
participants with confirmed virologic failure will be permanently discontinued from study 
product. Refer to Section 8.7 for participant management regarding permanent discontinuation of 
study product, and Section 6.5 for those participants who will be followed per the LSFU visit 
schedule upon permanent discontinuation of study product. 
 
HIV genotypic and phenotypic resistance samples will be processed, stored, and shipped per 
Section 6.16.2 and the LPC. Upon confirmation of virologic failure, testing of resistance samples 
will be performed in real time, per Section 6.16.2 and the LPC. These resistance test results will 
be reviewed by the site investigator of record, or designee, and used to inform a recommended 
cART regimen, in consultation with the CMC. Cohort 1 participants may be recommended to 
change their ongoing cART regimen, based on these results. Cohort 2 participants should resume 
the recommended non-study provided oral cART as soon as possible and within 4 weeks. 
 
8.5 
Substitution or Dose Modification of cART for Cohort 1 Participants 
 
Cohort 1 participants will continue their pre-study cART regimen while receiving study products 
in both Step 1 and Step 2. Dose changes for growth are permitted. In the event that a change or 
substitution is required for an acute safety event that requires regimen changes (e.g. renal 
compromise on TDF for which alternative NRTI is sought), sites should consult CMC for 
guidance for drugs that can be co-administered. Cohort 1 participants will be permanently 
discontinued from study product use if a cART regimen change is required that would affect 
Cohort 1C vs Cohort 1R assignment.  
 
8.6 
Deferring Study Product and Criteria for Temporary Hold of Study Product 
 
At each study product administration time point, the site investigator or designee must confirm 
participant eligibility to receive study product based on review of medical and medications 
history, physical examination findings, and prior laboratory test results (see Section 6.9). Study 
product administration must be deferred consistent with the guidance provided in Section 8.  
 


 
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For any other significant medical condition that, in the opinion of the investigator, would make it 
unsafe to administer study product or make it difficult to assess for subsequent product related 
adverse events, if present on the scheduled day of study product administration, administration 
must be deferred, and the CMC should be consulted on next steps and continued study product 
management. 
 
For Cohort 2 participants who have a temporary hold, both study products should be held, and the 
CMC should be consulted as soon as possible and within 48 hours of site awareness; the CMC 
may recommend resuming a (non-study provided) cART regimen in these situations. For 
participants resuming a cART regimen for the duration of a temporary study product hold, site 
staff should provide the participant and the participant’s parent or guardian with referrals to non-
study sources of treatment for the participant, as applicable. See the IMPAACT 2017 MOP for 
operational consideration and guidance. 
  
Study product will be temporarily held from a participant for any of the following reasons: 
 
• 
Study product management per Sections 8.1 through 8.5. 
 
• 
Report of use of prohibited concomitant medications (as listed in Section 5.7). Study product 
use may resume upon consultation with the CMC and when the participant reports that he/she 
is no longer taking the prohibited medication, provided other reasons for temporary study 
product hold/permanent discontinuation do not apply. The CMC should be consulted in all 
cases of a participant reporting taking a prohibited concomitant medication during the course 
of the study. 
 
• 
The participant is unable or unwilling to comply with required study procedures, such as 
protocol-required laboratory assessments or injectable study product visits, or otherwise 
might be put at undue risk to their safety and well-being by continuing study product use, 
according to the judgment of the site investigator. The site investigator must consult the CMC 
on all temporary study product holds instituted for this reason, for further guidance on 
resuming study product use, continuing the temporary hold, or progressing to permanent 
discontinuation. 
 
Participants who temporarily or permanently discontinue oral study product during the oral phase 
(Step 1 or Step 3), or during oral bridging (in Step 4) will be instructed to return all oral study 
products to the site clinic as soon as possible.  
 
8.7 
Criteria for Premature Permanent Discontinuation of Study Product  
 
See Section 8.8 for guidance regarding participant management in the event of early termination 
or withdrawal from study participation. Administration of study product will be permanently 
discontinued in the following circumstances:  
 
• 
Participant intention to discontinue study product or study follow-up 
• 
During the oral phase (Cohort 1 Step 1, or Cohort 2 Step 3), sustained non-adherence to oral 
regimen (study product, or non-study provided cART for Cohort 1 participants) that, in the 
opinion of the investigator and in consultation with the CMC, warrants early study product 
discontinuation. 


 
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• 
Sustained non-adherence to injection visit schedule that, in the opinion of the investigator and 
in consultation with the CMC, warrants early study product discontinuation (per IoR 
discretion, a temporary product hold may be initially implemented; see Section 8.6). 
• 
The participant requires treatment with prohibited medications (see Section 5.7). 
• 
Pregnancy (see Section 8.3) 
• 
The participant experiences an adverse event that requires discontinuation as defined in 
Sections 8.1 through 8.5. 
• 
Virologic failure as described in Section 8.4. 
• 
The site investigator determines that further administration of study product would be 
detrimental to the participant’s health or well-being. 
• 
New data become available that indicate study products should be discontinued as determined 
by the CMC.  
 
In the event of premature permanent discontinuation of study product, participants will either be 
followed per the LSFU visit schedule or complete an Early Termination visit, as described below. 
For Cohort 2 participants, in the event of a permanent discontinuation of study product, both 
study products will always be discontinued, and participants should immediately resume (non-
study provided) oral cART.  
 
See Section 6.5 for the specified participants who will be followed per the LSFU visit schedule 
upon permanent discontinuation of study product. 
 
Cohort 1 Step 1 and Cohort 2 Step 3 participants (without prior Cohort 1 Step 2 participation) not 
eligible to progress to their respective injection phase will complete an Early Termination visit 
upon permanent discontinuation of study product.   
 
8.8 
Participant Withdrawal or Termination from the Study 
 
Regardless of the participant retention procedures referenced in Section 4, participants may 
voluntarily withdraw from the study. Participants may also be terminated from the study by the 
site investigator or designee under the following circumstances: 
 
• 
Participant re-locates away from the study site, is otherwise determined to be lost-to-follow-
up, or withdraws consent/assent 
• 
Investigator or designee determines that continued participation in the study would be unsafe 
or otherwise not in the best interest of the participant, after consultation with the CMC 
• 
The study is stopped or canceled at the discretion of the FDA, IMPAACT, the site IRB or 
EC, US Office for Human Research Protection (OHRP), NIAID, NICHD, or other country-
specific governmental agencies 
 
A participant may voluntarily discontinue study participation at any time, and the site investigator 
may also, at their discretion, discontinue the participant from the study at any time. Participants 
who are withdrawn from the study will not be replaced.  
 
Should the consenting parent or guardian of an enrolled participant die or no longer be available 
for any reason, study product should be temporarily held and no further study products should be 
administered, cART resumed for Cohort 2 participants, and no further study-specific evaluations 
should be performed until informed consent for continued study participation is obtained from an 
authorized guardian, as defined locally. Study sites may continue to provide care for the 
participant as needed and as appropriate (outside of the study), consistent with the local standard 


 
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of care, but no study-specific procedures may be performed. If an authorized guardian cannot be 
identified, or if the authorized guardian does not consent to continued study participation, the 
participant must be terminated from the study. Refer to Section 8.6 for additional guidance on 
communication with the CMC for temporary study product holds, and Section 14.3 for guardian 
consent for study participation. 
 
For any participant who withdraws/is withdrawn or is terminated from the study prior to 
scheduled completion of follow-up, study staff will document the reason for the withdrawal or 
termination in detail and will make every effort complete final evaluations as described in Section 
6.5.4. In the event that the circumstances that led to a participant’s withdrawal or termination 
change (e.g., he or she returns to the study site area after having re-located previously), the site 
investigator or designee should contact the CMC to discuss options for resumption of follow-up. 
 
 
9 
STATISTICAL CONSIDERATIONS 
 
For all PK-related matters, including PK endpoints, outcome measures and analyses, refer to 
Section 10. 
 
9.1 
General Design Issues 
 
This is a Phase I/II, multi‐center, open‐label, non‐comparative dose-finding study with the 
primary objective of evaluating the safety, acceptability, tolerability, and pharmacokinetics of 
oral CAB and CAB LA as well as RPV LA in virologically suppressed HIV-1 infected children 
and adolescents 12 to < 18 years of age. 
 
This statistical section describes the methodology and analyses planned for the primary endpoints 
and outcome measures with respect to safety and the secondary endpoints and outcome measures 
other than PK. Please refer to Section 10 for all matters which deal with pharmacokinetics (PK), 
including the outcome measures and primary analyses, in more detail.  
 
It is expected that up to 55 participants will be enrolled into Cohort 1 to achieve approximately 
15-20 dose-evaluable for CAB and approximately 15 dose-evaluable for RPV, with CAB and 
RPV to be evaluated separately in this stage of the study. Most (or all) of these participants are 
expected to proceed to Cohort 2, where they will take the full regimen (CAB + RPV), consisting 
of both products. There is not a restriction (minimum or maximum) on the number of eligible 
Cohort 1 participants allowed to proceed to Cohort 2, to provide the most flexibility in study 
design. It is expected that 100 additional participants will need to be enrolled directly into Cohort 
2 to achieve an approximate additional 70 evaluable participants receiving the final recommended 
dose of CAB and RPV. This sample of participants (approximately 100 for 70 evaluable) will be 
treated as the primary subgroup of Cohort 2 participants, since their results will generalize to the 
population of patients who would be treated by simultaneous exposure to the two study products 
without a prior period of exposure to one or the other as in Cohort 1.  
 


 
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For analysis purposes, evaluable participants will be defined as (1) having been treated 
exclusively on the final recommended dose for a given cohort and having either completed all 
treatment regimen through the said week periods (Week 4 or Week 16 for Cohort 1, Week 24 for 
Cohort 2), or (2) having experienced any of the following:  
•     death that is attributable to the study product/s, OR 
•     study product-related Grade 3+ events (excluding injection-site AEs) OR 
•     permanently discontinued from treatment due to study product-related toxicities (regardless 
of grade) during these weeks of treatment. Note that dose-evaluable participants for dose-finding 
purposes will be defined separately in Section 9.5.1.3.  
 
In making dosing decisions, the protocol team will review Cohort 1 safety data, as well as the 
results of PK data (modeling data as needed). Please refer to Section 9.5.1.3 (Dose 
Finding/Confirmation) for the dose-finding algorithm and the safety guidelines for making dosing 
decisions. 
 
To assess the acceptability and tolerability of the study products based on the perceptions of 
parents and caregivers, up to 60 parents or caregivers of the adolescent participants, as selected 
by the protocol team, will be accrued to complete a single qualitative phone interview. 
 
9.2 
Outcome Measures 
 
For all PK-related matters, including PK outcome measures and analyses, refer to Section 10. 
 
For safety monitoring and reporting purposes, a study product related AE is defined as an adverse 
event that is judged (based on attribution by the site with concurrence from the CMC) to be 
related to the study products (CAB/RPV). To document the attribution concurrence or lack 
thereof, the CMC assessment will be collected.  
 
Primary and secondary outcome measures listed below will be addressed in the study’s primary 
Statistical Analysis Plan, which will define the content of the Primary Analysis Report. This 
report will form the basis for the primary study manuscript and results reporting to 
ClinicalTrials.gov. Outcomes of interest intended for subsequent publications are listed under 
“Other Outcome Measures”. 
 
9.2.1 Primary Endpoints and Outcome Measures 
9.2.1.1 
Safety through Week 4 for oral CAB, through Week 16 (CAB LA or RPV LA) for 
Cohort 1 
• Safety Outcome: All adverse events, regardless of grade 
• Number of participants who: 
o Had Grade 3 or higher adverse events 
o Had Grade 3 or higher adverse events assessed as related to study 
product/s 
o Had serious adverse events meeting ICH criteria assessed as related to 
study product/s 
o Permanently discontinued study product due to adverse events assessed as 
related to study product/s   
o Died due to adverse events assessed as related to study product/s 


 
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9.2.1.2 
Safety through Week 24 for CAB LA+RPV LA for Cohort 2 
• Safety Outcome: All adverse events, regardless of grade 
• Number of participants who: 
o Had Grade 3 or higher adverse events 
o Had Grade 3 or higher adverse events assessed as related to study 
product/s 
o Had serious adverse events meeting ICH criteria assessed as related to 
study product/s 
o Permanently discontinued study product due to adverse events assessed as 
related to study product/s   
o Died due to adverse events assessed as related to study product/s 
9.2.2 Secondary Endpoints and Outcome Measures 
9.2.2.1 
HIV-1 RNA through Week 16 for Cohort 1 
• Number of participants with HIV-1 RNA < 50 copies/mL  
9.2.2.2 
Tolerability of CAB LA or RPV LA through Week 16 for Cohort 1 
• Tolerability measures will include measures of side effects, pain during and after 
injections, injection site reactions, and perceptions of injections from 
comprehensive surveys of adolescents 
 
Acceptability of CAB LA or RPV LA through Week 16 for Cohort 1 
• Acceptability measures will include assessments of motivation for changing 
regimens, satisfaction with treatment, preferences for injectable versus oral 
regimen, quality of life, changes in attitudes towards the study products from 
comprehensive surveys of adolescents  
9.2.2.3 
Safety through Week 48 for CAB LA+RPV LA for Cohort 2 
• Safety Outcome: All adverse events, regardless of grade 
• Number of participants who: 
o Had Grade 3 or higher adverse events 
o Had Grade 3 or higher adverse events assessed as related to study 
product/s 
o Had serious adverse events meeting ICH criteria assessed as related to 
study product/s 
o Permanently discontinued study product due to adverse events assessed as 
related to study product/s   
o Died due to adverse events assessed as related to study product/s 
9.2.2.4 
Virologic activity of CAB LA+RPV LA through Weeks 24 and 48 for Cohort 2 
• Outcome: Plasma HIV-1 RNA  
• Number of participants with HIV-1 RNA ≥50 copies/mL, HIV-1 RNA ≥200 
copies/mL, per snapshot algorithm  
9.2.3 Other Endpoints and Outcome Measures  


 
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9.2.3.1 
Tolerability of CAB LA+RPV LA through Week 24, through Week 48, and 
through Week 96 for Cohort 2 
• Tolerability measures will include measures of side effects, pain during and after 
injections, injection site reactions, and perceptions of injections from 
comprehensive surveys of adolescents 
 
Acceptability of CAB LA+ RPV LA through Week 24, through Week 48, and 
through Week 96 for Cohort 2 
• Acceptability measures will include assessments of motivation for changing 
regimens, satisfaction with treatment, preferences for injectable versus oral 
regimen, quality of life, changes in attitudes towards the study products from 
comprehensive surveys of adolescents  
9.2.3.2 
Safety through Week 96 weeks for CAB LA+ RPV LA for Cohort 2 
• Safety Outcome: All adverse events, regardless of grade 
• Number of participants who: 
o Had Grade 3 or higher adverse events 
o Had Grade 3 or higher adverse events assessed as related to study 
product/s 
o Had serious adverse events meeting ICH criteria assessed as related to 
study product/s 
o Permanently discontinued study product due to adverse events assessed as 
related to study product/s   
o Died due to adverse events assessed as related to study product/s 
9.2.3.3 
Virologic activity of CAB LA+RPV LA through Week 96 for Cohort 2 
• Outcome: Plasma HIV-1 RNA  
• Number of participants with HIV-1 RNA >200 copies/mL, missing HIV-1 RNA, 
study treatment discontinuations  
 
Immunologic activity of CAB LA+RPV LA through Week 96 for Cohort 2 
• Outcome: CD4 count and percentage 
9.2.3.4 
Participants’ and parents/caregivers’ overall perceptions of their/their child’s 
experience with CAB LA and/or RPV LA for Cohorts 1 and 2 as elicited through 
in-depth interviews centered around an ecological model of health behavior 
9.2.3.5 
Tolerability through 48 weeks following permanent discontinuation of CAB LA or 
RPV LA for Cohort 1 and CAB LA+RPV LA for Cohort 2 
• Tolerability measures will include measures of side effects, pain during and after 
injections, injection site reactions, and perceptions of injections from 
comprehensive surveys of adolescents 
 
Acceptability through 48 weeks following permanent discontinuation of CAB LA 
or RPV LA for Cohort 1 and CAB LA+RPV LA for Cohort 2 
• Acceptability measures will include assessments of motivation for changing 
regimens, satisfaction with treatment, preferences for injectable versus oral 
regimen, quality of life, changes in attitudes towards the study products from 
comprehensive surveys of adolescents  


 
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9.2.3.6 
Long-term safety through 48 weeks following permanent discontinuation of CAB 
LA or RPV LA for Cohort 1 and CAB LA+RPV LA for Cohort 2 
• 
Safety Outcome: All adverse events, regardless of grade 
• 
Number of participants who: 
o Had Grade 3 or higher adverse events 
o Had Grade 3 or higher adverse events assessed as related to study 
product/s 
o Had serious adverse events meeting ICH criteria assessed as related to 
study product/s 
o Died due to adverse events assessed as related to study product/s 
9.2.3.7 
HIV-1 genotype and phenotype resistance to CAB and/or RPV in participants 
experiencing confirmed virologic failure (defined in Section 9.6.3.3) in both Cohort 
1 and Cohort 2 
 
9.3 
Randomization and Stratification 
 
There will be no randomization for Cohorts 1 and 2. Participants for Cohort 1 will be placed into 
CAB or RPV arms based on suppressive oral cART at entry: participants on PI-based or NNRTI-
based cART will be assigned to Cohort 1C, while participants on INSTI-based cART will be 
assigned to Cohort 1R. In Cohort 2, participants will all receive both study products.  
 
9.4 
Sample Size and Accrual 
 
The sample size is the minimum number of participants, driven primarily by safety 
considerations, which is likely to be needed to determine the dosage across the possible weight, 
age and sex at birth distributions. Monte Carlo simulations based on existing PK models in adults 
with extrapolation to the study population characteristics were performed to estimate the 
variability for selected primary and secondary parameters and confidence intervals.  
 
(i) 
To ensure a Cohort 1 sample size able to provide precise estimates of apparent clearance 
(CL/F) consistent with the FDA guidelines for pediatric trials. Monte Carlo (MC) 
simulations incorporated adult CAB and RPV population PK model and the expected 
adolescent IMPAACT 2017 participant characteristics.  One hundred virtual PK trials 
were generated with 20 CAB and 15 RPV simulated participants for each study. Each 
simulated trial was analyzed independently for median PK parameter estimates (including 
CL/F) specific for that trial, resulting in 100 median values for each PK parameter. 
Confidence intervals of the individual median PK parameters (from each study) were 
generated from these 100 values. The 90% CI of the medians from the 100 simulated trial 
CAB CL/F estimates ranged from 0.84 -1.17 of the overall adolescent median CL/F value 
and no study estimated deviated from the overall median by > 25%. The corresponding 
90% CI for CAB median V/F estimates were 0.92-1.09 of the overall median V/F. For 
RPV the 90% CI for RPV CL/F was 0.86-1.15 of the overall adolescent median value. 
 
(ii) 
To ensure a sample size able to provide precise estimates of oral CAB AUC (Cohort 1C); 
CAB LA and RPV LA concentration at 28 days (C28D) (Cohort 1C and 1R). Simulated 
PK trials were also used to construct confidence intervals for these exposure parameters. 
For CAB, the AUC 90% CI ranged from 0.86-1.19 of the overall value and the C28D 
90% CI ranged from 0.80-1.29 of the overall value. For RPV LA the C28D 90% CI 
ranged from 0.80-1.29. While a few individual simulated participants had concentrations 


 
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outside of target, all 100 of the virtual trials had median exposure parameters within the 
target range.  
 
Table 9 presents exact 95% confidence intervals around various potential rates of Grade 3+ AEs 
which might be observed in a total sample of 100 participants who might contribute data to the 
safety analysis, a minimum sample of 15 participants from Cohort 1C, a minimum of 15 
participants from Cohort 1R, a potential sample of 30 or 35 participants which represents the 
combined arms of Cohort 1, and a potential sample of 70 participants who enrolled directly into 
Cohort 2 and who will be regarded as the primary sample for the Cohort 2 safety assessment. This 
table indicates that confidence intervals will be quite wide around the sample size of 15 
participants but would be considerably more precise around the target samples of 70 primary or 
100 overall Cohort 2 participants. 
 
Table 9. Percent of Participants Experiencing ≥ Grade 3 Adverse Events (or ≥ Grade 3 
Adverse Events Attributed to the Study Medications) with Exact 95% Confidence 
Intervals 
N* 
n (%) With ≥ Grade 3 Adverse Events 
95% C.I. 
15 
0 (0%) 
0.00, 0.22 
20 
0 (0%) 
0.00, 0.17 
30 
0 (0%) 
0.00, 0.12 
35 
0 (0%) 
0.00, 0.10 
70 
0 (0%) 
0.00, 0.05 
100 
0 (0%) 
0.00, 0.04 
 
 
 
15 
3 (20%) 
0.04, 0.48 
20 
4 (20%) 
0.06, 0.44 
30 
6 (20%) 
0.08, 0.39 
35 
7 (20%) 
0.08, 0.37 
70 
14 (20%) 
0.11, 0.31 
100 
20 (20%) 
0.13, 0.29 
* Note: N refers to total sample size of possible sub-group analysis but note that dosing decisions 
will make use of all available data. 
 
9.5 
Monitoring 
 
Implementation of this study will be monitored at multiple levels, consistent with standard 
procedures described in the IMPAACT Network Manual of Procedures. A study monitoring plan 
that details monitoring roles and responsibilities and data to be reviewed at each level will be 
prepared before the study opens to accrual. Sections 12 and 13 provide more information 
concerning on-site monitoring and quality management at the site level. Further information on 
monitoring of study progress, quality of study conduct, and participant safety across sites is 
provided below. 
 
9.5.1 
Monitoring by the Protocol Team 
 
9.5.1.1 Study Progress and Quality of Study Conduct 
 
The Protocol Team is responsible for continuous monitoring of study progress, including timely 
achievement of key milestones, and the quality of study conduct.  


 
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The team will closely monitor participant accrual and retention based on reports that will be 
generated at least monthly by the SDMC. The team has developed a study accrual plan that 
includes site-specific and total enrollment projections over the course of the accrual period, and 
actual accrual will be monitored relative to these projections. The team will monitor the timing of 
site-specific study activation, which will determine when each site will begin accruing 
participants, and accrual performance following activation. For any site that is delayed in 
completing the study activation process, or that falls short of its accrual projections, the team will 
communicate with the site to identify the barriers it has encountered and the operational strategies 
and action plans to address these.  
 
The Protocol Team will monitor participant retention in a manner similar to participant accrual. 
On behalf of the Protocol Team, the CMC will monitor other key indicators of the quality of 
study conduct (e.g., adherence to study product regimen, data quality, and data and specimen 
completeness), based on reports generated by the SDMC, and will take action with study sites as 
needed to ensure high quality study conduct throughout the period of study implementation.  
 
9.5.1.2 Participant Safety 
 
On behalf of the Protocol Team, the CMC will closely monitor participant safety through routine 
review of safety reports generated by the SDMC. These reports will provide tabulations of 
adverse events specified for entry into eCRFs, as described in Section 7.2. The CMC will review 
these reports via conference call or other meeting at least monthly. At the time of each review, the 
DAIDS Medical Officer will also review any EAEs (defined in Section 7.3) reported to the 
DAIDS Safety Office that are not yet reflected in the data reports. The CMC will continually 
evaluate the pattern and frequency of reported events and will identify any individual issues or 
trends of concern.  
 
The CMC will assess the relationship of adverse events listed in toxicity summary reports and 
these assessments will be recorded by the SDMC. Except in the two specific scenarios listed in 
this section and in Section 9.5.2, the CMC’s assessments will not be used for study-related 
decision-making. 
 
The CMC will also monitor whether any of the safety-related triggers specified in Section 9.5.2 
are met. If so, the CMC will rapidly review the triggering events and notify the SMC that an ad 
hoc review is required. The CMC will likewise request SMC review of any other safety concerns 
that may be identified throughout the course of the study.  
 
9.5.1.3 Dose Finding/Confirmation 
 
During the dose finding/confirmation stages of this study (Cohort 1), the CMC will also review 
the pharmacokinetic data, with the aim of determining the appropriate dose of each product for 
Cohort 2, while protecting participant safety. The CMC will review PK and safety data reports at 
least monthly and take action as needed according to the guidelines in Section 10.3 (PK) and 
Section 9.5.1.2, Participant Safety, above. In addition, the CMC and relevant members of the 
protocol team in conjunction with the SMC will discuss any dose adjustment changes based on 
the PK (of cohort level data) and safety reviews. 
 
In the case of any pause to address safety concerns, participant accrual may be resumed if 
recommended by the CMC and SMC. 
 


 
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For the purpose of dose-finding, dose-evaluable participants will be defined as participants 
having been treated exclusively on the dose being evaluated for a given cohort, and having either 
completed all treatment regimen and completed Week 16 visit or having experienced any of the 
following:  
• 
death that is attributable to the study product/s, OR 
• 
study product-related Grade 3+ events (excluding injection-site AEs) OR 
• 
permanently discontinued from treatment due to study product-related toxicities (regardless 
of grade) during the dose-finding period. 
 
Dose Finding/Confirmation Algorithm 
 
Cohort 1 
 
The study will implement a dose-finding/confirmation algorithm separately for oral CAB/CAB 
LA and RPV LA based on PK and safety data through Week 16. The PK elements from this 
algorithm are based on CAB and RPV exposures seen in adult studies that maintain 
concentrations above the protein adjusted (PA) 90% inhibitory concentration (IC90). Cohorts 1C 
and 1R will each enroll an initial group of 7 dose-evaluable participants and their PK and safety 
data will be evaluated as follows: 
• 
If these 7 dose-evaluable participants meet the PK guidelines (see Section 10) and there are 
no safety concerns (see Safety Guidelines for the First 7 Participants Started at a Given Dose 
Level in Each Group in Cohort 1 below), then the oral/LA IM doses for CAB and LA IM 
doses for RPV in Cohort 2 will be established and Cohort 2 will be open to accrue for Cohort 
1 participants, following an interim analysis (see Section 9.5.2, Monitoring by the SMC).  
• 
If either group fails the safety or PK criteria and an alternative dose is determined by the 
study team to be needed to safely achieve necessary study product concentrations, another 
N=7 dose-evaluable participants will be enrolled into that group and administered a modified 
dose which will be evaluated as described above. 
• 
If there is more variability than expected in the PK results in each or both groups of Cohort 1, 
such that a confident determination regarding achievement of the PK targets cannot be made, 
an additional interim evaluation of the PK results will be done after additional 4 participants 
have been enrolled into the appropriate group/s of Cohort 1 to clarify the PK results as 
needed.  In this scenario, Cohort 2 accrual for Cohort 1 participants will be delayed until an 
interim analysis which includes these extra participants has been performed and Cohort 2 
dosing established by the study team.   
• 
Cohort 1 study enrollment and study procedures will not be interrupted for the preliminary 
PK and safety assessments to be performed on the first 7 dose-evaluable participants enrolled 
into each group. (Note: interim analysis #1 was conducted under protocol Version 2.0; see 
Section 1.3) 
• 
Once approximately 15-20 Cohort 1C participants and approximately 15 Cohort 1R 
participants contributing to the dose-finding algorithm have enrolled, and 80% of these 
participants have completed the Step 2 Week 8 visit, an interim analysis of all available 
safety and PK data will be conducted to determine if Cohort 2 accrual can be opened to 
study-naïve participants. Once all Cohort 1C and 1R participants complete Week 16 visit, the 
final analysis of all safety and PK data for Cohort 1 will be conducted to confirm the oral and 
LA IM doses for Cohort 2.  
 


 
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Cohort 2 
 
Cohort 2 will begin to enroll, starting with the participants who passed Cohort 1, once the dosing 
of the oral/IM CAB and oral/IM RPV been established, based on data of the first 7 dose-
evaluable participants from Cohorts 1C and 1R, as described above. Once approximately15-20 
participants in Cohort 1C and approximately 15 participants in Cohort 1R who could contribute to 
the dose-finding algorithm are enrolled with 80% of participants in each arm passing the Week 8 
visit, another interim analysis of the safety and PK data will be conducted and Cohort 2 will open 
to accrual for study-naïve participants if approved by SMC. 
 
Sparse PK sampling will be collected from Cohort 2 participants to further describe the oral/IM 
CAB and RPV exposure.  
 
Safety Guidelines for the Evaluation of Cohort 1 Starting Doses 
 
The study site’s attribution of any serious adverse event to study product will be used for the 
purposes of employing the start, stop and pause rules. However, when assessments will affect 
conduct of the study or dose-finding decisions, the CMC will review the AE and the site’s 
attribution. In an event of disagreement in assessments, the protocol team will try to reach a 
consensus with the site with respect to attribution. If this should prove impossible, the SMC will 
be consulted and will make the final judgment concerning the relationship between study 
product/s and the adverse event. Gradation of relationship will use the following terminology: 
‘Not related’ and “Related”. 
 
Table 10 and Table 11 use a multinomial response model to assess the probability of failing the 
safety criteria under each of the hypothetical situations in those tables. The calculations are 
performed as follows: Each of the total number of participants represents a trial, which may have 
1 of 3 mutually exclusive outcomes: (1) a life threatening study product-related adverse event or a 
grade 4 event judged to be at least probably related to treatment; (2) a Grade 3+ event, not 
satisfying the criteria set forth in #1, immediately above, but judged to be at least possibly related 
to study treatment and resulting in termination of study treatment; and (3) a relatively benign 
outcome, satisfying neither the criteria in #1 nor #2, immediately above.  
 
Each table has its sets of results under which the set of trials would pass the safety criteria. The 
probability of passing the safety criteria represents the sum of the probabilities of these sets of 
results, and “1 minus the probability of passing the safety criteria” represents the probability of 
failing them. The “True Toxicity Rates” presented in the tables, along with the true rate of having 
neither of the types of toxicity represented by the true toxicity rates (which is 1 - the sum of the 
true toxicity rates), provide the probabilities for the outcomes which are used in the multinomial 
calculations for each of the hypothetical situations. 
 
Safety Guidelines for the First 7 Dose-evaluable Participants Started at a Given Dose Level in 
Each Group in Cohort 1  
 
 
For each group in Cohort 1, the frequency of adverse reactions to the starting dose of the study 
medication will be evaluated on the first 7 dose-evaluable participants, and will include all their 
safety data through the Week 16 visit. Safety data will be monitored on frequent conference calls 
to assess safety across both oral dosing and injections. Moreover, a CMC review of safety will be 
triggered during which accrual into Cohort 1C or 1R will be paused, if the following safety issues 
are encountered:   
 


 
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If any of the first 7 dose-evaluable participants should experience death or a life-threatening event 
that is attributable to the study product/s, or 3 or more participants have experienced study 
product-related Grade 3+ events (excluding injection-site AEs) or have been permanently 
discontinued from treatment due to study product-related toxicities (regardless of grade), accrual 
will be stopped into this dose group. In addition, if patterns of concern are noted, a safety review 
by the CMC will be conducted.  
 
If these safety issues have been encountered, all of the relevant safety and pharmacokinetic data 
will be reviewed. If the CMC determines that it is safe to proceed, it will recommend any changes 
in the dosing and/or monitoring procedures which have been judged to be necessary. The SMC 
will then review all of the relevant safety and pharmacokinetic data, along with the 
recommendations of the CMC, and will determine whether and under what conditions further 
dose finding activities for this group may proceed. Note that there may be a point, prior to 
accruing and evaluating the 7 participants, where it becomes inevitable that the dose under 
consideration will fail the safety criteria. In this event, the reviews described above will be 
performed immediately and no further accrual will occur until the CMC and SMC determine the 
conditions under which further treatment may proceed. 
 
The protocol will only proceed if this review has led to a CMC recommendation that it is safe to 
do so, and the SMC agrees. The safety review may lead to a recommendation that the dose be de-
escalated. Before implementing such a recommendation, the CMC will review the PK data to 
determine whether a lower dose is likely to achieve adequate study product exposure. 
 
If none of the first 7 dose-evaluable participants has experienced death or life-threatening event 
that is attributable to the study products, and fewer than 3 of these 7 dose-evaluable participants 
have experienced study product-related Grade 3+ event (excluding injection-site AEs) or have 
been permanently discontinued for study product-related toxicities (regardless of grade) then this 
group has passed the initial safety guidelines. The safety and PK results of the overall group of 
approximately 15-20 (Cohort 1C) or approximately 15 (Cohort 1R) participants will be evaluated 
when all participants in these groups have reached Week 16. 
 
Given the small sample sizes within each cohort, the information available for preliminary safety 
decisions will be imperfect. Two types of sampling errors are possible:  
1) In a group where the true rate of toxicity is too high to warrant increased exposure to the 
current starting dose of the medication, the sample data may pass the safety guidelines;  
2) In a group where the true rate of toxicity is low enough that further exposure to the current 
starting dose is warranted, the sample data may fail the guidelines.   
 
The extent to which the safety guidelines protect against the errors described above can be 
assessed by examining various hypothetical rates of "true toxicity" which could occur, if the 
study medication were used extensively among the participant population at the dose level under 
question. The hypothetical situations presented in Table 10 range from conditions under which a 
given dose level would cause a high incidence of study product-related severe and life-
threatening AEs to conditions under which severe adverse events would be relatively rare and 
would not be life threatening. For each of these hypothetical situations it is assumed that a sample 
of 7 participants is drawn from the participant population and that the safety guidelines, 
summarized above, are followed.  
 
As an example of how to read Table 10, the second row shows that there is a 87% chance of 
failing the safety guidelines at doses in which the true rate of study product-related life-


 
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threatening AEs is 5% and the true rate of study product-related non-life-threatening adverse 
events is 50%. 
 
Table 10. Probability of Failing Dose Guidelines Under Potential Rates of True Toxicity 
True Toxicity Rates 
Probability of 
Failing Safety 
Guidelines 
Non-life-threatening study product-
related Grade 3+ AEs,  
Study product related life-
threatening Grade 4 AEs 
0.50 
0.00 
0.77 
0.50 
0.05 
0.87 
0.50 
0.25 
0.99 
0.25 
0.00 
0.24 
0.25 
0.05 
0.49 
0.25 
0.25 
0.92 
0.05 
0.00 
0.004 
0.05 
0.05 
0.30 
0.05 
0.25 
0.87 
0.00 
0.05 
0.30 
0.00 
0.25 
0.87 
 
Under the conditions specified in row 2 of the table, assuming that it would be undesirable to treat 
additional participants at a dose that had these true rates of adverse events, the 13% chance of 
NOT failing the safety guidelines would represent the probability of error. As a further example, 
the table also shows that there is 0.4% chance of failing, when the true rate of study product-
related non-life-threatening AE is only 5% and the true rate of study product-related life-
threatening AE is zero. Assuming that the potential benefits associated with exposing additional 
participants to this dose of the study product would outweigh the risks associated with this 
relatively low rate of toxicity, failing the safety guidelines under these conditions would be an 
error. 
 
If the safety criteria discussed above are met by the initial 7 dose-evaluable participants treated 
with each of the study products, and the PK estimates are judged to be sufficiently precise and 
indicate adequate exposure to each of these medications, then participants who have participated 
in Cohort 1 will be allowed to progress to Cohort 2 upon completion of their Week 16 visit.  


 
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Safety Guidelines for the Total Group of Approximately 15-20 (Cohort 1-C) or Approximately 
15 (Cohort 1-R) Potentially Dose-evaluable/ Dose-evaluable Participants Started at a Given 
Dose Level in Cohort 1  
 
The second safety evaluation of a given starting dose of the study medication administered to 
each Cohort 1 group will happen once approximately 15-20 participants in Cohort 1C and 
approximately 15 participants in Cohort 1R who could contribute to the dose-finding algorithm 
are enrolled with 80% of participants in each arm passing the Week 8 visit. The safety evaluation 
will make use of available safety data from all enrolled participants except those who have been 
determined to be not dose-evaluable at that time. The final safety evaluation of a given starting 
dose of the study medication administered to each Cohort 1 group will make use of data from all 
dose-evaluable participants in that group who started at that dose.  In both evaluations, if any of 
these participants has experienced death or a life-threatening event that is attributable to the study 
product/s, or more than 25% of the participants have experienced study product-related Grade 3+ 
events (excluding injection-site AEs) or have been permanently discontinued from treatment due 
to study product-related toxicities (regardless of grade), this starting dose will fail the safety 
guidelines for the group under investigation. If none of these participants has experienced a study 
product-related death or life-threatening AE and no more than 25% have experienced study 
product-related Grade 3+events or have been permanently discontinued for study product-related 
toxicities (regardless of grade), then this starting dose will pass the safety guidelines for the group 
under investigation. Some participants may have Cohort 1 data well beyond Week 16, and the 
CMC will examine events occurring during this extended time period to determine whether there 
are serious or life-threatening events which may be study product related and may require SMC 
review before determining whether and under what conditions further treatment with this dose of 
the medication may proceed.  
 
As in Table 10, the hypothetical rates of "true toxicity" which could occur if the study medication 
were used extensively among the participant population at the dose level are again presented in 
Table 11, this time assuming that a sample of 15 or 20 participants is drawn from the participant 
population and the safety guidelines allow no drug-related death or life-threatening events or no 
more than a 25% rate of drug-related Grade 3+ events. 
 
Table 11. Probability of Failing Dose Guidelines Under Potential Rates of True Toxicity 
True Toxicity Rates 
Probability of Failing Safety 
Guidelines 
N=20/  
N=15   
Non-life-threatening study product 
related Grade 3+ AEs 
Study product-related 
life-threatening Grade 
4+ AEs 
0.50 
0.00 
           0.98 / 0.98 
0.50 
0.05 
          1.00 / 0.99 
0.50 
0.25 
          1.00 / 1.00 
0.25 
0.00 
          0.38 / 0.54 


 
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0.25 
0.05 
          0.80 / 0.81 
0.25 
0.25 
         1.00 / 1.00 
0.05 
0.00 
          0.00 / 0.01 
0.05 
0.05 
          0.64 / 0.54 
0.05 
0.25 
         1.00 / 0.99 
0.00 
0.05 
         0.64 / 0.54 
0.00 
0.25 
         1.00 / 0.99 
 
9.5.2 
Monitoring by the SMC  
 
An independent IMPAACT SMC will review this study regularly, following policies described in 
the IMPAACT Network Manual of Procedures.  
 
SMC reviews will occur at least annually and may also occur on a more frequent or ad hoc basis 
if any issues or concerns arise, or if requested by the CMC. Reviews will focus on participant 
accrual, retention, study conduct, safety, and PK. In addition, analyses of the safety and PK data 
will take place: 1) interim analysis #1 prior to opening Cohort 2 for Cohort 1 participants, 2) 
interim analysis #2 prior to opening Cohort 2 for accrual of study-naïve participants, and 3) the 
final Cohort 1 analysis after all Cohort 1 participants have completed Week 16 visit. Additional 
SMC reviews focused on safety may also occur as indicated below (Participant Safety). Based on 
any of its reviews, the SMC may recommend that the study proceed as currently designed, 
proceed with design modifications, or be discontinued. The SMC may also provide operational 
recommendations to help address any study implementation challenges identified during their 
reviews.  
 
Study Progress and Quality of Study Conduct 
 
The SMC will monitor study progress and the quality of study conduct through review of the 
same types of data reports as the Protocol Team and CMC.  
 
Participant Safety 
 
The SMC will monitor participant safety through review of the same types of safety data reports 
as the CMC, which will be described in a separate Study Monitoring Plan. For ad hoc or triggered 
safety reviews, more limited data may be provided, focusing on the events that triggered the 
reviews. 
 
Triggered SMC reviews will occur in the following scenarios: 
 


 
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(1) In the event of any adverse event that is life-threatening or results in death, the CMC will 
review the event as soon as possible (ideally within three business days of site awareness) and 
assess its relationship to study product: 
• 
If either the site investigator or the CMC assesses the event as related to study product/s, 
participant accrual will immediately be paused. An ad hoc SMC review will be convened 
as soon as possible to discuss how the study should proceed. 
• 
If the site investigator and the CMC assess the event as not related to study product, 
participant accrual will continue. The SMC will be informed of any of these events along 
with the CMC’s assessment and decision-making. 
(2) In the event of any unresolvable disagreement within the CMC on an issue that would impact 
decision making or if the CMC requests SMC review of any other event or trend of concern, 
an SMC review of the relevant data will be convened. The CMC may choose to pause 
participant accrual and/or administration of study product, pending the outcome of the SMC 
review.  
(3) If, for each cohort, more than 25% of the planned total sample for that cohort experiences 
study product-related Grade 3+ events, an ad hoc SMC review will be convened as soon as 
possible. The SMC will review all the relevant safety and pharmacokinetic data, along with 
the recommendations of the CMC, and will determine whether and under what conditions 
further accrual and/or opening of Cohort 2 may proceed.  
 
9.6 
Analyses 
 
9.6.1 
Analyses of the Dose-Finding Data 
 
The analysis of dose finding data will consist of descriptive statistics summarizing the safety and 
PK data from the dose finding phase in Cohort 1 of the study. The safety data of all treated 
participants in Cohort 1 will be used and will be broken down by group (Cohort 1R and Cohort 
1C) and will present the results of the safety evaluations applied to each starting dose tested 
within each group, including information indicating which starting doses have passed or failed the 
safety guidelines. For each starting dose within each group, every adverse event of grade 3 or 
higher will be listed, along with patient demographics, the dose prescribed to the participant at the 
time of the event and the site’s assessment of the probability that this event was due to the study 
treatment. 
 
9.6.2 
Primary Safety Analyses  
 
The primary safety analyses will focus on the Week 4 (CAB), Week 16 (CAB LA or RPV LA) 
periods for Cohort 1 and Week 24 (oral CAB and oral RPV followed by CAB LA+RPV LA) 
period for Cohort 2, where the primary safety analysis will include only evaluable participants. 
An additional requirement for inclusion in the primary analyses for Cohort 2 is that the 
participants be directly accrued to this cohort and be exclusively treated with the combination of 
the two study products without a prior period of exposure to one or the other; this will be 
approximately 70 participants.   
 
Two primary safety analyses will be performed: (1) after the last participant in Cohort 1 has 
completed the Week 16 visit, and (2) after the last participant in Cohort 2 has completed 24 
weeks on therapy. 
 
Each participant’s safety data will be summarized as:    
(1) the worst grade of AEs, and  


 
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(2)  the worst grade of AEs judged to be related to study treatment.  
 
Proportions will present participants experiencing:  
(1) ≥ Grade 3 AEs,   
(2) ≥ Grade 3 events which have been judged to be related to study product/s,  
(3) serious adverse events assessed as related to study products,   
(4) permanent discontinuation of study product due to adverse events assessed as related to 
study product/s, and  
(5) deaths due to product-related adverse events. 
 
Overall proportions of participants meeting any of these criteria will be presented, in addition to 
specific proportions meeting each individual criterion. 
 
Listings of all ≥ Grade 3 events regardless of treatment attribution, ≥ Grade 3 events and serious 
adverse events assessed as related to study product/s, as well as AEs which resulted in permanent 
discontinuation of study product/s or deaths will be provided, broken down by System Organ 
Class and Preferred Term. 
 
The proportions of participants meeting each of the endpoints which would trigger an SMC 
review will be presented descriptively. 
 
All proportions will be presented together with their 95% confidence intervals. 
 
Details concerning the analyses will be included in a separate analysis plan. 
 
For regulatory submission purposes, all the above analyses will be performed and will include all 
Cohort 1 and Cohort 2 evaluable participants. For Cohort 2, frequency distributions of the safety 
outcomes will be presented in aggregate and will be broken down by prior participation in Cohort 
1 vs. exclusive participation in Cohort 2. In addition, the safety data will be presented separately 
for those who were in Q4W and Q8W LA IM dosing.  
 
9.6.3 
Secondary Analyses  
 
9.6.3.1 Maintenance of Viral Suppression 
 
Virologic outcomes, based on HIV-1 RNA (copies/mL), will be assessed through Week 16 for 
Cohort 1 participants.  The proportion of participants maintaining suppression (<50 copies/mL) 
will be presented, along with the Exact 95% confidence intervals. 
 
9.6.3.2 Acceptability and Tolerability 
 
Acceptability and tolerability measures on CAB LA or RPV LA reported by the Cohort 1 
participants through Week 16 will be summarized.  
 
9.6.3.3 Safety  
 
Week 24 (for Cohort 2) analyses described above for the primary analysis will be repeated as 
secondary analyses through Week 48 for the same participants mentioned under the primary 
analysis. 
 


 
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In addition to the primary analyses restricting the sample to appropriate participants as described 
above, further analyses which include safety data from all treated participants through all 
mentioned periods will be performed. These secondary safety analyses will cover all safety data 
collected from first patient exposure to the end of the study. The Cohort 2 secondary analyses will 
include approximately 30-35 participants whose treatment started in Cohort 1 at the final 
recommended dose and who progressed to Cohort 2 after completing participation in Cohort 1 
(see Section 9.1 for a discussion of about the potential for selection bias in this group, and this 
section on how this bias will be addressed). 
 
Descriptive and exposure-related analyses will present safety data from participants who were 
treated on doses other than the final recommended dose for their cohorts. This will include data 
representing the final dose for each cohort, as well as data gathered during the dose finding stage, 
which may represent exposure to doses which have failed. For each starting dose, every AE of ≥ 
Grade 3 will be listed, along with participant demographics, the dose prescribed to the patient at 
the time of the event and the protocol team’s assessment of the probability that this event was due 
to the study products. 
 
9.6.3.4 Virologic activity 
 
Virologic outcomes, based on HIV-1 RNA (copies/mL), will be assessed at Weeks 24 and 48 for 
evaluable Cohort 2 participants. At both of these time points the virologic outcome will be 
calculated according to the FDA’s snapshot algorithm with three main categories (i.e. HIV-1 
RNA<50 c/mL, HIV-1 RNA≥50 c/mL, and no virologic data). The detailed algorithm for 
defining virologic response will be described in the study analysis plan. The snapshot outcome 
will be presented at both Week 24 and Week 48. The Exact 95% confidence intervals for the 
proportion of participants with HIV-1 RNA<50 c/mL will be calculated. The similar summary 
and analysis will also be performed using the cutoff of HIV-1 RNA 200 c/mL. In addition to the 
snapshot analysis, the proportions of participants meeting the criteria for confirmed virologic 
failure through Week 24 and Week 48 will also be presented.  
 
In addition, the above analyses results will also be presented for all treated Cohort 2 participants. 
 
Table 12 presents exact 95% confidence intervals around various potential rates of virologic 
success which might be observed in a total sample of 100 participants or in subsamples of various 
sizes (N=15, 20, 35, 70).  
 
Table 12. Percent of Participants with HIV-1 RNA<50 c/mL per Snapshot algorithm with Exact 95% 
Confidence Intervals 
N 
% Undetectable RNA 
95% C.I. 
15 
40% 
0.16, 0.68 
20 
40% 
0.15, 0.59 
35 
40% 
0.24, 0.58 
70 
40% 
0.28, 0.52 
100 
40% 
0.30, 0.50 
15 
80% 
0.52, 0.96 
20 
80% 
0.56, 0.94 
35 
80% 
0.63, 0.92 
70 
80% 
0.69, 0.89 
100 
80% 
0.71, 0.87 


 
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15 
90% 
0.68, 1.00 
20 
90% 
0.68, 0.99 
35 
90% 
0.77, 0.98 
70 
90% 
0.80, 0.96 
100 
90% 
0.82, 0.95 
 
9.6.4 
Other Analyses 
 
9.6.4.1 Acceptability and Tolerability 
 
The acceptability and tolerability measures on CAB LA + RPV LA through Week 24, through 
Week 48, and through Week 96 of Cohort 2 participants will be summarized. Additionally, these 
participants’ acceptability and tolerability measures through 48 weeks following permanent 
discontinuation of CAB LA or RPV LA (Cohort 1), through 48 weeks following permanent 
discontinuation of CAB LA + RPV LA (Cohort 2) will be summarized.  
 
See Section 11.6 for the planned analyses regarding the adolescent and parent/caregiver 
interviews and relating to the outcomes listed in Section 9.2.3.4. 
 
9.6.4.2  Safety 
 
The Week 16 (for Cohort 1) and Week 24 (for Cohort 2) analyses described above for the 
primary analysis will be repeated as secondary analyses through Week 96 and through 48 weeks 
following permanent discontinuation of CAB LA or RPV LA, and CAB LA+PRV LA for the 
same participants mentioned under the primary analysis. 
 
In addition to the primary analyses restricting the sample to appropriate participants as described 
above, further analyses which include safety data from all treated participants through all 
mentioned periods will be performed. These secondary safety analyses will cover all safety data 
collected from first patient exposure to the end of the study. Descriptive and exposure-related 
analyses will present safety data from participants whose doses have undergone cohort-based 
adjustment or who were treated on doses other than the final recommended dose for their cohorts. 
This will include data representing the final dose for each cohort, as well as data gathered during 
the dose finding stage, which may represent exposure to doses which have failed. 
 
For each starting dose, every AE of ≥ Grade 3 will be listed, along with participant demographics, 
the dose prescribed to the patient at the time of the event and the protocol team’s assessment of 
the probability that this event was due to the study products. 
 
9.6.4.3  Virologic Activity 
 
The Weeks 24 and 48 analyses described in Section 9.6.3.3 for the secondary analysis on 
virologic activity will be repeated as other analysis through Week 96 for the same participants 
mentioned under said secondary analysis.  
 
9.6.4.4  Immunologic Activity 
 
Absolute values and change from baseline in CD4+ lymphocyte count and percentage will be 
summarized over time for Cohort 2 participants.  
 


 
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Median and the associated interquartile range for changes in CD4+ count and percentage from 
baseline to Weeks 24, 48, 72 and 96 will be presented. Missing CD4+ values for participants who 
discontinued study drug prior to the time point of interest due to safety or virologic failure will be 
replaced with their baseline CD4+ values. 
 
9.6.4.5  Genotype and Phenotype Resistance  
 
The incidence of HIV drug resistance for Cohorts 1 and 2 participants will be presented 
descriptively at the point of failure for those who meet the criteria for confirmed virologic failure 
(CVF). Participants will be evaluated for HIV genotypic and phenotypic drug resistance for CAB 
and/or RPV at the time of CVF. Plasma collected at the Confirmation of Virologic Failure visit, 
the visit in which the participant had an initial elevated viral load test result, whole blood 
collected at the Entry (baseline) visit, and any other study visits as requested by the CMC for 
genotypic and phenotypic resistance testing will be shipped per Section 6.16 and the LPC for 
testing. See Section 6.16 and the LPC for more details. 
 
9.6.4.6 Additional considerations 
 
Additionally, special statistical and data analysis considerations may be warranted in the event 
that the COVID-19 or related epidemics or natural disasters may affect the study and data 
integrity.  To the extent possible, these will be described in the main study analysis plan; 
alternatively, a separate analysis plan focusing on modified data handling rules (e.g., changes to 
analysis populations, visit windows and endpoints) and analyses (e.g., sensitivity analyses to 
assess impact of and account for missing data) may be prepared, taking in to account applicable 
regulatory guidance and industry best practices for handling such situations. (21-23) 
 
Further data cuts and analyses may be conducted as necessary to support regulatory submissions 
and publications.  The details for such analyses will be described in the statistical analysis plan, 
which will be finalized prior to database lock. 
 
 
10 
CLINICAL PHARMACOLOGY PLAN 
 
10.1 
Clinical Pharmacology Objectives 
 
10.1.1 Cohort 1 
 
Under protocol Version 2.0 (see Section 1.3), injectable CAB and RPV were evaluated with a 
Q4W injection dosing regimen i.e. oral CAB 30mg once daily followed by CAB LA 600mg then 
400mg every 4 weeks (Cohort 1C) or oral RPV 25mg once daily followed by RPV LA 900mg 
then 600mg every 4 weeks (Cohort 1R) in HIV-infected virologically suppressed adolescents 
weighing at least 35kg.  Recent results from clinical studies (FLAIR, ATLAS, ATLAS-2M) in 
adults now justify use of CAB LA and RPV LA with every 8 week administration: IM CAB LA 
600 mg at Week 4b and Week 8 and every 8 weeks thereafter and IM RPV LA 900 mg at 
Week 4b and Week 8 and every 8 weeks thereafter. 
 
Since daily oral RPV 25mg is already approved in this population, the approved oral dose will be 
used for both Cohort 1R and Cohort 2, and only limited intensive RPV PK will be collected in 
Step 1 (oral lead-in phase) of Cohort 1R. In Cohort 1C and 1R, study product will be added onto 
the participants’ existing ARV therapy and participants will be assigned into Cohort 1C versus 1R 


 
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based on the agents used in their suppressive ARV regimen (avoiding study product interactions 
between the ARVs). Multiple PK samples will be collected throughout the oral and LA dose 
intervals to allow determination of PK parameters for CAB or RPV, as applicable, using 
appropriate analyses.  
 
The PK results from all evaluable Cohorts 1C and 1R participants will be used to confirm the use 
of adult doses for the oral (CAB only) and LA (CAB and RPV) products in adolescents, to be 
used in combination in Cohort 2: oral CAB + oral RPV in Cohort 2, Step 3, and CAB LA+RPV 
LA in Cohort 2, Step 4. The exposures observed with the proposed CAB and RPV doses 
evaluated in HIV-infected adolescent participants in the study will be characterized and compared 
to exposures observed in adult pivotal efficacy trials to aid dosing recommendation in this 
population. 
 
Primary Pharmacology Objectives within Cohort 1 
 
• 
To confirm the doses for oral CAB followed by injectable CAB LA in HIV-infected, 
virologically suppressed adolescents by evaluating: 
o Safety and multiple dose PK of oral CAB through Week 4 
o Safety and multiple dose PK of CAB LA through Week 16 
 
• 
To confirm doses for injectable RPV LA in HIV-infected, virologically suppressed 
adolescents by evaluating safety and multiple dose PK of RPV LA through Week 16 
 
Other Pharmacology Objectives within Cohort 1 
 
• 
To characterize washout PK through 48 weeks following the final Cohort 1 dose of CAB LA 
or RPV LA (except when subjects rollover into Cohort 2) 
 
10.1.2 Cohort 2 
 
Cohort 2 will use CAB and RPV in combination, first oral and then as an IM injectable with the 
LA formulations, as a complete ARV regimen, in HIV-infected virologically suppressed 
adolescents weighing at least 35kg. The Cohort 2 dosage regimen will be the confirmed dosages 
based on data observed in Cohorts 1C and 1R, with the exception of oral RPV for which the dose 
of daily 25 mg has already been previously approved.   
 
The overall PK goal for Cohort 2 is to characterize the plasma concentrations following more 
prolonged LA dosing in Cohort 2 confirming their ability to achieve concentrations comparable 
to those observed in adults. Only sparse PK samples will be collected during Cohort 2 which may 
limit the PK analysis to descriptive summaries of study product concentrations and future 
population pharmacokinetic analyses. 
 
Secondary Pharmacology Objectives within Cohort 2 
 
• 
To evaluate repeat-dose pharmacokinetics of CAB LA + RPV LA through Week 24, and 
through Week 48 in HIV-infected, virologically suppressed adolescents. 
 


 
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Other Pharmacology Objectives within Cohort 2 
 
• 
To characterize PK of CAB LA + RPV LA through Week 96 in HIV-infected, virologically 
suppressed adolescents 
 
• 
To characterize long-term safety and PK through 48 weeks following permanent 
discontinuation of CAB LA + RPV LA 
 
10.2 
Primary and Secondary Data: Cohorts 1 and 2 
 
Demographic data used in the PK analysis will include age, sex at birth, race, ethnicity, height, 
weight, weight Z score, weight group (35-<50kg vs >50kg), BMI, and BSA.  Available laboratory 
data will include serum creatinine, albumin, ALT, bilirubin and hemoglobin. Complete dosing 
information will also be utilized including dose dates, times, dose amounts, food intake (Step 1 
and 3 only), dose administration, location of injections, and sample collection dates and times.  
 
Plasma concentrations will be measured: 
• 
Cohort 1C (CAB) 
o Step 1 (oral dosing):  Wk. 2: Pre-dose, 1, 2, 3, 4 and 8h post dose (6 samples)  
o Step 2 (LA dosing):  Wk. 4b: Pre-dose and 2h post dose, Wk. 5: Day 3-7 post-dose, Wk. 
8: pre-dose, Wk. 9: Day 3-7 post-dose, Wk. 12: Day 28 post dose, Wk. 16: Day 56 post-
dose.  
• 
Cohort 1R (RPV) 
o Step 1 (oral dosing):  Wk. 2:  Pre-dose, 4, and 8h post dose (3 samples)  
o Step 2 (LA dosing):  Wk. 4b: Pre-dose and 2h post dose, Wk. 5: Day 3-7 post-dose, Wk. 
8: pre-dose, Wk. 9: Day 3-7 post-dose, Wk. 12: Day 28 post dose, Wk. 16: Day 56 post-
dose. 
• 
Cohort 2 (CAB and RPV) 
o Step 3 (oral dosing):  Wk. 2:  Pre-dose and 3h post dose (2 samples) 
o Step 4 (LA dosing):  Wk. 4b: Pre-dose and 2h post dose, Wk. 5 and Wk. 25: Day 3-7 
post-dose, pre-dose prior to every injection at Wk. 8, Wk. 16, Wk. 24, Wk. 32, Wk. 40, 
Wk. 48, Wk. 64, Wk. 80, Wk. 88, Wk. 96. 
• 
LSFU 
o Samples collected 8, 24, 36 and 48 weeks after the final injection (random PK samples). 
 
Assay Site: Plasma pharmacokinetic samples collected will be sent to the IMPAACT 
Pharmacology Laboratory listed in the LPC for both CAB and RPV containing specimens. 
Sample collection, processing, storage and shipping details are provided in the LPC. Of note RPV 
samples need to be protected from light as detailed in the LPC. 
 
Methods to be used: All assay methods will be standardized with a filed Methods Report, under 
Good Laboratory Practice (GLP) conditions and cross-validated with primary assay providers 
used for CAB and RPV. The assays will be performed using high-performance liquid 
chromatography and tandem mass spectrometry (HPLC/MS/MS). 
 
Reporting of Assay Data:  Cohort 1 samples will undergo ongoing analysis and reporting with a 
scheduled interim PK analysis to assess if the initial dosing is achieving the PK targets. Assaying 
of Cohort 2 PK samples through the Wk. 24 visit, and then through the Wk. 48 visit, may be 
performed in batches and reported. Remaining Cohort 2 PK samples may be assayed in batches 
and reported at completion of the study, along with PK samples collected during LSFU for the 


 
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final PK analyses. PK samples collected from Cohort 2 after Wk. 48 and collected from any 
Confirmation of Virologic Failure visit, will be assayed as requested by the team. Additional 
sample PK analysis may be performed prior to the completion of the study based on the study 
team’s review of the initial interim analysis or at the request of the CMC or SMC. 
 
10.3 
Endpoints and Outcome Measures 
 
10.3.1 Primary Endpoints and Outcome Measures 
10.3.1.1 
Pharmacokinetic output measures as data permit 
• 
Cohort 1C – Step 1 PO dosing: Wk. 2 AUC, CL/F, Cmax, Tmax, and pre-dose 
concentrations (C0).  
• 
Cohort 1C – Step 2 LA dosing:  Wk. 16 concentrations (C16WK), Cmax, Tmax 
(Dose 1) and C0 prior to IM doses.   
• 
Cohort 1R – Step 2 LA dosing:  Wk. 16 concentrations (C16WK), Cmax, Tmax 
(Dose 1) and C0 prior to IM doses.   
10.3.2 Secondary Endpoints and Outcome Measures 
10.3.2.1 
Pharmacokinetic outcome measures as data permit 
• 
Cohort 2:  CAB and RPV pre-dose concentrations following PO 
administration at Step 3 Wk. 2. 
• 
Cohort 2:  CAB and RPV concentrations following IM administration at 
Step 4 from Wk. 8 (after the first LA injections) to Wk. 24 and 
accumulation ratio (Wk. 24 Pre-dose Conc: Wk. 8 Pre-dose concentration). 
• 
Cohort 2:  CAB and RPV concentrations following IM administration at 
Step 4 from Wk. 8 (after the first LA injections) to Wk. 48 and 
accumulation ratio (Wk. 48 Pre-dose Conc: Wk. 8 Pre-dose concentration). 
• 
Cohort 2:  CAB and RPV concentrations following IM administration at 
Step 4 from Wk. 16 (after the first LA injections) to Wk. 24 and 
accumulation ratio (Wk. 24 Pre-dose Conc: Wk. 16 Pre-dose 
concentration). 
• 
Cohort 2:  CAB and RPV concentrations following IM administration at 
Step 4 from Wk. 16 (after the first LA injections) to Wk. 48 and 
accumulation ratio (Wk. 48 Pre-dose Conc: Wk. 16 Pre-dose 
concentration). 
10.3.3 Other Endpoints and Outcome Measures  
10.3.3.1 
CAB and RPV Pharmacokinetic outcome measures as data permit 
• 
Cohort 2:  CAB and RPV concentrations following IM administration at 
Step 4 from Wk. 48 to Wk. 96 and accumulation ratio (Wk. 96 Pre-dose 
Concentration: Wk. 48 Pre-dose Concentrations). 
• 
Cohort 1:  CAB or RPV concentrations 8 to 48 weeks following final IM 
dose. 
• 
Cohort 2:  CAB and RPV concentrations 8 to 48 weeks following final IM 
dose.  
 
 
10.4 
Study Design, Data Analysis, and Modeling 
 
Pharmacokinetic blood samples will be collected as noted in Section 6.16 and Appendix I-A: 
Schedule of Evaluations for Cohort 1 Adolescents (Cohort 1C and Cohort 1R), Appendix I-B: 
Schedule of Evaluations for Cohort 2 Adolescents, and Appendix I-C: Schedule of Evaluations 
for Long-Term Safety and. The samples will be 2 mL whole blood for Cohort 1 (and for Cohort 1 


 
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participants during the LSFU visit schedule) and 4 mL whole blood for Cohort 2 (and for Cohort 
2 participants during the LSFU visit schedule). Cohort 2 plasma samples, which should be 
protected from light, will be split into individual aliquots for CAB and RPV each containing 0.4-
1.2 mL plasma; same will be done for Cohort 2 participants during the LSFU visit schedule. RPV 
samples should be protected from light at all times from collection through storage and during 
sample analysis. Plasma concentrations will be summarized by Cohort, analyte and nominal time. 
PK analysis will be performed by appropriate methodology e.g. noncompartmental methods 
and/or population methods.  
 
CAB:  The observed concentrations and parameter estimates will be compared to those seen in 
adults (Sections 1.3.9.1 and 1.3.9.2).  
 
Specifically, following oral CAB 30mg once daily in adolescents  35kg Cmax and C are 
expected to be at steady state. Owing to the lower body weight of adolescents, their exposures are 
predicted to be 60-70% higher than the exposures seen with the 30mg daily oral dose in adults but 
comparable to the 60 mg dose in adults. These differences are considered to be not clinically 
relevant and higher CAB exposures have been observed without any safety findings in adults at 
supratherapeutic doses (150 mg administered orally every 12h x 3 doses). 
 
Little accumulation between LA doses is expected following the CAB LA Q8W regimen (IM 
CAB 600 mg at Week 4 and Week 8 and every 8 weeks thereafter).  In the adult clinical study 
(207966) with the same regimen, the geometric mean (5th and 95th percentiles) of the trough 
concentration following the initiation injection was 1.50 mcg/mL (0.65 mcg/mL – 2.90 mcg/mL), 
similar to that following the 6th LA IM injection (44 weeks after the initiation injection) of 
1.61 mcg/mL (0.80 mcg/mL – 2.99 mcg/mL). Based on the POP PK model and simulations of the 
Q8W dosing in adolescents, the CAB concentrations are expected to be slightly higher but 
comparable to the levels observed in adults given the lower body weight in adolescents as 
compared to adults. These CAB levels are several folds higher than the PA-IC90 (CAB PA-
IC90=0.166 mcg/mL). 
 
RPV:  The observed concentrations and parameter estimates following IM administration will be 
compared to those seen in adults (Section 1.3.9.4). With the every 2 months dosing regimen in the 
adult clinical study 207966 (ATLAS-2M, RPV oral 25mg for 4 weeks followed by IM RPV 
900 mg at Week 4 and Week 8 and every 8 weeks thereafter), the median (5th and 95th 
percentiles) trough concentration was 49.1 ng/mL (20.9 ng/mL – 116 ng/mL) at Week 8 (4 weeks 
following the first initiation injection), and was 64.7 ng/mL (33.0 ng/mL – 120ng/mL) following 
the 6th LA IM injection (44 weeks after the initiation injection). Greater than 80% of the RPV 
steady-state concentrations are reached within 48 weeks, with limited further accumulation 
thereafter.  
 
10.4.1 Interim Pharmacokinetic Analyses  
 
A non-compartmental pharmacokinetic analysis (NCA) will be performed on the plasma CAB or 
RPV concentration-time data generated for each individual in Cohort 1C and 1R. Calculated 
pharmacokinetic parameters will include, as permitted by data:  
• 
area-under-the-curve during the dosing interval (AUC0-),  
• 
maximum concentration (Cmax),  
• 
time to Cmax (Tmax),  
• 
trough concentration (C), 
• 
apparent clearance (CL/F),  


 
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• 
terminal rate constant (z) and  
• 
the terminal half-life (T1/2).  
 
The accumulation for C28D from Dose 1 to the last dose following LA administration will also be 
determined. Cmax and Tmax will be taken directly from the observed concentration-time data. Data 
permitting, the terminal slope, z, will be determined from log- linear portion of the curve and the 
terminal half-life (T1/2) calculated as 0.693/z. AUC0- will be determined using the linear 
trapezoidal method and C0 will be used as an estimate of C24h (for oral), when needed, assuming 
steady-state conditions. In absence of adequate PK data to perform an NCA, other appropriate 
analyses may be undertaken to support dose recommendations. 
 
Pharmacokinetic analyses will be performed as data from each Cohort become available.  
Individual participant’s PK data results will be included if they are available for analysis.  
   
10.4.2 Population Pharmacokinetic Analysis  
 
POP PK analyses may be performed using the IMPAACT 2017 PK data alone or in combination 
with existing adult PK data using appropriate methodology. There are no population PK analysis 
outputs required for the dose selection in Cohort 1 nor do any Cohort 1 or 2 PK objectives require 
POP PK analysis for generation. Thus, POP PK analysis will be considered outside of the scope 
of this protocol and will be reported separately. However, other PK analyses of collected data, 
including POP PK evaluations, may be performed to assist the study team with assessment of 
safety or dosing. 
 
10.5 
Expected Outcome 
 
Based on simulations presented in Section 1.3.9, oral and LA regimens in this adolescent patient 
population are expected to achieve concentrations within an acceptable range of those observed 
clinically in adults. If results deviate from expected predictions, dose modifications will be 
considered.    
 
PK Acceptance Criteria 
Oral CAB (Cohort 1C, Step 1) 
 
The CAB PK acceptable criteria following oral administration in Cohort 1C Step 1 is: 
• 
A median Wk. 2 AUC0- between 46 and 277 mcg*h/mL (approximately 33-200% of the 
geometric mean in adults which is 134 mcg*h/mL).  
• 
Median Trough (C) concentrations >0.45 mcg /mL  
• 
Median Cmax ≤ 22.5 mcg/mL that was observed in the TQT study in adults without any 
impact on QT interval.  
 
The study team will review all of the PK parameters following oral CAB, safety and tolerability 
data to determine if a dose modification is warranted. In general, slightly higher exposures may 
be expected in adolescents when administered the same dose as adults due to lower body weight.    
 
Dose Modification (Cohort 1C, Step 1) 
 
No individual dose modification for the use of short-term oral lead-in will be explored in Cohort 
1C. In the event of failure with respect to safety concerns and/or PK criteria that are deemed 
potentially avoidable by a lower exposure to CAB, as judged by the protocol team, dose 


 
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adjustment will be considered for a future Cohort 1C, subject to availability of a suitable 
formulation if deemed appropriate. Any participant that fails Cohort 1C due to safety concerns 
will not receive CAB LA in Cohort 1C Step 2. 
 
CAB LA (Cohort 1C, Step 2) 
 
For the participants that received CAB LA with Q4W dosing under protocol version 2.0, the 
Week 16 Ct data were within the median target range applicable for that dosing regimen (see 
Section 1.3.2) at the time of safety review (January 2020).  The study exposure will also be 
assessed against the 5th percentile CAB concentration (0.45 mcg/mL) observed in the pivotal 
successful efficacy trials in adults, ATLAS and FLAIR, and similar to ATLAS-2M and oral 
CAB.  
 
The CAB PK acceptable criteria following LA administration in Cohort 1C Step 2 is: 
• 
A median Wk. 16 Ct between 0.71-6.7 mcg/mL  
• 
A calculated 5th percentile Wk. 16 Ct ≥0.45 mcg/mL 
 
If the PK results fail to meet the above Wk. 16 Ct acceptability criteria, the IMPAACT 2017 
study team will review the all available PK data to determine if any changes are deemed 
necessary in the proposed dosing regimen. 
  
RPV LA (Cohort 1R, Step 2) 
 
For the participants that received RPV LA with Q4W dosing under protocol version 2.0, the 
Week 16 Ct data were within the median target range applicable for that dosing regimen (see 
Section 1.3.2) at the time of safety review (January 2020).  The study exposure will also be 
assessed against the 5th percentile RPV concentration (17.3 ng/mL) observed in the pivotal 
successful efficacy trials in adults, ATLAS and FLAIR, and similar to ATLAS-2M and oral RPV.  
 
The RPV PK acceptable criteria following LA administration in Cohort 1R Step 2 is: 
• 
A median Wk. 16 Ct between 25-100 ng/mL  
• 
A calculated 5th percentile Wk. 16 Ct ≥17.3 ng/mL 
 
If the PK results fail to meet the above Wk. 16 Ct acceptability criteria, the IMPAACT 2017 
study team will review the all available PK data to determine if any changes are deemed 
necessary in the proposed dosing regimen. 
 
 
11 
QUALITATIVE PHONE INTERVIEWS (U.S. Sites Only) 
 
A single in-depth qualitative phone interview will be conducted with a sub-set of adolescent 
participants enrolled at U.S. study sites and as selected by the protocol team, to identify 
acceptability and tolerability concerns unique to the participant population, and to evaluate 
adolescent participants’ experience of CAB LA and/or RPV LA. This section provides details on 
the qualitative phone interviews, including selection of participants, coordinating the phone 
interviews, conducting the interviews, and data analysis. 
 
See Appendix V-A for details regarding qualitative phone interviews with the parents/caregivers 
of adolescent participants. 
 
 


 
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11.1 
Sample Size and Selection Process 
 
Adolescent participants will be selected to take part in a single in-depth qualitative interview to 
achieve up to 30 completed phone interviews in each Cohort (for a maximum of 60 completed 
phone interviews in Cohort 1 and Cohort 2 combined). The sample size is based on the likely 
number of interviews needed to achieve thematic saturation. For each Cohort, selection for the 
interviews will continue until there is either saturation of themes, or the maximum sample size is 
reached, whichever occurs first. See Section 11.6 regarding thematic saturation and qualitative 
interview data analyses. 
 
Self-reported demographics from Screening and Entry visits will be used to inform selection with 
the goal of balancing participant sex at birth and age (both older and younger adolescents) in the 
completed interviews. This will ensure that perspectives from both males and females, as well as 
older and younger participants, are reflected in the final analysis. Additionally, participants who 
permanently discontinue injectable study product will be purposefully selected to ensure reasons 
for discontinuing the injections are also reflected in the final analysis. Participants will be 
selected across multiple U.S. sites but restricted to those willing and able to conduct the interview 
by phone in English. 
 
Participants will be selected on an on-going basis as they approach the respective interview 
procedure window for their Cohort, and some participants may be selected after they have entered 
the interview procedure window. The selection process will continue until thematic saturation or 
the sample size is reached for each Cohort; see Section 11.2 below for the interview procedure 
windows for each Cohort. The interviews must be completed within the specified interview 
window to allow for comparison between participants. Participants enrolling to the study early 
will thus be selected for interviews first, as they will be the first to enter the specified interview 
windows. 
 
11.2 
Qualitative Phone Interview Procedural Window 
 
The qualitative phone interviews will be conducted with selected participants within the 
following timeframes:  
• 
For selected Cohort 1 participants: Between the Week 4b and Week 12 visits (inclusive), 
or during LSFU visits.  
• 
For selected Cohort 2 participants: Between the Week 24 and Week 96 visits (inclusive), 
or during LSFU visits.  
 
11.3 
Consenting Considerations and Scheduling Qualitative Phone Interviews 
 
For all adolescent participants, consent (or assent, as applicable) for the possibility of being 
selected for a phone interview will be obtained from the adolescent and their parent/guardian as 
part of the informed consent process (or informed assent process, as applicable) for the 
IMPAACT 2017 study. The protocol interview team will notify site staff when participants are 
selected for an interview; see Section 11.1 above for details on the selection process.  
 
Upon notification of selection by the protocol interview team, site staff will approach selected 
participants (either in person or by phone) to confirm willingness to take part in the phone 
interview. Willingness to take part in the phone interview does not affect overall study 
participation or other scheduled study visit procedures. 
 


 
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Upon confirmation of the selected participant being willing to take part in the phone interview, 
site staff will work with the protocol interview team and the selected participant to schedule the 
phone interview. Operational considerations and guidance, including coordinating the interview, 
are provided in the IMPAACT 2017 MOP.  
 
11.4 
Conducting Qualitative Phone Interviews 
 
Once the phone interview is scheduled, site staff will provide the selected participant with 
detailed instructions and guidance on accessing the phone interview platform. Phone interviews 
may be completed either in the study clinic during a scheduled study visit, or from a phone 
outside the study clinic at a time that is convenient for the participant and within the interview 
procedural window. All phone interviews will be conducted by a protocol interview team member 
external to participating clinical research sites, following an interview guide, and will be audio 
recorded and transcribed.  
 
Sites must source document notification by the protocol interview team of participant selection, 
and all attempts to contact the participant. Sites must source document and enter into eCRFs 
willingness to take part in the phone interview, whether they are able to conduct the interview in 
English, and the date the phone interview occurred. Operational and logistical details regarding 
communication with the protocol interview team members and site staff are provided in the 
IMPAACT 2017 MOP. 
 
11.5 
Disclosure of Harm 
 
As described above, the purpose of conducting in-depth qualitative phone interviews with 
participants is to identify acceptability and tolerability concerns unique to the participant 
population, and to evaluate adolescent participant’s experience of CAB LA and/or RPV LA. 
Conducting the interviews is not expected to increase the likelihood or risk of self-harm or harm 
to others.    
 
During the consent (or assent, as applicable) process, participants will be informed that the 
information that they provide in the interview will be kept confidential, with the exception of 
disclosures of significant risk for harm, including being abused or experiencing violence, 
suicidality or homicidality. 
 
If at any time during a qualitative phone interview, a participant divulges that s/he is at risk for 
harm, including but not limited to being abused or experiencing violence, if harm is suspected or 
likely, or if the participant states s/he is suicidal or homicidal, the following will occur to ensure 
his or her safety: 
• 
The protocol interview team member conducting the interview will immediately contact 
the site IoR or designee and share any time-sensitive, potentially life-threatening 
information received from the study participant as part of the phone interview 
discussions. 
• 
The IoR or designee contacted with this information will follow local policies for 
management of such situations including engaging immediate/first responders as 
applicable. 
• 
The IoR or designee will also follow local reporting policies and legal statutes, including 
reporting to child protection or other appropriate agencies, as well as arranging referrals 
to appropriate support, counseling or treatment resources. 
 


 
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After the safety of the participant is addressed according to the steps above, the IoR or designee 
will notify the CMC and document the event, as applicable per Section 7. 
 
To facilitate rapid communications, the IoR or designee is expected to provide up-to-date contact 
information to the protocol interview team while phone interviews are being scheduled and 
conducted with participants from the site.  
 
11.6 
Qualitative Phone Interview Data Analyses 
  
This section provides an overview of the qualitative data analysis process, which will be a 
descriptive analysis without formal inference, with a more detailed description presented in the 
qualitative analysis plan. See Section 12 for details regarding data management responsibilities 
and source data of the in-depth qualitative phone interviews, audio files, and transcriptions. 
 
Analysis will begin during data collection to allow for an iterative process through which 
questions and probes can be refined to enhance the depth of understanding elicited, so that topics 
for further exploration can be noted and incorporated into ongoing interviews. Contemporaneous 
analysis will also be used for determination of the achievement of thematic saturation. Thematic 
saturation is determined on the basis of analysis of the completed scripts by multiple investigators 
who agree that novel information has ceased to arise as new interviews are completed. The 
qualitative data analysis will utilize a thematic approach whereby the protocol interview team will 
search for patterns in data and will conceptualize ideas that help explain the presence of those 
patterns (24). Analysis of textual data will consist of 5 main steps:  
1) Reading for content: Analysis will begin with reading and rereading transcripts until content 
becomes intimately familiar (25). As data are reviewed, emergent themes will be noted;  
2) Coding: A list of codes will be created based on both pre-specified and identified themes. 
Codes will then be assigned to specific sections of text so that the text can be easily and 
meaningfully searched (26). Code definitions will be documented in a code book and will 
include information about the code’s central meaning and may also provide examples of text 
considered within and outside the code’s parameters (25). To ensure inter-coder reliability, all 
transcripts will be double-coded (i.e. by two separate coders who will compare and reconcile 
coding results);  
3) Displaying: Once transcripts have been coded, principle sub-themes will be identified within 
each code that reflect finer distinctions in the data;  
4) Data Reduction: Matrices and tables that categorize and display data will be used to help the 
analysts understand the dimensions by which the data are categorized and facilitate 
comparisons (26);  
5) Interpretation: Themes will be identified and explained. Relationships between themes and 
speakers (e.g. adolescents/parents, males/females, older/younger adolescents) will be mapped 
to highlight similarities and differences of perspective. 
 
 
12 
DATA HANDLING AND RECORD KEEPING 
 
12.1 
Data Management Responsibilities 
 
As described in Section 4.7, data on screening and enrollment in this study will be collected using 
the DMC SES.  
 


 
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Study sites must maintain adequate and accurate research records containing all information 
pertinent to the study for all screened and enrolled adolescent participants, and all enrolled 
parents/caregivers, including paper-based CRFs (if used), eCRFs, and supporting source data. In 
maintaining these records, sites must comply with the standards of source documentation 
specified in the DAIDS policy on Requirements for Source Documentation in DAIDS Funded 
and/or Sponsored Clinical Trials (available on the website referenced in Section 12.2). 
 
eCRFs and an eCRF completion guide will be made available to study sites by the DMC. Study 
site staff will enter required data into eCRFs, with system checks applied and data queries 
generated immediately upon saving the entered data. Data must be entered within timeframes 
specified by the DMC; queries must also be resolved in a timely manner. Selected laboratory data 
will be transferred electronically to the DMC through the LDMS.  
 
Further information on eCRFs and IMPAACT data management procedures will be provided by 
the DMC. A User Manual for the Subject Enrollment System is available on the DMC portal at: 
 https://www.frontierscience.org 
 
For US sites: The protocol interview team at the Children’s Hospital of Philadelphia (CHOP) will 
collect and manage qualitative phone interview data for the study. In-depth phone interview 
guides will be developed by the protocol interview team at CHOP and will receive IRB/EC 
review and approval. The protocol interview team at CHOP will conduct the phone interviews 
with participants (and parents/caregivers) using a secure teleconference platform. The phone 
interviews will be digitally-audio recorded, downloaded to a secure server, and subsequently 
transcribed by an external transcription service. The audio recordings and transcripts will be 
securely electronically transferred to the protocol interview team at CHOP. Transcripts will then 
be processed by the protocol interview team at CHOP for quality assurance, including ensuring 
that all personal identifiers have been removed. After completion of quality assurance processing, 
de-identified transcripts will be labeled as final source data of the phone interview. The audio 
recordings and transcripts generated by the external transcription service will be deleted from 
their secure server, as well as from any back-up servers. The audio recordings and finalized 
transcripts will be kept on a password-protected secure server at CHOP. At no time will study 
sites have access to the audio files or the transcripts. 
 
For US sites: The finalized transcriptions of interviews will be uploaded and managed by the 
protocol interview team at CHOP using a qualitative software package (e.g. NVivo). The DMC 
will serve as a repository for the following data, which will be securely transferred by the 
protocol interview team at CHOP:  finalized transcripts, codebook, and output data.  
 
12.2 
Essential and Source Documents and Access to Source Data 
 
All DAIDS policies referenced in this section are available at: 
https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 
Study sites must comply with DAIDS policies on Requirements for Essential Documents at 
Clinical Research Sites Conducting DAIDS Funded and/or Sponsored Clinical Trials and 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials. In 
its policy on Requirements for Manual of Operational Procedures, DAIDS requires sites to 
establish SOPs for maintaining essential and source documents in compliance with these policies. 
Site SOPs should be updated and/or supplemented as needed to describe roles, responsibilities, 
and procedures for this study, and site SOPs should be followed throughout the study.  
 


 
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For U.S. sites: In-depth qualitative phone interviews will be digitally audio-recorded and 
transcribed. See Section 12.1 above regarding data management and processing of the audio files 
and transcripts. 
 
Per the DAIDS policy on Storage and Retention of Clinical Research Records, study records must 
be stored in a manner that ensures privacy, confidentiality, security, and accessibility during the 
conduct of the study and after the study is completed. Records must be retained for a minimum of 
three years after the completion of the study. Per 21 CFR 312.62, records must be maintained for 
two years after the date a marketing application is approved for one or more of the study products 
for the indication for which it is evaluated in this study; or, if no application is filed, or if the 
application is not approved for this indication, records must be retained two years after the study 
is discontinued and the FDA is notified. 
 
All study records must be accessible for inspection, monitoring, and/or auditing during and after 
the conduct of the study by authorized representatives of the study sponsors and their contracted 
monitors, IMPAACT, ViiV Healthcare, Janssen Pharmaceuticals, the US Food and Drug 
Administration, site drug regulatory authorities, site IRBs/ECs, OHRP, and other US, local, and 
international regulatory entities. Records must be kept on-site throughout the period of study 
implementation; thereafter, instructions for off-site storage may be provided by NIAID. No study 
records may be removed to an off-site location or destroyed prior to receiving approval from 
NIAID.  
 
12.3 
Quality Control and Quality Assurance 
 
Study sites must ensure that essential documents and participant research records are subject to 
continuous quality control and quality assurance procedures consistent with the DAIDS policy on 
Requirements for Clinical Quality Management Plans, which is available at: 
https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 
 
13 
CLINICAL SITE MONITORING 
 
Site monitors under contract to NIAID or NICHD will visit study sites to inspect study facilities 
and review participant study records including consent and/or assent forms, paper-based CRFs (if 
used), eCRFs, medical records, laboratory records, and pharmacy records, to ensure protection of 
study participants, compliance with the IRB/EC approved protocol, and accuracy and 
completeness of records. The monitors will also review essential document files to ensure 
compliance with all applicable regulatory requirements. Site investigators will make study 
facilities and documents available for inspection by the monitors.  
 
 
14 
HUMAN SUBJECTS PROTECTIONS 
 
14.1 
Institutional Review Board/Ethics Committee Review and Approval  
 
Prior to study initiation, site investigators must obtain IRB/EC review and approval of this 
protocol and site-specific ICFs in accordance with 45 CRF 46; subsequent to initial review and 
approval, IRBs/ECs must review the study at least annually. Site investigators must also promptly 
report to the IRB/EC any changes in the study and any unanticipated problems involving risks to 
participants or others. 


 
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All IRB/EC policies and procedures must be followed and complete documentation of all 
correspondence to and from the IRBs/ECs must be maintained in site essential document files. 
Sites must submit documentation of both initial review and approval, and continuing review to 
the DAIDS Protocol Registration Office (PRO) in accordance with the DAIDS Protocol 
Registration Manual (see also Section 15.2). 
 
14.2 
Vulnerable Participants 
 
The NIH is mandated by law to ensure that children be included in clinical research when 
appropriate (27, 28). This study responds to that mandate and will provide clinical research data 
to inform oral CAB, CAB LA, RPV LA, as well as oral CAB + oral RPV, and CAB LA + RPV 
LA safety and dosing in children and adolescents. Nonetheless, the children and adolescents who 
take part in this study are considered vulnerable participants per the US Code of Federal 
Regulations, and site IRBs/ECs must consider the potential risks and benefits to child and 
adolescent participants as described in 45 CFR 46 Subpart D (for children). 
 
With respect to 45 CFR 46 Subpart D, IRBs/ECs must determine the level of risk to children in 
the categories specified in 45 CFR 46.404-407. Documentation of this determination is required 
to complete the DAIDS protocol registration process described in Section 15.2, and the risk 
category assigned by the IRB/EC further determines the parental informed consent requirements 
for the study at each site. Per 45 CFR 46.408 (b), the IRB/EC may find that the consent of one 
parent is sufficient for research to be conducted under 46.404 or 46.405. If the IRB/EC finds that 
the research is covered by 46.406 or 46.407, both parents must give their consent, unless one 
parent is deceased, unknown, incompetent, or not reasonably available or when only one parent 
has legal responsibility for the care and custody of the child (as determined locally). IRBs/ECs 
must document their risk determination, and study sites should adapt the signature pages of their 
site-specific ICFs as needed to accommodate the parental consent requirements associated with 
the IRB/EC determination. 
 
Study sites must comply with the requirements of the DAIDS policy on Enrolling Children 
(including Adolescents) in Clinical Research, which is available at: 
https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 
14.3 
Informed Consent 
 
This section provides details regarding informed consent and assent requirements and procedures 
for adolescents. Refer to Section 4.7 and the IMPAACT 2017 MOP for further information on 
informed consent and assent procedures for this study. 
 
As indicated in Section 4.1.2, site investigators and their designees will be required to determine 
participant age and ability to provide independent informed consent for study participation 
consistent with IRB/EC policies and procedures. Each site must establish SOPs, roles, and 
responsibilities for completing these determinations, and study staff involved in completing these 
determinations must have documented training in the relevant policies and procedures prior to 
study initiation.  
 
Written informed consent and written assent will be obtained for study participation as follows: 
 


 
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• 
If the potential participant is not of legal age to provide independent informed consent as 
determined by site SOPs:  Parent, legal guardian, or other legally authorized representative 
must provide written informed consent for study participation and the potential participant 
must provide written assent for study participation.  
 
Note:  Refer to Section 14.2 for considerations related to parental consenting requirements; 
IRB/EC risk determinations will guide whether the consent of one or both parents may be 
required for this study. All IRB/EC requirements must be followed.  
 
• 
If the potential participant is of legal age and able to provide independent informed consent 
as determined by site SOPs:  The potential participant must provide written informed consent 
for study participation. 
 
Written informed consent and assent (as applicable) for participation will be obtained before any 
study-specific procedures are performed. The informed consent process will include information 
exchange, detailed discussion, and assessment of understanding of all required elements of 
informed consent, including the potential risks, benefits, and alternatives to study participation. 
The process will describe what is known about the safety and tolerability of the study products 
and participants and parents/guardians will be extensively counseled on the importance of 
adherence to the study product regimen, as well as to cART regimen (for Cohort 1 and LSFU). 
The informed assent process will include a similar process, with the amount of information and 
level of detail provided as part of assent processes tailored to the age of the potential participant, 
guided by IRB/EC policies and procedures.  
 
As part of the informed consent and assent process, consenters will be asked whether they agree 
to storage and future research testing of biological specimens remaining after all protocol-
specified testing has been performed. This storage and future use is optional and may be declined 
with no impact on other aspects of study participation. Likewise, genetic testing of residual 
specimens is optional and may be declined.  
 
Appendix II provides sample informed consent forms for obtaining parent or legal guardian 
consent for study participation for adolescents who are unable to provide consent. Appendix III:  
provides sample informed consent forms for adolescents who are able to provide consent for their 
own study participation (i.e., do not require parent or legal guardian consent). Appendix IV 
provides sample informed assent forms for adolescents who are unable to provide consent (i.e., 
require parent or legal guardian consent for study participation). Each of these appendices also 
includes a sample consent or assent form for storage and future research testing (Appendix II-C:  , 
Appendix III-C, and Appendix IV-C). All sample informed consent and assent forms provided in 
Appendix II-Appendix IV may be modified by sites to meet IRB/EC requirements. Study sites are 
permitted to develop separate assent and consent forms for this study, if required by site or 
IRB/EC policies and procedures; for example, sites may develop one assent form for children 12 
years of age at lower reading and comprehension levels than another assent form for children 13 
to less than 18 years of age. 
 
If the participant, parent, or guardian (as applicable) is unable to read, the process for consenting 
illiterate participants, as defined or approved by the local IRB/EC, should be followed. Sites must 
also establish and maintain written procedures describing standards for obtaining informed assent, 
reflective of applicable IRB/EC guidance. 
 


 
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As indicated above, parental consenting requirements at each site will depend on the IRB/EC risk 
determination described in Section 14.2; all IRB/EC requirements will be followed. Participants 
enrolling in the study as minors will generally require consent from a parent or guardian.  
 
In general, each participant is expected to take part in the informed consent process with his or 
her parent or legal guardian, and both the assent of the participant and the consent of the parent or 
legal guardian will be required for all consent decisions. For example, if the participant does not 
provide assent, or the parent or legal guardian does not provide consent, the participant will not 
be enrolled in the study. The same approach will be taken for consent for storage and future 
research testing of biological specimens. However, should the participant be unaware of his/her 
HIV infection status, the informed consent process may be conducted with the parent or legal 
guardian separately and without the presence of the participant, per IRB/EC policies. In these 
circumstances, the assent process must be conducted with both the parent or legal guardian and 
the participant present. Per IRB/EC policies, sites may modify the consent and/or assent (as 
applicable) forms and processes to remove mentioning of HIV for participants who do not know 
their status.  
 
Should the consenting parent (or guardian) of a participant die or no longer be available for any 
reason, sites should follow the guidelines and procedures in Section 8.8, in addition to those 
described by their IRBs/ECs. Study sites may continue to provide care for the participant as 
needed and appropriate (outside of the study), consistent with local standard of care. If a guardian 
cannot be identified, or if the guardian does not consent to continued study participation, the 
participant must be withdrawn from the study. In accordance with the DAIDS policy on Enrolling 
Children (including Adolescents) in Clinical Research (available at the website referenced in 
Section 14.2), all sites must establish and maintain written procedures describing the standards 
that will be followed to identify who may serve as guardian for an enrolled child or adolescent, 
reflective of applicable IRB/EC guidance for conduct of human subjects research within the 
context of available local law, regulation, or government policy.  
 
Participants may also reach the legal age of consent during follow-up. In this case, written 
informed consent for continued participation (Appendix III-A and Appendix III-B) and specimen 
storage and future use (Appendix III-C) will be obtained from participants once they reach legal 
age at their next study visit. If participants do not consent for continued study participation, they 
should be discontinued from the study; similarly, if they do not consent for specimen storage and 
future use, all specimens will be destroyed after all protocol-related testing is complete. 
 
See Appendix V-A for informed consent considerations for parent/caregivers who may enroll to 
the study to participate in a single in-depth qualitative phone interview.  
 
14.4 
Potential Benefits 
 
There may be no direct benefit to participants who take part in this study although there is a 
potential benefit for improved understanding of, and engagement in, HIV care. Information 
learned in this study may be of benefit to participants and others in the future, particularly 
information that may lead to more treatment options for HIV-infected children and adolescents. 
As mentioned in Section 1.4 there is also the potential risk-benefit of early access to Cohort 2 and 
its related benefits with the opportunity to stop oral cART and switch to an entirely long-acting 
injectable regimen. Lastly, participants may also appreciate the opportunity for themselves to 
contribute to HIV-related research. 
 


 
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14.5 
Potential Risks  
 
The potential risks of participation in this study include risks associated with study procedures 
and risks associated with receipt of CAB and RPV.  
 
Most study procedures are routine medical procedures that are associated with minimal to no risk 
in participants. Blood collection may cause pain, bruising, swelling, or fainting. There is a very 
small chance of infection where the needle is inserted, though the injections may cause pain, 
swelling, reddening of the skin, and nodule formations where the needle is inserted. 
 
Although there is already a great deal of robust safety, PK and efficacy data in adults, these drugs 
have not yet been studied in adolescents. There may also be additional risks associated with use 
of these study products in adolescence. Refer to Section 1.2.3 for a complete description of the 
potential risks associated with the use of these drugs.  
 
A preliminary analysis of an ongoing birth outcome surveillance study in Botswana involving 
women exposed to DTG a different molecule in the same integrase class of medications as CAB, 
identified five cases (as of March 2019) of neural tube defects in 1,683 infants born to mothers 
who were exposed to DTG-containing regimens from the time of conception. In the same study, 
one infant born to a woman who started DTG during pregnancy had a neural tube defect, out of 
3,840 women. More recent data from this same study suggest an even lower incidence of neural 
tube defects amongst women taking dolutegravir-containing regimens from the time of 
conception.  A causal relationship of these events to the use of DTG has not been established. The 
incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live 
births. As neural tube defects occur within the first 4 weeks of fetal development (at which time 
the neural tubes are sealed) this potential risk would concern women exposed to DTG at the time 
of conception and in early pregnancy. Cabotegravir is not dolutegravir. While these medications 
share a common molecular backbone, and have a similar mechanism of activity, they are separate 
chemical compounds and have differences in antiviral activity, pharmacokinetics, metabolism and 
drug-drug interactions. It is not known if the safety signal identified with dolutegravir will be 
observed with cabotegravir. Cabotegravir was evaluated in a complete package of reproductive 
toxicology studies, including embryofetal development studies, and no safety findings suggestive 
of teratogenesis or neural tube defects were identified in the 17 December 2019 version of the 
Investigator’s Brochure. Every effort will be made in this study to avoid the occurrence of 
pregnancies among female participants. 
 
The CAB LA and RPV LA injections are long-acting and may be present in the participant’s 
blood one year, and for some participants more than one year, after a single injection. The amount 
of drug will decrease overtime and will eventually disappear. 
 
For virologically suppressed, ART-experienced participants enrolling into Cohort 2, and dropping 
their background cART, there is the potential risk that the study products may not be as effective 
in maintaining viral suppression as participants’ current regimen. 
 
Despite all efforts to maintain confidentiality, involvement in the study could become known to 
others, possibly leading to unfair treatment, discrimination, or other social impacts (e.g., because 
participants could become known as having HIV). For example, participants could be treated 
unfairly or discriminated against or could have problems being accepted by their families and/or 
communities. Refer to Section 14.7 for further information on privacy and confidentiality.  
 


 
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14.6 Reimbursement/Compensation 
 
Pending IRB/EC approval, participants will be reimbursed for costs associated with completing 
study visits (e.g., transport costs). Reimbursement amounts will be specified in site-specific ICFs 
or other materials if applicable per IRC/EC policies and procedures.  
 
14.7 
Privacy and Confidentiality 
 
All study procedures will be conducted in private and every effort will be made to protect 
participant privacy and confidentiality to the extent possible. Participant information will not be 
released without written permission from the parent/guardian, as well as the adolescent, to do so 
except as necessary for review, monitoring, and/or auditing as described in Section 12.2. 
 
All study-related information will be stored securely. Participant research records will be stored 
in locked areas with access limited to study staff. All laboratory specimens, CRFs, and other 
documents that may be transmitted off-site (e.g., EAE report forms) will be identified by PID 
only. Likewise, communications between study staff and protocol team members regarding 
individual participants will identify participants by PID only. Audio files and transcripts will be 
kept on a secure and password protected server with the protocol interview team, and will be 
identified by PID only when transmitted to contracting services (e.g., a transcription service 
provider).  
 
Study sites are encouraged but not required by DAIDS policies to store study records that bear 
participant names or other personal identifiers separately from records identified by PID. All local 
databases must be secured with password protected access systems. Lists, logbooks, appointment 
books, and any other documents that link PID numbers to personal identifying information should 
be stored in a separate, locked location in an area with limited access.  
 
In addition to the above, a Certificate of Confidentiality has been obtained for this study from the 
US Department of Health and Human Services. This certificate protects study staff from being 
compelled to disclose study-related information by any US Federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings. It thus serves to protect the identity and privacy 
of study participants. Because the certificate cannot be enforced outside of the US, however, it 
applies only to US sites and participants. 
 
14.8 
Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases including HIV 
infection identified among study participants to health authorities. Participants will be made 
aware of all applicable reporting requirements as part of the study informed consent process. 
 


 
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14.9 
Management of Incidental Findings 
 
Site clinicians will inform parents (or other authorized guardians if applicable) of all clinically 
meaningful physical exam findings and laboratory test results, including results of HIV tests (if 
applicable), and hematology and chemistry tests. Pregnancy test results will be disclosed to 
participants and their parent/guardians consistent with local standards of care; local standard 
procedures will be noted in site-specific informed consent and assent forms. When applicable, 
site clinicians will provide referrals to non-study sources of medical care for further evaluation 
and/or treatment of these findings. 
 
14.10 Management of New Information Pertinent to Study Participation 
 
Participants, and their parent (or other authorized guardians if applicable) will be provided any 
new information learned over the course of the study that may affect their willingness to allow 
their adolescent to continue receiving study product and/or remain in follow-up in the study.  
 
14.11 Post-Trial Access to Study Product 
 
Participants will be transitioned into care and treatment outside of the study at the end of their 
study participation. If CAB LA + RPV LA is not locally available for a participant in Cohort 2 
completing the study, then the pharmaceutical company or their partners will provide access to 
CAB LA + RPV LA following the participant’s completion of the study through a mechanism 
outside of the IMPAACT 2017 protocol until one or more of the following events occur:  
• 
CAB LA + RPV LA is available from another source (e.g., government programs, aid 
programs, assistance programs, etc.); OR 
• 
If development of CAB LA + RPV LA is terminated. 
 
 
15 
ADMINISTRATIVE PROCEDURES 
 
15.1 
Regulatory Oversight 
 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), 
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), 
and National Institute of Mental Health (NIMH), which are part of the United States National 
Institutes of Health (NIH). Study products are provided by ViiV Healthcare; however, this 
organization is not involved in sponsorship or regulatory oversight of this study.  
 
The Division of AIDS (DAIDS) within the NIAID is responsible for regulatory oversight of this 
study. DAIDS will distribute safety-related information pertaining to the study products prior to 
and during the conduct of the study, in accordance with its sponsor obligations.  
 
NIAID and NICHD provide funding to the clinical research sites at which this study will be 
conducted. Each institute contracts with independent clinical site monitors who will perform 
monitoring visits as described in Section 13. As part of these visits, monitors will inspect study-
related documentation to ensure compliance with all applicable US and local regulatory 
requirements. 
 


 
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15.2 
Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol ICFs approved, as appropriate, by their local IRB/EC, 
local IBC, and any other applicable regulatory entity. Upon receiving final approval, sites will 
submit all required protocol registration documents to the DAIDS PRO at the RSC. The DAIDS 
PRO will review the submitted protocol registration packet to ensure that all of the required 
documents have been received.  
 
Site-specific ICFs will be reviewed and approved by the DAIDS PRO and sites will receive an 
Initial Registration Notification from the DAIDS PRO that indicates successful completion of the 
protocol registration process. A copy of the Initial Registration Notification should be retained in 
the site's regulatory files. 
 
For any future protocol amendments, upon receiving final IRB/EC and any other applicable 
regulatory entity approvals, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the RSC. The DAIDS 
PRO will review the submitted protocol registration packet to ensure that all the required 
documents have been received. Site-specific ICFs will NOT be reviewed and approved by the 
DAIDS PRO and sites will receive an Amendment Registration Notification when the DAIDS 
PRO receives a complete registration packet. A copy of the amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific documents required 
for initial and amendment registrations, refer to the current version of the DAIDS Protocol 
Registration Manual, which is available on the RSC website: https://rsc.niaid.nih.gov/clinical-
research-sites/daids-protocol-registration-policy-and-procedures-manual 
 
15.3 
Study Implementation 
 
This study will be conducted in accordance with the protocol, international good clinical practice 
guidelines, and all applicable US and local regulations. Study implementation will also be guided 
by the IMPAACT MOP, study-specific MOP, LPC, and other study implementation materials, 
which will be available on the IMPAACT web site:  www.impaactnetwork.org. 
 
Study implementation at each site will also be guided by site-specific SOPs. The DAIDS policy 
on Requirements for Manual of Procedures specifies the minimum set of SOPs that must be 
established at sites conducting DAIDS funded and/or sponsored clinical trials (available on the 
website referenced in Section 12.2). These SOPs should be updated and/or supplemented as 
needed to describe roles, responsibilities, and procedures for this study. 
 
15.4 
Protocol Deviation Reporting 
 
Per the policy for Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials (available at the website referenced in Section 12.2), all protocol deviations must 
be documented in participant research records. Reasons for the deviations and corrective and 
preventive actions taken in response to the deviations should also be documented.  
 


 
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Deviations should be reported to site IRBs/ECs and other applicable review bodies in accordance 
with the policies and procedures of these review bodies. Serious deviations that are associated 
with increased risk to one or more study participants and/or significant impacts on the integrity of 
study data must also be reported within IMPAACT, following procedures specified in the 
IMPAACT Network Manual of Procedures. 
 
15.5 
Critical Event Reporting 
 
Per the DAIDS policy on Identification and Classification of Critical Events, a critical event is 
defined as an unanticipated study-related incident that is likely to cause harm or increase the risk 
of harm to participants or others or has a significant adverse impact on study outcomes or 
integrity. All such events must be reported following procedures specified in the DAIDS Critical 
Events Manual, which is available at: 
https://www.niaid.nih.gov/research/daids-clinical-research-event-reporting-safety-monitoring 
 
15.6 
ClinicalTrials.gov 
 
This protocol is subject to the United States Food and Drug Administration Amendments Act of 
2007 (FDAAA), including registration in ClinicalTrials.gov. 
 
 
16 
PUBLICATIONS 
 
All presentations and publications of data collected in this study are governed by IMPAACT 
policies, which are available in the IMPAACT Network Manual of Procedures.  
 
 
17 
REFERENCES 
 
1. 
Kim S-H, Gerver SM, Fidler S, Ward H. Adherence to antiretroviral therapy in adolescents living 
with HIV: Systematic review and meta-analysis. AIDS (London, England). 2014;28(13):1945. 
2. 
Shaw S, Amico KR. Antiretroviral therapy adherence enhancing interventions for adolescents and 
young adults 13–24 years of age: A review of the evidence base. Journal of acquired immune 
deficiency syndromes (1999). 2016;72(4):387. 
3. 
Santer M, Ring N, Yardley L, Geraghty AW, Wyke S. Treatment non-adherence in pediatric 
long-term medical conditions: Systematic review and synthesis of qualitative studies of 
caregivers’ views. BMC Pediatr. 2014;14(1):63. 
4. 
Zanoni BC, Mayer KH. The adolescent and young adult HIV cascade of care in the united states: 
Exaggerated health disparities. AIDS Patient Care STDS. 2014;28(3):128-35. 
5. 
Saitoh A, Foca M, Viani RM, Heffernan-Vacca S, Vaida F, Lujan-Zilbermann J, et al. Clinical 
outcomes after an unstructured treatment interruption in children and adolescents with perinatally 
acquired HIV infection. Pediatrics. 2008;121(3):e513-e21. 
6. 
Achhra AC, Mwasakifwa G, Amin J, Boyd MA. Efficacy and safety of contemporary dual-drug 
antiretroviral regimens as first-line treatment or as a simplification strategy: A systematic review 
and meta-analysis. The Lancet HIV. 2016;3(8):e351-e60. 
7. 
Boffito M, Jackson A, Owen A, Becker S. New approaches to antiretroviral drug delivery: 
Challenges and opportunities associated with the use of long-acting injectable agents. Drugs. 
2014;74(1):7-13. 
8. 
Landovitz RJ, Kofron R, McCauley M. The promise and pitfalls of long acting injectable agents 
for HIV prevention. Curr Opin HIV AIDS. 2016;11(1):122. 


 
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9. 
Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, Eron JJ, Yazdanpanah Y, Podzamczer D, et al. 
Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (latte-2): 
96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 
2017;390(10101):1499-510. 
10. 
Orkin C, Arasteh K, Górgolas Hernández-Mora M, Pokrovsky V, Overton ET, Girard PM, et al. 
Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 
2020;382(12):1124-35. 
11. 
Swindells S, Andrade-Villanueva JF, Richmond GJ, Rizzardini G, Baumgarten A, Masiá M, et al. 
Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 
2020;382(12):1112-23. 
12. 
Overton ET, Richmond GJ, Rizzardini G, Jaeger H, Orrell C, Nagimova F, et al. Cabotegravir + 
rilpivirine every 2 months is noninferior to monthly: Atlas-2m study. In: Conference on 
Retroviruses and Opportunistic Infections; 8-11 March 2020; Boston, MA. Available from: 
https://www.croiconference.org/abstract/cabotegravir-rilpivirine-every-2-months-is-noninferior-
to-monthly-atlas-2m-study/. 
13. 
ViiV Heathcare. Cabotegravir (CAB, GSK1265744) investigator's brochure. December 2019. 
14. 
New study suggests risk of birth defects in babies born to women on HIV medicine dolutegravir 
[press release]. 2018. 
15. 
Janssen. Edurant® (rilpivirine) tablets for oral use [package insert, revised 05/2019]. Titusville, 
NJ, USA: Janssen Products, LP; 2019. 
16. 
Janssen. TMC278 (rilpivirine, oral [edurant] and parenteral) investigator's brochure. April 2017. 
17. 
Lombaard J, Bunupuradah T, Flynn PM, Ramapuram J, Ssali F, Crauwels H, et al. Rilpivirine as 
a treatment for HIV-infected antiretroviral-naive adolescents: Week 48 safety, efficacy, virology 
and pharmacokinetics. Pediatr Infect Dis J. 2016;35(11):1215-21. 
18. 
Eron J, Margolis, D., Gonzalez-Garcia, J., Stellbrink, H-J., Yazdanpanah, Y., Podzamczer, D.,  
Lutz, T., Angel, JB., Richmond, GJ., Clotet, B., Gutierrez, F., Sloan, L., Sutton, KC.,  Dorey, D., 
Smith, KY., Williams, PE., Spreen, WR., editor Safety and efficacy of long-acting cab and rpv as 
two drug im maintenance therapy: Latte-2 week 96 results. 9th IAS Conference on HIV Science; 
2017; Paris, France. 
19. 
Momper JD, Mulugeta Y, Green DJ, Karesh A, Krudys KM, Sachs HC, et al. Adolescent dosing 
and labeling since the food and drug administration amendments act of 2007. JAMA pediatrics. 
2013;167(10):926-32. 
20. 
Orkin C, Oka S, Philibert P, Brinson C, Bassa A, Gusev D, et al. Long-acting cabotegravir + 
rilpivirine for HIV treatment: Flair week 96 results. In: Conference on Retroviruses and 
Opportunistic Infections; 8-11 March 2020; Boston, MA. Available from: 
https://www.croiconference.org/abstract/long-acting-cabotegravir-rilpivirine-for-hiv-treatment-
flair-week-96-results/. 
21. 
U.S. Department of Health and Human Services. Fda guidance on conduct of clinical trials of 
medical products during covid-19 pandemic - guidance for industry, investigators, and 
institutional review boards. In: (FDA) FaDA, editor. 2020. 
22. 
European Medicines Agency (EMA). Guidance on the management of clinical trials during the 
covid-19 (coronavirus) pandemic. 2020. 
23. 
European Medicines Agency (EMA). Points to consider on implications of coronavirus disease 
(covid-19) on methodological aspects of ongoing clinical trials. 2020. 
24. 
Bernard HR, Wutich A, Ryan GW. Analyzing qualitative data: Systematic approaches: SAGE 
publications; 2016. 
25. 
Ulin PR, Robinson ET, Tolley EE. Qualitative methods in public health. San Francisco, CA: 
JosseyBass. 2005. 
26. 
Miles MB, Huberman AM. Qualitative data analysis: An expanded sourcebook: sage; 1994. 
27. 
National Institutes of Health. Guidelines for the inclusion of women and minorities as subjects in 
clinical research. Federal register.; 1994 March 18. 


 
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28. 
National Institutes of Health. Nih policy and guidelines on the inclusion of children as 
participants in research involving human subjects. 1998 March 6. 
 


 
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Appendix I: Schedule of Evaluations 
Appendix I-A: Schedule of Evaluations for Cohort 1 Adolescents (Cohort 1C and Cohort 1R)  
Cohort 1 (CT 1) 
Study Visit1 
CT 1 
Screen 
Step 1 (oral phase) 
Step 2 (injection phase) 
 
CT 1 
Entry 
  
CT 1 
Wk 2 
  
CT 1 
Wk 4a 
  
 CT 1  
Wk 4b  
(Step 2 Entry) 
CT 1 
Wk 5 
  
CT 1 
Wk 8 
  
CT 1 
Wk 9 
  
CT 1 
Wk 12 
  
CT 1 
Wk 16 
  
Confirmation of 
Virologic 
Failure 
Behavioral Evaluations 
Acceptability/Tolerability assessment2 
 
X  
* 
*  
X 
*  
X  
  
 
X  
  
Qualitative Interview3 
  
  
  
  
* 
* 
* 
* 
*  
  
  
Clinical Evaluations 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence assessment 
 
 
X 
X 
X 
 
 
 
 
 
 
Complete physical examination 
X 
 
 
X 
 
 
 
 
 
X 
 
Symptom-directed physical examination 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
Sexual Maturity Rating 
X 
 
 
 
 
 
 
 
 
X 
 
ECG4 
X 
* 
 
 
 
 
 
X 
 
X 
 
Study Product 
Dispense oral study product (for up to 6 
wks) 
  
X 
* 
* 
  
  
  
  
  
  
  
Administer injection study product 
  
  
  
  
X 
  
X 
  
  
  
  
Laboratory Evaluations 
hCG (females only) 
X 
X 
X 
X 
X 
  
X 
  
  
X 
X 
Confirmation of HIV infection 
0-6 mL* 
 
  
  
  
  
  
  
  
  
  
Hematology 
2 mL 
2 mL 
2 mL 
2 mL 
  
2 mL 
2 mL 
  
  
2 mL 
  
Chemistries 
3 mL 
3 mL 
3 mL 
3 mL 
  
3 mL 
3 mL 
  
  
3 mL 
  
CD4 count and percentage 
 
3 mL 
 
 
 
 
 
 
 
3 mL 
 
HIV-1 RNA 
6 mL 
6 mL 
6 mL 
  
6 mL 
  
6 mL 
  
  
6 mL 
6 mL 
Whole blood for genotypic resistance 
testing5 
 
4 mL 
 
 
 
 
 
 
 
 
 
Plasma for genotypic and phenotypic 
resistance testing5 
 
 
6 mL 
  
6 mL 
  
6 mL 
  
  
6 mL 
6 mL 
Pharmacology Evaluations 
PK Sampling6 
  
  
6-12 mL 
  
4 mL 
2 mL 
2 mL 
2 mL  
2 mL 
2 mL 
2 mL  
Total maximum blood volume 
11-17 mL 
18 mL 
23-29 mL 
5 mL 
16 mL 
7 mL 
19 mL 
2 mL  
2 mL 
22 mL 
14 mL 
Notes:  X – required; * - if indicated 


 
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1) Target dates and visit windows may vary per visit. See Section 6.3 for Cohort 1 study visits, procedures, and target dates associated with each visit. See Section 6.1 for 
further details regarding target dates, target visit windows, and allowable visit windows. See Section 6.5.4 and Appendix I-C for details on conducting an Early 
Termination visit. 
2) Acceptability/tolerability assessment questionnaires will be administered at the following Cohort 1 study visits (required): Step 1 Entry, Week 4b, Week 8, and Week 16. 
Additionally, acceptability/tolerability assessment questionnaires will be administered at indicated visits should premature permanent study product discontinuation be 
initiated (noted in the table as if indicated). See Section 6.15 and the IMPAACT 2017 MOP for further details on the specific questionnaires and timing of administration. 
3) Only a sub-set of participants will be selected for the qualitative phone interview. For selected Cohort 1 participants, the qualitative phone interview may be conducted 
between and including the Week 4b and Week 12 visits (noted in the table as if indicated). See Section 11 for qualitative interview window and details on participant 
selection. 
4) See Section 6.12 for details regarding performing an ECG/EKG. 
5) HIV genotypic and phenotypic resistance samples (collected at the Confirmation of Virologic Failure visit and other visits) will be processed, stored, and shipped for 
testing per Section 6.16.2 and the LPC. 
6) See Sections 6.3 and 6.6 for PK sample collection timepoints and windows. 
 
 
 


 
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Appendix I-B: Schedule of Evaluations for Cohort 2 Adolescents 
Cohort 2 (CT 2) 
Study Visit1 
CT 2 
Screen 
Step 3 (oral phase) 
Step 4 (injection phase) 
Confirmation 
of Virologic 
Failure 
CT 2 
Entry 
CT 2 
Wk 2 
CT 2 
Wk 4a 
CT 2  
Wk 4b 
(Step 4 
Entry) 
CT 2 
Wk 5 
CT 2 
Wks 8 
and 16 
CT 2 
Wk 24 
CT 2 
Wk 25 
CT 2 
Wks 32 
and 40 
CT 2 
Wk 48 
CT 2 
Wks 56, 
64, 72, 80, 
and 88 
CT 2 
Wk 96 
Interim 
Injection 
Visit7 
Behavioral Evaluations 
Acceptability/ 
Tolerability 
assessment2 
 
X 
* 
* 
X 
* 
Wk 8 (X) 
Wk 16(*) 
X 
* 
* 
X 
* 
X 
 
 
Qualitative 
Interview3 
 
 
 
 
 
 
 
* 
* 
* 
* 
* 
* 
 
 
Clinical Evaluations 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence 
assessment 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Symptom-directed 
physical 
examination 
 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Sexual Maturity 
Rating 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
ECG4 
X 
* 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study Product 
Dispense oral study 
products (for up to 
6 wks) 
 
X 
* 
* 
 
 
 
 
 
 
 
 
 
 
 
Administer 
injection study 
products 
 
 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
Laboratory Evaluations 
hCG (females 
only) 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Confirmation of 
HIV infection 
0-6 mL* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
2 mL 
2 mL 
2 mL 
2 mL 
 
2 mL 
2 mL 
2 mL 
 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
 


 
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Chemistries  
3 mL 
3 mL 
3 mL 
3 mL 
 
3 mL 
3 mL 
3 mL 
 
3 mL 
3 mL 
3 mL 
3 mL 
3 mL 
 
CD4 count and 
percentage 
 
3 mL 
 
 
 
 
 
3 mL 
 
 
3 mL 
Only Wk 72 
(3 mL) 
3 mL 
 
 
HIV-1 RNA 
6 mL 
6 mL 
6 mL 
 
6 mL 
 
6 mL 
6 mL 
 
6 mL 
6 mL 
Only Wks 
64 and 80 
(6 mL) 
6 mL 
6 mL 
6 mL 
Whole blood for 
genotypic 
resistance testing5 
 
4 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma for 
genotypic and 
phenotypic 
resistance testing5 
 
 
6 mL 
 
6 mL 
 
6 mL 
6 mL 
 
6 mL 
6 mL 
Only Wks 
64 and 80 
(6 mL) 
6 mL 
6 mL 
6 mL 
Pharmacology Evaluations 
PK Sampling6 
 
 
8 mL 
 
 8 mL 
4 mL 
4 mL 
4 mL 
4 mL 
4 mL 
4 mL 
Only Wks 
64, 80, and 
88  
(4 mL) 
4 mL 
4 mL 
4 mL 
Total maximum 
blood volume 
11-17 mL 
18 mL 
 25 mL 
5 mL 
 20 mL 
9 mL 
21 mL 
24 mL 
4 mL 
21 mL 
24 mL 
5-21 mL 
21 mL 
21 mL 
16 mL 
Notes:  X – required; * - if indicated 
1) Target dates and visit windows may vary per visit. See Section 6.4 for Cohort 2 study visits, procedures, and target dates associated with each visit. See Section 6.1 for 
further details regarding target dates, target visit windows, and allowable visit windows. See Section 6.5.4 and Appendix I-C for details on conducting an Early 
Termination visit. 
2) Acceptability/tolerability assessment questionnaires will be administered at the following Cohort 2 study visits (required): Step 3 Entry, Week 4b, 8, 24, 48, and Week 96. 
Additionally, acceptability/tolerability assessment questionnaires will be administered at indicated visits should premature permanent study product discontinuation be 
initiated (noted in the table as if indicated). See Section 6.15 and the IMPAACT 2017 MOP for further details on the specific questionnaires and timing of administration  
3) Only a sub-set of participants will be selected for the qualitative phone interview. For selected Cohort 2 participants, the qualitative phone interview may be conducted 
between and including the Week 24 and Week 96 visits (noted in the table as if indicated). See Section 11 for qualitative interview window and details on participant 
selection. 
4)  See Section 6.12 for details regarding performing an ECG/EKG. 
5) HIV genotypic and phenotypic resistance samples (collected at the Confirmation of Virologic Failure visit and other visits) will be processed, stored, and shipped for 
testing per Section 6.16.2 and the LPC. 
6) See Sections 6.4 and 6.6 for PK sample collection timepoints and windows. 
7) See Section 6.4.14 for interim injection visit scheduling considerations and required procedures for Cohort 2 Step 4 participants resuming study product injections 
following short-term oral bridging. 
 
 


 
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Appendix I-C: Schedule of Evaluations for Long-Term Safety and  
Washout PK Follow-Up (LSFU) Adolescents 
(Cohort 1 Step 2 and Cohort 2 Step 4 participants who have been permanently discontinued  
from injectable study product, and pregnant participants) 
Study Visit1 
LSFU Week 
82 
LSFU Week 
24 
LSFU Week 
36 
LSFU Week 48/  
Early Termination3 
 
Confirmation of 
Virologic Failure 
Behavioral Evaluations 
Acceptability/ Tolerability 
assessment 
X 
 
 
X 
 
Qualitative Interview4 
* 
* 
* 
* 
 
Clinical Evaluations 
Medical history 
X 
X 
X 
X 
X 
Complete physical examination 
X 
 
 
X 
 
Symptom-directed physical 
examination 
 
X 
X 
 
X 
Sexual Maturity Rating 
 
 
 
X 
 
Laboratory Evaluations 
hCG (females only)5 
X 
X 
X 
X 
X 
Hematology  
2 mL 
2 mL 
2 mL 
2 mL 
 
Chemistries 
3 mL 
3 mL 
3 mL 
3 mL 
 
HIV-1 RNA 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
Plasma for genotypic and 
phenotypic resistance testing6 
6 mL 
6 mL 
6 mL 
6 mL (LSFU Week 48 
only) 
6 mL 
Whole blood for genotypic 
resistance testing3, 6 
 
 
 
4 mL (Early 
Termination visit only) 
 
Pharmacology 
PK Sampling7 
2-4 mL 
2-4 mL 
2-4 mL 
0-4 mL3,7 
2-4 mL7 
Total maximum blood volume 
19-21 mL 
19-21 mL 
19-21 mL 
15-21 mL 
14-16 mL 
Notes:  X – required 
1) Target dates and visit windows may vary per visit. See Section 6.5 for LSFU study visits, procedures, and target 
dates, and target visit windows associated with each visit.  
2) Participants completing the Cohort 1 Step 2 Week 16 visit will not complete the LSFU Week 8 visit.  
3) See Sections 6.5.4 and 6.7 for more details on conducting Early Termination visits. Participants completing an Early 
Termination visit will have whole blood collected for genotypic and phenotypic resistance testing. Cohort 1 Step 1 
and Cohort 2 Step 3 participants completing an Early Termination visit will not have a PK evaluation performed and 
a PK sample will not be collected. 
4) Only a sub-set of participants will be selected for the qualitative phone interview. For selected Cohort 1 or Cohort 2 
participants being followed per the LSFU schedule, the qualitative phone interview may be conducted between and 
including the LSFU Week 8 and LSFU Week 48 visits (noted in the table as if indicated). See Section 11 for 
qualitative interview window and details on participant selection. 
5) Pregnancy testing will not be required for participants who are currently pregnant. 
6) HIV genotypic and phenotypic resistance samples (collected at the Confirmation of Virologic Failure visit and other 
visits) will be processed, stored, and shipped for testing per Section 6.16.2 and the LPC. 
7) See Sections 6.5 and 6.6 for PK sample collection timepoints and windows. Cohort 1 Step 2 participants being 
followed per the LSFU visit schedule will have 2 mL collected for each PK sampling timepoint, whereas Cohort 2 
Step 4 participants being followed per the LSFU visit schedule will have 4 mL collection for each PK sampling 
timepoint.  


 
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Appendix II: Sample Parental Informed Consent Forms 
 
Appendix II-A:  Sample Parental Informed Consent Form for Participation in Cohort 1 
for parents/guardians of adolescents who cannot provide independent informed consent for study participation 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 3.0, dated 13 August 2020 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
Introduction 
 
Your child is being asked to take part in the research study named above. 
 
This form gives information about the study. Please read it, or have it read to you, and ask any questions you may 
have. We will take as much time as needed for you to fully understand the study. We will ask you questions to see 
if we have explained the study clearly. 
 
Here is a summary of important information about the study: 
 
• 
The study is testing two anti-HIV medicines (ARVs), Cabotegravir (CAB) and Rilpivirine (RPV), taken as 
pills and given as long-acting shots in adolescents 12 to less than 18 years of age.  
• 
The RPV pills are approved for adolescents in Botswana, Uganda, United States and for adults in Botswana, 
South Africa, Thailand, Uganda, United States. The CAB pills, and the CAB and RPV shots are now being 
tested in adults with HIV but have not yet been tested in adolescents.  
• 
There are two parts to this study, Cohort 1 and Cohort 2. This form is about Cohort 1. Adolescents who 
participate in Cohort 1 may qualify for Cohort 2 of the study after completing Cohort 1. 
• 
Adolescents in Cohort 1 will be in this part of the study for at least 4 months and up to 16 months. 
• 
Adolescents in Cohort 1 will continue taking their usual ARVs while also taking the study medicine. After 
entering the study, adolescents will take daily CAB or RPV pills for 4 to 6 weeks while taking their usual 
ARVs. Adolescents will then switch to getting CAB or RPV shots 4 weeks apart (for a total of 2 shots) while 
continuing to take their usual ARVs.  
• 
After the last shot, adolescents will be followed for up to 1 year for long-term safety follow-up. During this 
time, adolescents will not take any study medicine (shots or pills) but will continue taking their usual ARVs.   
• 
While in the study, adolescents will have clinic visits with physical examinations and blood draws for 
laboratory tests. Some visits will include a review of adolescents’ medical records and ECG tests to look at 
the adolescent’s heart. Female participants will also be tested for pregnancy.  
• 
If interested, participants in the U.S. may be eligible to do one in-depth phone interview where they will talk 
about their experience getting their ARVs as shots. 
• 
There are some possible risks for adolescents in the study. One possible risk is that the pills or shots being 
tested could cause side effects.  The most severe side effects include allergic reaction, liver problems, and 
mental health problems.  These side effects are uncommon. 


 
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• 
There are some possible benefits for adolescents in the study. One possible benefit is you and your child 
having a better understanding of your child’s health and HIV care.  Another possible benefit is early access 
to the Cohort 2 part of the study, if your child qualifies.  
• 
Your decision on your child’s participation in the study will have no effect on the medical care your child 
receives at this clinic. Your child’s access to services, and the benefits and rights he or she normally has, will 
not be affected. You or your child may choose to leave the study at any time.  
 
More information is given in this form about the study, its risks and benefits. You should feel that you understand 
the study before deciding whether your child will participate. If you decide that your child will participate, you 
will be asked to sign or make your mark on this form. You will be offered a copy to keep. 
 
About the study 
 
This study is being done by the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
(IMPAACT) and [insert site name]. The person in charge of the study at [insert site name] is [insert name of 
IoR].  
 
The study is being done to test two anti-HIV medicines (antiretrovirals or ARVs) in adolescents 12 to less than 18 
years old who have HIV. The study ARVs are called cabotegravir (CAB) and rilpivirine (RPV). HIV is the virus 
that can lead to AIDS.  
 
The study will include up to 155 adolescents from the United States, Botswana, South Africa, Thailand and 
Uganda. There will be two groups of adolescents, called Cohort 1 and Cohort 2. This form is about Cohort 1. 
Participants in Cohort 1 will be in the study for at least 16 weeks (4 months) and then up to an additional 48 
weeks (12 months) as part of long-term follow-up, for a total of 64 weeks (16 months).  
 
The United States National Institutes of Health and the companies that make CAB and RPV, ViiV Healthcare and 
Janssen Pharmaceuticals, are paying for this study.  
 
1. The study is testing CAB and RPV in adolescents. 
 
People with HIV usually take a combination of ARVs daily to stay healthy. There are not as many ARVs 
available for adolescents as for adults because many ARVs have not yet been tested in adolescents. ARVs can be 
made in different forms, such as liquids, pills, and injections (shots). The study will test CAB and RPV when 
taken as pills and when given as shots in adolescents. The pills are taken every day. The shots can be given every 
4 weeks or every 8 weeks. The shots are being developed because it can be difficult to take pills every day, and 
some people may prefer to have the shots rather than taking pills.  
 
RPV pills (25mg taken once daily) have been shown to be safe and effective for both adults and adolescents 12 
years and older with HIV. The RPV pills are already approved by the US Food and Drug Administration (FDA) 
for adults and adolescents with HIV.  The FDA is the part of the government that regulates medicines in the 
United States. The RPV pills have also been approved for use for adults and adolescents in Cambodia, Canada, 
China, Ethiopia, the European Union, Gabon, Ghana, Hong Kong, Ivory Coast, Japan, Kazakhstan, Kenya, 
Malawi, Mali, Namibia, Nigeria, Russia, Taiwan, Tanzania, Ukraine and Zimbabwe. 
 
RPV shots (600mg and 900mg), CAB pills (30mg), and CAB shots (400mg and 600mg) are now being tested in 
adults with HIV. The FDA is asking for more information on how these medicines are made before they can 
approve them in adults.  The FDA has no safety concerns regarding these medicines. RPV shots, CAB pills and 
CAB shots have been approved in Canada for monthly dosing. 
 


 
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This will be the first study of these ARVs in adolescents.  So far, the testing in adults has shown that RPV shots, 
CAB pills, and CAB shots work as well as other ARVs that are approved. However, because these ARVs are still 
being tested, there may be some effects that we do not know about yet.  
 
This study will test the effects of these ARVs in adolescents. The study will look at whether these ARVs:  
• 
Are being given at the correct dose for adolescents  
• 
Are safe and well-tolerated in adolescents 
• 
Can control HIV in adolescents as well as other ARVs 
 
The study will also look at how willing adolescents are to take these ARVs.  
 
Cohort 1 of this study will be done first to test CAB and RPV pills when taken for about 1 month followed by 
CAB and RPV shots. Adolescents in Cohort 1 will take either CAB pills followed by CAB shots or RPV pills 
followed by RPV shots. They will keep taking their usual ARVs (see #4 below for more information). 
 
Some adolescents have already taken part in Cohort 1 of this study. They received the study pills for about 1 
month followed by 3 study shots given over 2 months. The RPV shots given at that time were 900mg for the first 
and second shots and then 600mg for the third RPV shot. The CAB shots given at that time were 600mg for the 
first and second shots and then 400mg for the third CAB shot.  
 
For adolescents now entering Cohort 1, the study pills will be taken for about 1 month and followed by 2 study 
shots given 1 month apart. There will now only be 2 study shots given in Cohort 1. Both RPV study shots will be 
900mg, while both CAB study shots will be 600mg. This is because the testing in adults has shown that fewer 
study shots can be given with these amounts. 
 
If the results from Cohort 1 show that CAB pills, CAB shots and RPV shots are safe and that the dose is correct, 
Cohort 2 will start. Cohort 2 will test whether CAB and RPV pills taken together, followed by CAB and RPV 
shots taken together are safe and can control HIV when adolescents stop taking their previous ARVs. Some 
adolescents from Cohort 1 may be eligible to also take part in Cohort 2.  
 
More information about the study, Cohort 1, and CAB and RPV is given in the rest of this form. 
 
2. Only adolescents who are eligible can participate in the study. 
 
If you decide to allow your child to join the study, we will first do some tests to find out if your child is eligible. 
More information about the tests is given in #5 (see below). If your child is eligible, they will be entered in the 
study. If your child is not eligible, they cannot be entered in the study.  
 
3. It is your decision whether or not your child joins the study. 
 
Deciding to join the study is voluntary (your choice). You may choose to allow your child to join or not join. 
Your child will also be asked if they want to join the study. You and your child must both agree. If you allow your 
child to join, you can change your mind and take your child out of the study. If your child does decide to join, 
they can also change their mind and stop being in the study at any time. Your and your child’s choices will have 
no effect on the medical care your child would normally receive. Your child’s access to services, and the benefits 
and rights your child normally has, will not be affected. 
 
Take your time and consider your decision carefully. If you wish, you can talk to other people about the study. 
You can bring other people here to learn about the study with you. 
 


 
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No matter what you decide about the study, it is important for your child to keeping taking ARVs. This is the best 
known way for your child to stay healthy. 
 
4. There are three phases in Cohort 1.  
 
For participants in Cohort 1, there are three phases of the study. All participants will take part in Cohort 1-Phase 
1. Only those who are eligible will then take part in Cohort 1-Phase 2. Participants who take part in Cohort 1-
Phase 2 will also take part in Cohort 1-Phase 3, called the long-term safety follow-up phase. 
 
In Cohort 1-Phase 1, your child will keep taking their usual ARVs. Your child will also take either the CAB or the 
RPV pills. The type of usual ARVs your child take will determine whether your child will take CAB or RPV in 
this study. The pills must be swallowed whole. They cannot be broken or crushed. They should be taken with a 
meal. This phase lasts for about 4-6 weeks. After the study entry visit (see #8 below), your child will have 2 more 
visits during Phase 1. At these visits, we will check to see how your child is doing while taking the pills (see #9 
for more information). We will also check to see if your child is eligible for Cohort 1-Phase 2.  
 
If your child is eligible for Cohort 1-Phase 2, your child will keep taking their usual ARVs. Your child will 
stop taking the CAB or the RPV pills and start getting either the CAB or the RPV shots. The study ARV your 
child gets in the shot will be the same study ARV they were taking by pill. The shots are long-acting, meaning the 
medicine stays in the body for a long time. This phase lasts about 12 weeks. Your child will have 6 visits during 
this time and will get shots at two of these visits. Each shot is about 3mL (about 1 teaspoon). The shots are given 
in the buttocks (bottom “cheeks”). At each of these two visits, your child will be given one shot of CAB or one 
shot of RPV. At all of the Phase 2 visits, we will check on how your child is doing while getting the shots (see 
#11 for more information). 
 
After Cohort 1-Phase 2, your child will take part in the long-term safety follow-up phase of the study. This phase 
lasts about 48 weeks. Your child will keep taking their usual ARVs. There will be 3 or 4 visits during long-term 
follow-up (see #16 for more information). 
 
Finding out if your child is eligible for Cohort 1 
 
5. We will ask questions, examine your child, and discuss the study requirements with you. 
 
To find out if your child is eligible for the study, we will: 
 
• 
Review your child’s medical records. 
• 
Ask questions about your child, your child’s health, and the medications your child takes.  
• 
Talk with your child about birth control (ways to prevent pregnancy). 
• 
Talk with you about the study requirements and if your child is able to meet these requirements. 
• 
Do a physical exam. This will include looking at your child’s genitals to see the stage of development. For 
girls, this will also include looking at the breasts. 
• 
Do an electrocardiogram (ECG). This is to test how well your child’s heart is working.  
• 
Draw between 11-17mL (about 2-3 teaspoons) of blood for tests. The tests will: 
o Check your child’s blood cells. 
o Check how well your child’s liver and kidneys are working. 
o Confirm that your child has HIV. There are certain HIV tests that are required for this study. If the 
required tests are not in the medical records, we will do the tests that are needed. 
o Check the amount of HIV in your child’s blood. This is called the HIV viral load.  
 


 
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These procedures will take about 4 hours [here and throughout this form, sites may modify the expected visit 
duration as needed]. 
 
6. For girls, we will also test for pregnancy. 
 
Girls in this study cannot be pregnant. Girls should not join this study if they are pregnant or intend to become 
pregnant within 30 days after stopping the study ARV pills or within 48 weeks after stopping the study shots. 
Because the effects of the study ARVs on unborn babies are unknown, your child should not become pregnant 
while in this study. For all girls in the study, we will collect urine or blood to test for pregnancy.  
 
There are certain effective methods of birth control that girls who are able to become pregnant must use while in 
this study. These effective methods must be continued for 30 days after stopping the study ARV pills, or for at 
least 48 weeks after stopping the study ARV shots. Girls who are able to become pregnant must agree to use these 
methods in order to take part in the study. We will help make sure your child can get effective methods by 
providing them here in the clinic or offering a referral. At study visits when your child will receive study 
medicines (either the pill or shot), we will need to confirm that your child is using effective birth control before 
giving her the study medicines. 
 
Girls who become pregnant during the study will stop taking the study medicines and enter the long-term safety 
follow-up phase of the study (see #16 below). They must continue taking their usual ARVs. We will contact 
you and your child to find out the outcome of the pregnancy even if the outcome occurs after leaving the study. 
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure of 
pregnancy results to parents or guardians: As soon as the pregnancy test result is available, we will go over it 
with your child in private, without parents/guardians present. Your child must give us permission before we can 
share these results with you. If the test shows that she is pregnant, we will give your child information on where 
medical care and other services can be received.] 
 
If your child is pregnant, your child’s doctor may report their pregnancy to the Antiretroviral Pregnancy 
Registry. The Antiretroviral Pregnancy Registry assists patients and doctors in gauging potential benefits 
and risks of treatment; however, the registry does not collect any identifying information about your 
child, such as name, initials, contact information, or date of birth.  
 
7. We will tell you if your child is eligible. 
 
We will give you the results of all procedures and explain the results to you. We will tell you about getting care, 
treatment and any other services your child may need. While waiting for the results, it is important for your child 
to keep taking their usual ARVs. 
 
If your child is not eligible for the study for any reason, we will tell you this. Your child will not be entered in the 
study. Your child can and should continue to receive medical care and treatment outside of the study. We will tell 
you more about getting this care and treatment and any other services your child may need.  
 
If your child does not enter the study, we will still use some information collected about your child (for example, 
age, sex, and race). We will use this information to look at patterns or common reasons for not entering the study.  
 
If your child is eligible for the study, your child will be entered into the study.  
 


 
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Entering the study 
 
8. If your child is eligible, your child will enter the study. 
 
On the day your child enters the study we will:  
• 
Review your child’s medical records 
• 
Talk with you about your child’s ARV use 
• 
Talk with your child about preventing pregnancy 
• 
Ask your child questions about what they think about CAB or RPV 
• 
Do a physical exam.  
• 
Draw about 18mL (about 4 teaspoons) of blood for tests. The tests will: 
o Check your child’s blood cells. 
o Check how well your child’s liver and kidneys are working. 
o Check how much the virus has affected your child’s ability to fight the virus. This is called CD4 cell 
count.  
o The tests will check your child’s HIV viral load.  
o Some blood will be saved for later testing for resistance to ARVs. This test shows whether different 
ARVs may work against the HIV in your child’s blood. 
• 
For girls, we will collect urine or blood for a pregnancy test.  
 
At the study entry visit we may also do an ECG to look at your child’s heart. This will only be needed if your 
child enters the study more than 2 weeks after their first visit.  
 
At this visit, your child will start taking CAB or RPV pills. We will give you the pills and explain how to take 
them. Your child will take their first dose at the visit. Your child will continue taking their usual ARVs. This 
visit will take about 4 hours.  
 
Being in the study 
 
9. After entering the study, your child will have two more visits in Cohort 1-Phase 1 (Weeks 2 and 4a).  
 
The first visit in Cohort 1-Phase 1 will be the study entry visit and is described in #8 above.  After that visit, your 
child will have 2 more visits in Cohort 1-Phase 1.  These visits will be scheduled 2 weeks apart. [Sites to modify] 
Each visit will take about 1-3 hours. At each of these visits, we will:  
 
• 
Review your child’s medical records.  
• 
Talk with you about your child’s ARV use. 
• 
Do a physical exam. 
• 
Talk with your child about preventing pregnancy.  
• 
For girls, we will also collect urine or blood to test for pregnancy. 
• 
Remind your child to bring the oral CAB or oral RPV to the study clinic. 
 
At two of these visits (Week 2 and Week 4a), we will draw about 5mL (about 1 teaspoon) of blood for tests. 
These tests will check your child’s blood cells and how well your child’s liver and kidneys are working.  
 
At the second visit (Week 2), we will also draw about 12mL (about 2-3 teaspoons) blood for tests. This test will 
check your child’s HIV viral load. Some blood will be saved for later resistance testing.  
 
At the second visit (Week 2), we will also do an intensive pharmacokinetic (PK) test. This is a test to look at the 
amount of CAB or RPV in your child’s blood. At this visit, we will ask you when your child took CAB or RPV in 


 
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the past three days. [Sites: modify language as appropriate to align the three prior doses with the timing (morning 
or evening) of the Week 4b pre-dose PK sample collection.] For three days before this visit, you must be sure to 
give your child CAB or RPV on time and in the morning. This is very important. We will help you remember this 
before the visit.  
 
If your child is taking oral CAB, we will need to draw your child’s blood six times during the visit, one time 
before and five times after taking CAB. We will also remind you not to give your child CAB before coming to 
this visit. When you come to the visit, we will draw your child’s blood, then your child will take CAB, and then 
we will draw your child’s blood 5 more times, about 1, 2, 3, 4, and 8 hours later. Each time we will draw 2mL 
(less than 1 teaspoon), for a total of 12mL (about 3 teaspoons).  
 
If your child is taking oral RPV, we will need to draw your child’s blood three times during the visit, before and 
after taking RPV. We will remind you not to give your child RPV before coming to this visit. When you come to 
the visit, we will draw your child’s blood, then your child will take RPV, and then we will draw your child’s 
blood 2 more times, about 4, and 8 hours later. Each time we will draw 2mL (less than 1 teaspoon), for a total of 
6mL (about 1 teaspoon). 
 
[Sites: modify language as appropriate to indicate procedures for the intensive PK collection. For the intensive 
PK tests, a small plastic tube will be placed in your child’s arm to draw blood samples. This tube is attached to a 
plastic needle so that we can draw blood several times. We will not need to stick your child with a needle each 
time. The plastic tube may stay in place for the blood draws.]  
 
[Sites: modify language as appropriate to indicate procedures for intensive PK visit and overnight stays – You 
and your child may need to stay at the clinic or hospital for up to 8 hours. If the study clinic is able, you may be 
allowed to stay at the clinic the night before and during your first PK visit.] 
 
[Sites to modify] On rare occasions, we may offer some of the visit activities off-site, or by phone. The study staff 
will discuss the location and best time to visit you so that the visit is at a convenient time and the visit is done at a 
place you and your child feel comfortable and confidentiality can be maintained. 
 
10. If your child is eligible, your child will enter Cohort 1-Phase 2 (Week 4b). 
 
At the Week 4b visit, we will determine if your child is eligible for the second phase. At this visit we will: 
• 
Review your child’s medical records.  
• 
Talk with you about your child’s ARV use. 
• 
Do a physical exam. 
• 
Ask your child questions about their experience with the study drug.  
• 
Talk with your child about preventing pregnancy.  
• 
Draw about 12mL (about 2-3 teaspoons) blood for tests. These tests will check your child’s HIV viral load. 
Some blood will be saved for later resistance testing.  
• 
For girls, we will also collect urine or blood to test for pregnancy. 
• 
Remind your child to bring the oral CAB or oral RPV to the study clinic. 
• 
[Sites: modify language as appropriate to align the three prior doses with the timing (morning or evening) of 
the Week 4b pre-dose PK sample collection. Remind your child to take his/her oral CAB or oral RPV in the 
morning for the three days before this visit.]  
 
If your child is not eligible, your child will stop taking oral CAB or oral RPV and will complete a final study visit 
about 4 weeks after your last oral dose (see #15 for more information). 
 


 
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If your child is eligible for Cohort 1-Phase 2, they will continue taking their usual ARVs. Your child will take 
their last dose of oral CAB or oral RPV at the Week 4b visit. We will also give your child the first shot of CAB or 
the first shot of RPV at the Week 4b visit. We will remind you not to give your child oral CAB or oral RPV 
before coming to this visit. Your child will take oral CAB or oral RPV at the study clinic before the first shot of 
CAB or the first shot of RPV.  
 
At this visit, we will also look closely at the amount of CAB or RPV in your child’s blood. To do this, we will 
need to draw your child’s blood two times during the visit, before taking oral CAB or RPV and after getting a 
shot of CAB or RPV. When you come to the visit, we will draw your child’s blood, then your child will take their 
oral CAB or RPV and get a shot of CAB or RPV, and then we will draw your child’s blood again, about two 
hours later. Each time we will draw 2mL (less than 1 teaspoon) for a total of 4mL (less than 1 teaspoon).  
 
[Sites to include if combined Week 4a and Week 4b visits are planned.] This visit may be combined with the 
previous study visit (Week 4a). 
 
11. Your child will have 5 more visits (Weeks 5-16) in Cohort 1-Phase 2.  
 
The first visit in Cohort 1-Phase 2 will be the Week 4b visit, which is described in #10 above. After that visit, 
your child will have 5 more visits in this phase.  These visits will take place 1-4 weeks apart. [Sites to modify] 
Each visit will take about 1-3 hours.  
 
At each of these visits, we will:  
• 
Review your child’s medical records.  
• 
Talk with your child about preventing pregnancy 
• 
Do a physical exam. At the Week 16 visit, this will include looking at your child’s genitals to see the stage of 
development. For girls, this will also include looking at the breasts. 
• 
Draw about 2mL of blood (less than 1 teaspoon) to look at the amount of CAB or RPV in your child’s blood.  
 
At 3 of these visits (Weeks 5, 8, and 16) we will also draw about 5mL of blood (about 1 teaspoon) to check your 
child’s blood cells and how well your child’s liver and kidneys are working.  
 
At 2 of these visits (Weeks 8and 16) we will also draw about 12mL of blood (about 2-3 teaspoons) to check your 
child’s HIV viral load. Some blood will be saved for later resistance testing. 
 
At 1 of these visits (Week 16), we will also draw about 3mL of blood (less than 1 teaspoons) for tests. These tests 
will check your child’s blood cells and CD4 count. 
 
At 2 of these visits (Weeks 9 and 16) we will also do an ECG to look at your child’s heart.  
 
At 1 of these visits (Week 8) we will also give your child a shot of either CAB or RPV. 
 
At 2 of these visits (Weeks 8 and 16) we will also talk with your child about your child’s experience with study 
ARVs.  
 
For girls, at 2 of these visits (Weeks 8 and 16) we will also collect urine or blood to test for pregnancy.  
 
12. In-depth phone interview [for U.S. sites only] 
 
We are very interested to understand what adolescents think about getting their ARV’s as shots. Your child may 
be asked if they would like to complete an in-depth phone interview. If your child would like to take part in the 


 
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interview, then your child may be contacted to have the interview after getting the first shot of CAB or RPV. Not 
all participants will be contacted for the interview. Your child does not have to do the interview to take part in this 
study. 
 
If contacted, an interviewer will talk to your child for about 1-2 hours and will ask your child how they feel about 
having shots of CAB or RPV. This information will help us understand if CAB shots and RPV shots have any 
side effects for adolescents. It will also help us understand how adolescents and families feel about the shots. The 
interview may take place at or in between the Week 4b, 5, 6, 8, and 12 study visits, or during the long-term 
follow-up safety phase. The interview will only take place once. The interview will be audio recorded and written 
down in a report. Your child’s name will not be included in the report.  
 
We may also ask you to complete an in-depth interview. This interview would ask you how you felt about your 
child having shots of CAB and RPV. 
 
13. We will tell you if your child is eligible for Cohort 2. 
 
After your child’s last visit in Cohort 1-Phase 2, we will tell you if your child is eligible for Cohort 2 or if your 
child needs additional tests to see if they qualify for Cohort 2.  
 
If your child is not eligible for Cohort 2, or if Cohort 2 is not ready to take participants, your child will stop 
getting shots of CAB or RPV and will enter Cohort 1-Phase 3, also called the long-term safety follow-up phase 
(see #16 below for more information). We will let you know when Cohort 2 is ready and if your child needs 
additional tests to see if they qualify for Cohort 2. 
 
If your child is eligible for Cohort 2, and Cohort 2 is ready to take participants, your child can enter into Cohort 2. 
 
14. Adolescents may have an extra visit if their HIV is not controlled. 
 
Participants will have viral load tests at almost all visits to check the amount of HIV in the blood. If tests show 
that the viral load is higher than expected (above 200 copies/mL) your child will have repeat testing. This may 
occur as part of another study visit or may occur as an extra study visit.  
 
The extra visit will take about 1-2 hours. At this visit we will: 
• 
Review your child’s medical records. 
• 
Do a physical exam.  
• 
Draw about 14mL (about 3 teaspoons) of blood for tests. The tests will: 
o Check your child’s HIV viral load.  
o Check the amount of CAB or RPV in the blood.  
o We will save some blood for later resistance testing. 
• 
Talk with your child about preventing pregnancy. 
• 
For girls, we will also collect urine or blood to check for pregnancy.  
 
If the repeat test also shows an increased amount of HIV in your child’s blood, your child will stop taking the 
study product. If your child was getting shots of CAB or RPV, your child will enter long-term safety follow-up 
(more information in #16 below).  
   
15. If your child is not eligible to receive shots of CAB or RPV your child will stop the study early. 
 
If your child is not eligible to get shots of CAB or RPV in Cohort 1-Phase 2, your child will stop taking oral CAB 
or oral RPV and will complete a final study visit about 4 weeks after your child’s last oral dose.  


 
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During this visit, we will:  
• 
Review your child’s medical records.  
• 
Do a physical exam. This will include looking at your child’s genitals to see the stage of development. For 
girls, this will also include looking at the breasts. 
• 
Draw blood for tests. This would be about 15-20mL of blood (about 3-4 teaspoons) for these tests. These tests 
will check:  
o Your child’s blood cells.  
o How well your child’s liver and kidneys are working. 
o Your child’s HIV viral load.  
o Some blood will be saved for future resistance testing. 
• 
Talk with your child about preventing pregnancy. 
• 
For girls, we will also collect urine or blood to check for pregnancy.  
• 
Ask your child questions about what it is like for them to take CAB or RPV.  
• 
We will also talk with you and your child about your child’s ARV use.  
 
16. If your child stops the shots of CAB or RPV early, or is not eligible to enroll in Cohort 2, or if Cohort 2 is not yet 
ready, your child will enter Cohort 1-Phase 3 (long-term safety follow-up phase). 
 
Your child will enter Cohort 1-Phase 3 (long-term safety follow-up phase) after the last shot of study product, if 
your child: 
• 
Stops the shots of CAB or RPV during Cohort 1-Phase 2 early, or 
• 
Is not eligible to enroll in Cohort 2, or 
• 
If Cohort 2 is not yet ready for participants 
 
If your child becomes pregnant, she will enter this phase of the study after her positive confirmatory pregnancy 
test result, whether she is taking the pill or the shot.  
 
Your child will keep taking their usual ARVs. There will be 3 or 4 visits during the long-term safety follow-up 
phase. These visits will be scheduled 8, 24, 36 and 48 weeks after your child’s last shot of CAB or RPV (or after a 
positive confirmatory pregnancy test result). [Sites to modify] Each of these visits will take about 1-3 hours. At 
these visits, we will:  
• 
Review your child’s medical records.  
• 
Do a physical exam. At the final long-term safety follow-up visit, this will include examination of your 
child’s genitals to see the stage of development. For girls, this will also include looking at the breasts. 
• 
Talk with your child about preventing pregnancy. 
• 
Draw blood for tests. This would be about 19mL of blood (about 4 teaspoons) for these tests. These tests will 
check:  
o Your child’s blood cells.  
o How well your child’s liver and kidneys are working. 
o Your child’s HIV viral load.  
o The amount of CAB or RPV in the blood.  
o Some blood will also be saved for future resistance testing. 
• 
For girls, we will also collect urine or blood to check for pregnancy.  
• 
At two of these visits (8 weeks and 48 weeks after your child’s last shot of CAB or RPV) we will talk with 
you about your child’s ARV use. 
• 
At two of the visits (8 weeks and 48 weeks after your child’s last shot of CAB or RPV), we will also ask your 
child questions about getting shots of CAB or RPV.  
 


 
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For participants who complete the Week 16 visit in Cohort 1-Phase 2, the first long-term follow-up visit will be 
skipped entirely. The Week 16 visit and the first long-term follow-up visit are very similar and do not need to be 
conducted twice. 
 
17. Different tests will be done at different laboratories. 
 
We will do most of the tests of blood or urine here at our laboratory. We will give you and your child the results 
of most of these tests at the next scheduled visit, or sooner, if necessary. We will explain the results and give you 
counseling and referrals for your child as needed.  
 
We will also draw blood to check the amount of CAB or RPV in your child’s blood. This is called a 
pharmacokinetic (PK) test. The PK test will be done at a laboratory in the United States. We will not usually give 
you the results of this PK test during the study.   
 
If your child needs a test for resistance (see #14 above), that test will be done at a laboratory in the United States.  
You and your child will be given the results of this resistance test and referrals if needed.  
 
18. We may take your child off of the study. 
 
We may take you off the study ARVs if: 
• 
Your child is not able to come to the study visits or we determine that your child cannot meet the study 
requirements. 
• 
Your child is not able to take the study ARVs. 
• 
The study ARVs are not controlling the HIV in your child’s blood. 
• 
Continuing the study ARVs may be harmful to your child. 
• 
You or your child request to stop the study ARVs for your child. 
• 
Your child is not able to follow the birth control requirements of this study. 
• 
Your child becomes pregnant. 
 
If your child stops the oral study ARVs early, we will ask you to come back to the clinic with your child about 
four weeks after they stop the oral study ARVs (see #15 above). Your child will not have any other visits after 
this. 
 
If your child stops the ARV shots early, we will ask you to come back to the clinic with your child for four 
additional study visits for long-term safety follow-up (see #16 above). Your child will not have any other visits 
after these four visits. 
 
We may also take your child off the study early if the study is stopped for any reason.  
 
The study cannot provide other types of ARVs, but we will give you information, counseling, and referrals to 
where your child can get care and treatment needed. We will help make sure your child can get ARVs from 
outside of the study. If the study stops early, every effort will be made to make certain that there is no interruption 
in your child’s therapy.  
 
19. Please tell us if you or your child want to leave the study. 
 
Your child is free to leave the study at any time for any reason. The care that your child receives at this clinic will 
not be affected, but it is important for us to know about you and your child’s decision.  
 


 
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If your child stops the study ARVs, we may ask you to return to the study clinic with your child for additional 
study visits described in #15 and #16 above. If your child stops the study early, we may ask you to return to the 
study clinic with your child for one final study visit, like the last study visit described in #16 above. 
 
We will answer any questions you or your child may have and give you information on how to contact us in the 
future, if you wish. 
 
Risks of the study 
 
Taking part in this study may involve some risks and discomfort. The risks are different for each phase of the 
study. Cohort 1-Phase 1 risks include: risks from blood draws, risks from the study pills (CAB or RPV), and risks 
to your child’s privacy.  
 
Cohort 1-Phase 2 risks include: risks from blood draws, risks from receiving the injection, risks from the study 
pills (CAB or RPV) and the study shots (long-acting CAB or RPV) and risks to your child’s privacy. 
 
Cohort 1-Phase 3 risks include: risks from blood draws, and risks to your child’s privacy.  
 
20. Risk from blood draws  
 
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted. Rarely, drawing blood 
can cause fainting or infection. 
 
21. Risk from receiving the injection  
 
People in other studies who have received the CAB and RPV shots said they had pain, skin irritation, skin 
redness, bumps, swelling, itching, bruising at the spot where they got the shot. Most reactions go away in a week 
or less but sometimes they can last longer. Most people usually do well with them and rarely need to stop the 
drug.  
 
The shots will be given in the muscles of your child’s buttocks. The injection could be given too deeply or not 
deeply enough, missing the muscle and entering your skin, blood, or a nerve.  
 
The risks of this are not well understood but could make CAB or RPV levels too low or too high. If too low, the 
drug may not work against your child’s HIV. If RPV is too high, there could be a change in your child’s 
heartbeat, which in severe cases can be life-threatening. In rare cases, symptoms such as feeling lightheaded, 
numbness or tingling, difficulty breathing, chest or stomach discomfort, sweating, nausea and/or feeling anxious 
have occurred after an injection with RPV LA. In these cases, high blood levels of RPV have been observed, 
which may be due to an accidental injection of part of the medication into a blood vessel instead of the muscle. 
Not all patients in whom an accidental injection in a blood vessel was suspected reported such symptoms. Most of 
the symptoms resolved within minutes. Your child’s doctor may need to administer treatment to help resolve 
these symptoms.  Everything possible will be done to decrease this risk, including watching your child for 
problems during the study. If your child’s doctor thinks that the injection was not given the right way, your child 
might be asked to stay in the clinic up to [sites to modify] 2 hours after the injection to watch how your child is 
doing and extra tests may be needed to be sure your child is safe. If you or your child are worried about this risk, 
talk to your child’s doctor. 
 
Receiving injections can cause some people to feel lightheaded or feel like they might pass out. Fainting can also 
occur. This reaction, called a ‘vasovagal reaction’, has been reported with other injectable medicines, and resolves 
quickly. 
 


 
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22. There are risks from the study ARVs 
 
All ARVs can cause side effects. This includes the ARVs your child is currently taking and the ARVs that are 
given in the study. Some side effects are minor; others can be severe. Some side effects are common; others are 
rare. Some people who take ARVs have some of the side effects. Other people have different side effects, or no 
side effects.  
 
The most common and most serious side effects of the study ARVs, CAB and RPV, are listed below. This is 
based on what we know now about CAB and RPV used in adults. There may be other side effects that we do not 
know about now. This may be especially true for adolescents, because this is the first study of CAB and RPV in 
adolescents.  
 
This form does not list all possible side effects of all ARVs. If your child joins the study, we will tell you more 
about the ARVs your child will be taking. At each study visit, we will check on whether the ARVs may be 
causing side effects. We will also tell you what to do if your child has side effects. If you or your child have 
questions or concerns at any time, please tell us.  
 
23. Some side effects from the CAB pills and the CAB shot 
 
Many people have received CAB pills or the CAB shot in other studies. The table below lists side effects from 
other studies of CAB with people who have HIV. It is not known if CAB, other drugs or the patient’s other health 
problems caused or affected these. Some of these are the same side effects as RPV (see #24 below).  
 


 
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Common Side Effects of CAB 
Very Common Side Effects of CAB 
Common Side Effects of CAB 
• Headache 
• Fever 
• Injection Site Reactions 
 
• Rash 
• Itching  
• Vomiting (being sick) 
• Nausea (feeling sick) 
• Stomach pain and discomfort  
• Problems sleeping  
• Abnormal dreams/nightmares 
• Anxiety 
• Feeling lightheaded 
• Depression 
• Passing gas or wind 
• Diarrhea 
• Muscle pain 
• Lack of energy 
• Increase in the level of enzymes produced 
in the muscles (creatine phosphokinase) 
• Weight increased 
 
The following effects have also been seen in some of the people who received CAB pills or the CAB shot in other 
studies: 
 
Abnormal liver tests: 
 
A small number of people across all studies (just over 1% of 1644 participants as of April 2017) had abnormal 
liver tests requiring them to stop CAB. Some abnormal liver tests were explained by other health conditions such 
as a new virus infection, like Hepatitis A, B or C.  A small number of people did not have health conditions that 
could explain the abnormal test, so it is possible that a mild form of liver damage happened from taking CAB. 
The liver tests got better after stopping CAB, showing that any damage was temporary. 
 
Blood tests to check the health of your child’s liver will be done during the study. Your child’s study doctor will 
tell you if your child needs to stop taking the study drugs or if other actions are needed. If your child stops taking 
the study drug, they may be able to re-start the study drug or they may need to change their usual ARVs.  
 
Seizures/convulsions: 
 
Seizures have been seen (rarely) in people with and without HIV who have taken CAB. They are not thought to 
be caused by CAB, but the study staff will ask you about them.  
 
In other studies, two people without HIV had a history of seizures (epilepsy), and had a seizure about 3 months 
and 9 months after starting CAB. One other person with HIV but without a history of seizures, had seizures about 


 
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one year after starting CAB. This participant had a long period of seizures without medical treatment and died. It 
is not known if CAB was part of the reason for seizures in these people. If your child has a history of seizures, 
please let your child’s study doctor know. 
 
24. Some side effects from the RPV pills and the RPV shot 
 
Oral RPV (Edurant) is a marketed drug which many people throughout the world have received to manage HIV. 
We know more about the side effects of Edurant than we do about CAB or RPV shots. The following side effects 
have been seen in studies in people with HIV taking RPV.  
 
Common Side Effects of RPV 
Common Side Effects of RPV 
Uncommon Side Effects of RPV 
• 
Problems sleeping, insomnia  
• 
Headache 
• 
Feeling lightheaded (dizziness) 
• 
Rash 
• 
Nausea (feeling sick to the stomach) 
• 
Vomiting 
• 
Abdominal (belly) pain 
• 
Increase in the level of liver enzymes 
• 
Decreased appetite 
• 
Depression 
• 
Abnormal dreams 
• 
Fatigue (tiredness, lack of energy) 
• 
Dry mouth 
 
• 
Sleepiness (somnolence) 
• 
Depressed mood 
• 
Stomach discomfort  
• 
Immune reconstitution syndrome (this can be 
an overreaction of the body’s recovering 
defense system to a previously present 
infection, or problems in the immune system) 
 
The following effects have also been seen in some people who received RPV in other studies: 
 
Abnormal blood tests: 
 
Other changes in blood tests have also been observed. People with Hepatitis B or C or who have possible liver 
damage before starting RPV may have worse liver tests while taking RPV. A few cases of liver problems were 
found in people taking RPV who did not already have any liver problems. 
 
Sometimes allergic reactions can affect body organs, like the liver, and cause liver problems which can lead to 
liver failure. Contact your child’s study doctor right away if your child has any of the following signs or 
symptoms of liver problems: 
• 
Yellowing of the skin or whites of the eyes 
• 
Dark or tea colored urine 
• 
Pale colored stools/bowel movements 
• 
Nausea/vomiting 


 
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• 
Loss of appetite 
• 
Pain, aching or tenderness on the right side below the ribs 
• 
Itchy skin  
 
Blood tests to check the health of your child’s liver will be done regularly during the study. Your child’s study 
doctor will tell you if your child needs to stop taking the study drugs or if other action is needed. If your child 
stops taking the study drug, they may be able to re-start the study drug or they may need to change their usual 
ARVs.  
 
Skin Rash: 
 
Most rashes were mild or moderate, and happened within the first 4 weeks of taking RPV. Most of rashes got 
better after one week, and the people did not need to stop taking RPV. However, the study ARVs will need to be 
stopped for some types of moderate rash and all types of severe rash, which can be life-threatening. If this 
happens to your child, they will need to come for extra study visits to monitor their health. Some people with rash 
may also have other signs and symptoms of allergic reaction. 
 
If your child has any type of rash or other skin problems during the study you must tell your child’s study doctor 
right away, and the doctor may tell your child to stop taking CAB and/or RPV. 
 
25. There may be other possible risks from the study ARVs. 
 
The study ARV shots stay in your body for a long time 
 
The shots your child gets in this study are long acting, meaning they stay in your child’s body for a long time. In 
most people, the drugs will no longer be in the body one year after an injection, while in some people low levels 
of CAB and RPV may still be in the body after one year. If your child develops a side effect to the study drug 
after the shot, there will be no way to remove the drug from your child’s body. If your child gets a shot of CAB or 
RPV, we will monitor their health for 48 weeks after their last shot. If your child develops a symptom from these 
drugs while the drugs are still in their body, every effort will be made to treat the side effects. The amount of drug 
will decrease overtime and will eventually disappear.  
 
While the amount of study drugs in your child’s body decrease slowly over time after they stop getting shots the 
study drugs could stop working against your child’s HIV. When stopping long acting HIV drugs, it will be very 
important to start taking other HIV medications, as your child’s study doctor tells you, so your child’s HIV 
medications do not stop working against their HIV. 
 
Risk of resistance 
 
All ARVs can cause some resistance if not taken correctly. Resistance means that the ARVs may not work against 
HIV if these ARVs are taken again in the future. To stop resistance, it is important that your child takes and/or 
receives the ARVs as instructed and does not miss any doses. 
 
Effects on other ARVs 
 
We do not expect the study ARVs to change the way other ARVs work in the body. For example, if your child 
was to join the study, we would expect the ARVs your child is currently taking to keep working to control the 
amount of HIV in their body. We also do not expect the study ARVs to cause more or worse side effects from 
other ARVs. However, this study is being done to learn more about these kinds of possible effects. 
 


 
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Mental illness or depression 
 
Some people with HIV sometimes have feelings of depression or may feel sad or hopeless, feel anxious or 
restless, or may have thoughts of hurting or killing themselves (suicide). A small number of people being treated 
with drugs called integrase inhibitors [INIs] for HIV like CAB, have had suicidal thoughts and actions, 
particularly patients with a prior history of depression or mental health illness.  
 
Tell the study doctor if your child has a history of mental health illness. If your child has thoughts of hurting or 
killing their self or have any other unusual or uncomfortable thoughts or feelings during this study, you should tell 
the study doctor or go to the nearest hospital right away.  
 
Possible effects on pregnancy or unborn babies 
 
HIV and ARVs may lead to some pregnancy complications, like early delivery or low weight of the baby at birth. 
We do not know if some ARVs are more likely to cause these effects than others. We do not yet know if CAB is 
safe in pregnancy. RPV does not appear to be a risk to pregnancy and the developing baby based on the 
information we know now, but additional data are still being collected. 
 
There are few data from humans on the effects of CAB in pregnancy. Most of the information we have comes 
from animal studies. In studies done in pregnant rats and their newborns, using very high amounts of CAB, there 
were more baby rats that died when they were born or right after they were born. This did not happen to the baby 
rats when the mother got lower amounts of the drug, or no drug. The amount of CAB that we are giving in this 
study is expected to be more than 7-times lower than the amount given to the pregnant rats. Birth defects have not 
been found in any animal studies of CAB so far. We do not know whether what happened to the baby rats has any 
impact on what will happen in pregnant humans taking this drug. 
 
Early results from one large study in Botswana showed that the ARV called dolutegravir (DTG) may increase the 
risk of serious birth defects of the brain or spine in the new baby. The increased risk was seen among babies 
whose mothers were taking DTG when they became pregnant. These birth defects happen during the first few 
weeks of pregnancy, before mothers may know they are pregnant. These birth defects have not been seen among 
babies whose mothers started taking DTG later in pregnancy.  
 
CAB is not the same drug as DTG. We do know that CAB and DTG belong to the same class of medications and 
work in a similar way to treat HIV infection. We do not know if CAB can cause brain or spine defects in babies.  
 
Girls who are able to become pregnant must agree to use certain effective methods of birth control to be in this 
study (see #6 above). If your child becomes pregnant during the study, please let us know right away. 
 
Immune reconstitution syndrome 
 
In some people with advanced HIV infection, signs and symptoms from other infections or certain diseases (for 
example a liver condition called autoimmune hepatitis) may occur soon after starting combination ARVs but can 
also occur later. Some of these symptoms may be life threatening. If your child starts having new symptoms, or if 
you notice that any of your child’s existing symptoms are getting worse after starting the ARVs, tell your child’s 
doctor immediately. 
 
Abnormal placement of body fat and wasting 
 
The use of potent antiretroviral drug combinations may be associated with an abnormal placement of body fat and 
wasting. Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 


 
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• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement 
 
26. There could be risks of disclosure of your child’s information. 
 
We will make every effort to keep your child’s information private and confidential. Study records and specimens 
will be kept in secure, locked locations. All specimens and most records will be labeled only with a code number. 
However, your child’s name will be written on some records.  
 
Despite our best efforts to keep your child’s information private, it is possible that the information could be 
obtained by someone who should not have it. If this were to happen, your child could be treated badly or unfairly. 
Your child could feel stress or embarrassment.  
 
To help us protect your child’s privacy, we have obtained a Certificate of Confidentiality that protects us from 
being forced to release information that may identify your child, such as by the courts or police. The certificate 
cannot be used in all situations, but it can be used to resist demands for information that would identify your 
child. The certificate does not protect against requests for information from the US federal government or from 
the US Food and Drug Administration. Regardless of the certificate, you can release information about your 
child’s participation in the study to others, if you wish. 
 
Information collected for this study may be used for other research in the future. For example, researchers may 
use information from this study to try to answer different questions about children or adolescents with HIV. Any 
future research done with the information from this study must be approved by the IMPAACT Network. If any 
future research is done, information about your child may be used, but your child’s name will not be shared. 
 
Benefits of the study 
 
27. There may be a direct benefit to your child from being in the study. 
 
By joining the study, your child will be part of the search for ARVs that may be better for adolescents. We do not 
know if being in the study will benefit your child in any way. There may be a direct benefit to your child by 
taking part in this study, but no guarantee can be made. For example, you and your child may gain a better 
understanding of your child’s health and HIV care.  Another possible benefit is early access to the Cohort 2 part 
of the study, if your child qualifies. There may also be benefit if the results from this study lead to a safe and 
effective dose of the study drugs for adolescents. It is also possible that your child may receive no direct benefit 
from this study. Information learned from this study may help other adolescents who have HIV. 
 
Your child will have regular visits here and frequent checks on your child’s health, including tests for the amount 
of HIV in your child’s blood, called viral load. It is possible that the study ARVs will slow your child’s HIV 
infection. Information learned from this study may help other adolescents with HIV. 
 
Other information about the study 
 
28. There are no costs from being in the study. 
 
There are no costs to you for study visits, CAB, RPV or procedures.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits. For each visit, you will be given (specify amount).] 
 


 
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29. Study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include:  
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your child’s name or identify your child personally.  
 
A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify your child. At most, the website will include a summary of the results. You 
can search this website at any time. 
 
Your child’s study information may be given to other authorities if required by law. [Sites add more specific 
detail here as needed; example follows:] For example, we are required to report any significant risk of harm to 
your child or others.  
 
30. If your child gets sick or injured, contact us immediately. 
 
Your child’s health is important to us. We will make every effort to protect your child’s well-being and minimize 
risks. It is possible, however, that your child could have an illness or injury that is study-related. This means that 
the illness or injury occurred as a direct result of the study procedures.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage available 
through clinical trial insurance obtained by the site should be included if applicable; the statement regarding no 
program for compensation through the NIH may not be removed.]  If a study-related illness or injury occurs, we 
will treat your child or tell you where your child can get treatment. The cost for this treatment may be charged to 
you or your insurance company. There is no program for compensation either through [site name or] the U.S. 
National Institutes of Health.  
 
Whom to contact 
 
31. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about your child’s rights as research participants or concerns about how your child is 
being treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 


 
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• 
If your child has any health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you want your child to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
Signatures 
 
If you agree to allow your child to participate in this study, please sign or make your mark below. 
Before deciding whether to allow your child to participate in this study, make sure you have read this form, or had 
it read to you, and that all of your questions have been answered. You should feel that you understand the study, 
its risks and benefits, and what is expected of your child if you decide to allow your child to join.  
 
If you decide to allow your child to join, we will tell you any new information from this study or other studies that 
may affect your willingness to stay in the study. You are welcome to ask questions or request more information at 
any time. If you want the results from this study, please tell the study staff. 
 
 
You do not give up any rights by signing this form. 
 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
 
 
 
 
 
 
Name of Participant (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Parent/Guardian/ 
 
Signature of Parent/Guardian  
 
Date 
Legally Authorized Representative 
Legally Authorized Representative 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
(as appropriate; print) 
 
 
 


 
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Appendix II-B:  Sample Parental Informed Consent Form for Participation in Cohort 2 
for parents/guardians of adolescents who cannot provide independent informed consent for study participation 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 3.0, dated 13 August 2020 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
Introduction 
 
Your child is being asked to take part in the research study named above. 
 
This form gives information about the study. Please read it, or have it read to you, and ask any questions you may 
have. We will take as much time as needed for you to fully understand the study. We will ask you questions to see 
if we have explained the study clearly. 
 
Here is a summary of important information about the study: 
 
• 
The study is testing two anti-HIV medicines (ARVs), Cabotegravir (CAB) and Rilpivirine (RPV), taken as 
pills and given as long-acting shots in adolescents 12 to less than 18 years of age.  
• 
The RPV pills are approved for adolescents in Botswana, Uganda, United States and for adults in Botswana, 
South Africa, Thailand, Uganda, United States. The CAB pills, and the CAB and RPV shots are now being 
tested in adults with HIV but have not yet been tested in adolescents.  
• 
There are two parts to this study, Cohort 1 and Cohort 2. This form is about Cohort 2.  
• 
Adolescents in Cohort 2 will be in this part of the study for at least 2 years up to 3 years.  
• 
Adolescents in Cohort 2 will switch from their usual ARVs to the study medicine. After entering the study, 
adolescents will stop taking their usual ARVs and start taking daily CAB and RPV pills for 4 to 6 weeks. 
Adolescents will then switch to CAB and RPV shots every 8 weeks for about 2 years.  
• 
After the 2 years of getting the CAB and RPV shots, adolescents might be able to continue getting the same 
CAB and RPV shots outside of the study. We will explain the options to you and help ensure your child’s 
access to ARVs outside the study. 
• 
Adolescents who stop taking the CAB and RPV shots may be followed for up to 1 year for long-term safety 
follow-up. During this time, adolescents will not take any study medicine (shots or pills) but will take ARVs.   
• 
While in the study, adolescents will have clinic visits with physical examinations and blood draws for 
laboratory tests. Some visits will include a review of adolescents’ medical records and ECG tests to look at 
the adolescent’s heart. Female participants will also be tested for pregnancy.  
• 
If interested, participants in the U.S. may be eligible to do one in-depth phone interview where they will talk 
about their experience getting their ARVs as shots.  
• 
There are some possible risks for adolescents in the study. One possible risk is that the pills or shots being 
tested could cause side effects. The most severe side effects include allergic reaction, liver problems, and 
mental health problems.  These side effects are uncommon. 
• 
There are some possible benefits for adolescents in the study. One possible benefit is your child not taking 
daily pills while getting the CAB and RPV shots.  Another possible benefit is that the shots being tested will 
be better for your child’s health and HIV care than the usual ARV pills.  


 
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• 
Your decision on your child’s participation in the study will have no effect on the medical care your child 
receives at this clinic. Your child’s access to services, and the benefits and rights he or she normally has, will 
not be affected. You or your child may choose to leave the study at any time. 
 
More information is given in this form about the study, its risks and benefits. You should feel that you understand 
the study before deciding whether your child will participate. If you decide to allow your child to participate, you 
will be asked to sign or make your mark on this form. You will be offered a copy to keep. 
 
About the study 
 
This study is being done by the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
(IMPAACT) and [insert site name]. The person in charge of the study at [insert site name] is [insert name of 
IoR].  
 
The study is being done to test two anti-HIV medicines (antiretrovirals or ARVs) in adolescents 12 to less than 18 
years old who have HIV. The study ARVs are called cabotegravir (CAB) and rilpivirine (RPV). HIV is the virus 
that can lead to AIDS.  
 
The study will include up to 155 adolescents from the United States, Botswana, South Africa, Thailand and 
Uganda. There will be two groups of adolescents, called Cohort 1 and Cohort 2. This form is about Cohort 2. 
Participants in Cohort 2 will be in the study for 2 to 3 years. In Cohort 2, participants will get study product for 96 
weeks (about 2 years). After 96 weeks, participants may continue getting the study medicines outside of the study. 
If your child continues getting the study medicines outside of the study, your child will not have any additional 
study visits. If your child stops getting the study medicines, your child will enter long-term safety follow-up and 
continue having study visits for an additional 48 weeks (about 1 year). 
 
The United States National Institutes of Health and the companies that make CAB and RPV, ViiV Healthcare and 
Janssen Pharmaceuticals, are paying for this study.  
 
1. The study is testing CAB and RPV in adolescents. 
 
People with HIV usually take a combination of ARVs daily to stay healthy. There are not as many ARVs 
available for adolescents as for adults because many ARVs have not yet been tested in adolescents. ARVs can be 
made in different forms, such as liquids, pills, and injections (shots). The study will test CAB and RPV when 
taken as pills and when given as shots in adolescents. The pills are taken every day. The shots can be given every 
4 weeks or every 8 weeks. The shots are being developed because it can be difficult to take pills every day, and 
some people may prefer to have the shots rather than taking pills.  
 
RPV pills (25mg taken once daily) have been shown to be safe and effective for both adults and adolescents 12 
years and older with HIV. The RPV pills are already approved by the US Food and Drug Administration (FDA) 
for adults and adolescents with HIV.  The FDA is the part of the government that regulates medicines in the 
United States. The RPV pills have also been approved for use for adults and adolescents in Cambodia, Canada, 
China, Ethiopia, the European Union, Gabon, Ghana, Hong Kong, Ivory Coast, Japan, Kazakhstan, Kenya, 
Malawi, Mali, Namibia, Nigeria, Russia, Taiwan, Tanzania, Ukraine and Zimbabwe. 
 
RPV shots (600mg and 900mg), CAB pills (30mg), and CAB shots (400mg and 600mg) are now being tested in 
adults with HIV. The FDA is asking for more information on how these medicines are made before they can 
approve them in adults.  The FDA has no safety concerns regarding these medicines. RPV shots, CAB pills and 
CAB shots have been approved in Canada for monthly dosing. 
 


 
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This will be the first study of these ARVs in adolescents. So far, the testing in adults has shown that RPV shots, 
CAB pills, and CAB shots work as well as other ARVs that are approved. However, because these ARVs are still 
being tested, there may be some effects that we do not know about yet.  
 
This study will test the effects of these ARVs in adolescents. The study will look at whether these ARVs:  
• 
Are being given at the correct dose for adolescents  
• 
Are safe and well-tolerated in adolescents 
• 
Can control HIV in adolescents as well as other ARVs 
 
The study will also look at how willing adolescents are to take these ARVs.  
 
Cohort 1 of this study was done first to test CAB and RPV pills when taken for about 1 month followed by 2 or 3 
CAB and RPV shots when taken 1 month apart. Cohort 2 is now being done to test CAB and RPV pills taken 
together for about 1 month, followed by CAB and RPV shots taken together. Both CAB and RPV shots will be 
given together about every 8 weeks for up to two years. Each time the shots are given, the RPV shot will be 
900mg and the CAB shot will be 600mg. Cohort 2 will look at whether these study ARVs are safe and can control 
HIV when adolescents stop taking their previous ARVs.  
 
More information about the study, Cohort 2, and CAB and RPV is given in the rest of this form. 
 
2. Only adolescents who are eligible can participate in the study. 
 
If you decide to allow your child to join the study, we will first do some tests to find out if your child is eligible. 
More information about the tests is given in #5 (see below). If your child is eligible, your child will be entered in 
the study. If your child is not eligible, your child cannot be entered in the study.  
 
3. It is your decision whether or not your child joins the study. 
 
Deciding to join the study is voluntary (your choice). You may choose to allow your child to join or not join. 
Your child will also be asked if they want to join the study. You and your child must both agree. If you allow your 
child to join, you can change your mind and take your child out of the study. If your child does decide to join, 
they can also change their mind and stop being in the study at any time. Your and your child’s choices will have 
no effect on the medical care your child would normally receive. Your child’s access to services, and the benefits 
and rights your child normally has, will not be affected.  
 
Take your time and consider your decision carefully. If you wish, you can talk to other people about the study. 
You can bring other people here to learn about the study with you. 
 
No matter what you decide about the study, it is important for your child to keeping taking ARVs. This is the best 
known way for your child to stay healthy. 
 
4. There are three phases in Cohort 2.  
 
For participants in Cohort 2, there are three phases of the study. All participants will take part in Cohort 2-Phase 
1. Only those who are eligible will take part in Cohort 2-Phase 2. Some participants who take part in Cohort 2-
Phase 2 will also take part in Cohort 2-Phase 3, called the long-term safety follow-up phase. 
 
In Cohort 2-Phase 1, your child will stop taking their usual ARVs and take CAB and RPV pills. The pills must be 
swallowed whole. They cannot be broken or crushed. They should be taken with a meal. This phase lasts for 
about 4-6 weeks. After the study entry visit (see #8 below), your child will have 2 more visits during Phase 1. At 


 
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these visits, we will check to see how your child is doing while taking the pills (see #9 for more information). We 
will also check to see if your child is eligible for Cohort 2-Phase 2.  
 
If your child is eligible for Cohort 2-Phase 2, your child will stop taking the CAB and the RPV pills and start 
getting CAB and RPV shots. This phase lasts 2-3 years. Your child will have 15 visits over about two years and 
will get shots at 13 of these visits. At each of these 13 visits, your child will be given one shot of CAB and one 
shot of RPV. Each shot is 3mL (about 1 teaspoon). The shots are given in the buttocks (bottom “cheeks”). The 
shots may be given on the same side of the buttocks or on different sides. The shots are long-acting, meaning the 
medicine stays in your child’s body for a long time. The first two visits with the CAB and RPV shots are 4 weeks 
apart. Then the CAB and RPV shots are given every 8 weeks. At all of these study visits, we will check on how 
your child is doing while getting the shots (see #11 for more information). 
 
After Cohort 2-Phase 2, your child might have the option to continue getting the long-acting injections (see #19 
for more information). If your child no longer wants to get the injections, they will take part in Cohort 2-Phase 3, 
the long-term safety follow-up phase of the study. This phase lasts about 48 weeks. Your child will also go back 
to taking their usual (pre-study) ARVs. There will be 3 or 4 visits during long-term follow up (see #15 for more 
information). 
 
Finding out if your child is eligible for Cohort 2 
 
5. We will ask questions, examine your child, and discuss the study requirements with you. 
 
To find out if your child is eligible for the study, we will: 
 
• 
Review your child’s medical records. 
• 
Ask questions about your child, your child’s health, and the medications your child takes.  
• 
Talk with your child about birth control (ways to prevent pregnancy). 
• 
Talk with you about the study requirements and if your child is able to meet these requirements. 
• 
Do a physical exam. This will include looking at your child’s genitals to see the stage of development. For 
girls, this will also include looking at the breasts. 
• 
Do an electrocardiogram (ECG). This is to test how well your child’s heart is working.  
• 
Draw between 11-17mL (about 2-3 teaspoons) of blood for tests. The tests will: 
o Check your child’s blood cells. 
o Check how well your child’s liver and kidneys are working. 
o Confirm that your child has HIV. There are certain HIV tests that are required for this study. If the 
required tests are not in the medical records, we will do the tests that are needed. 
o Check the amount of HIV in your child’s blood. This is called the HIV viral load.  
 
These procedures will take about 4 hours [here and throughout this form, sites may modify the expected visit 
duration as needed]. 
 
6. For girls, we will also test for pregnancy. 
 
Girls in this study cannot be pregnant. Girls should not join this study if they are pregnant or intend to become 
pregnant within 30 days after stopping the study ARV pills or within 48 weeks after stopping the study shots. 
Because the effects of the study ARVs on unborn babies are unknown, your child should not become pregnant 
while in this study. For all girls in the study, we will collect urine or blood to test for pregnancy.  
 
There are certain effective methods of birth control that girls who are able to become pregnant must use while in 
this study. These effective methods must be continued for 30 days after stopping the study ARV pills, or for at 


 
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least 48 weeks after stopping the study ARV shots. Girls who are able to become pregnant, must agree to use 
these methods in order to take part in the study. We will help make sure your child can get effective methods by 
providing them here in the clinic or offering a referral. At study visits when your child will receive study 
medicines (either the pill or shot), we will need to confirm that your child is using effective birth control before 
giving her the study medicines. 
 
Girls who become pregnant during the study will stop taking the study medicines and enter the long-term safety 
follow-up phase of the study (see #15 below). They must continue taking their usual ARVs. We will also 
contact you and your child to find out the outcome of the pregnancy even if the outcome occurs after leaving the 
study.  
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure of 
pregnancy results to parents or guardians: As soon as the pregnancy test result is available, we will go over it 
with your child in private, without parents/guardians present. Your child must give us permission before we can 
share these results with you. If the test shows that she is pregnant, we will give your child information on where 
medical care and other services can be received.] 
 
If your child is pregnant, your child’s doctor may report their pregnancy to the Antiretroviral Pregnancy 
Registry. The Antiretroviral Pregnancy Registry assists patients and doctors in gauging potential benefits 
and risks of treatment; however, the registry does not collect any identifying information about your 
child, such as name, initials, contact information, or date of birth.  
 
7. We will tell you if your child is eligible. 
 
We will give you the results of all procedures and explain the results to you. We will tell you about getting care, 
treatment and any other services your child may need. While waiting for the results, it is important for your child 
to keep taking their usual ARVs. 
 
If your child is not eligible for the study for any reason, we will tell you this. Your child will not be entered in the 
study. Your child can and should continue to receive medical care and treatment outside of the study. We will tell 
you more about getting this care and treatment and any other services your child may need.  
 
If your child does not enter the study, we will still use some information collected about your child (for example, 
age, sex, and race). We will use this information to look at patterns or common reasons for not entering the study.  
 
If your child is eligible for the study, your child will be entered into the study.  
 
Entering the study 
 
8. If your child is eligible, your child will enter the study. 
 
On the day your child enters the study we will:  
• 
Review your child’s medical records 
• 
Talk with you about your child’s ARV use 
• 
Talk with your child about preventing pregnancy 
• 
Ask your child questions about what they think about CAB and RPV 
• 
Do a physical exam.  
• 
Draw about 18mL (about 4 teaspoons) of blood for tests. The tests will: 
o Check your child’s blood cells. 
o Check how well your child’s liver and kidneys are working. 


 
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o Check how much the virus has affected your child’s ability to fight the virus. This is called CD4 cell 
count. 
o The tests will check your child’s HIV viral load.  
o Some blood will be saved for later testing for resistance to ARVs. This test shows whether different 
ARVs may work against the HIV in your child’s blood. 
• 
For girls, we will collect urine or blood for a pregnancy test.  
 
At the study entry visit we may also do an ECG to look at your child’s heart. This will only be needed if your 
child enters the study more than 2 weeks after your child’s first visit. 
 
At this visit, your child will stop taking their usual ARVs and start taking CAB and RPV pills. We will give you 
the pills and explain how to take them. Your child will take their first dose at the visit.  
 
This visit will take about 4 hours.  
 
Being in the study 
 
9. After entering the study, your child will have two more visits in Cohort 2-Phase 1 (Weeks 2 and 4a).  
 
The first visit in Cohort 2-Phase 1 will be the study entry visit and is described in #7 above.  After that visit, your 
child will have 2 more visits in Cohort 2-Phase 1.  These visits will be scheduled 2 weeks apart. [Sites to modify] 
Each visit will take about 1-3 hours. At each of these visits, we will:  
 
• 
Review your child’s medical records.  
• 
Talk with you about your child’s ARV use 
• 
Do a physical exam. 
• 
Talk with your child about preventing pregnancy.  
• 
For girls, we will collect urine or blood to test for pregnancy.  
• 
Remind your child to bring the oral CAB and oral RPV to the study clinic. 
 
At two of these visits (Week 2 and Week 4a), we will draw about 5mL (about 1 teaspoon) of blood for tests. 
These tests will check your child’s blood cells and how well your child’s liver and kidneys are working.  
 
At the second visit (Week 2), we will draw about 12mL (about 2-3 teaspoons) blood for tests. This test will check 
your child’s HIV viral load. Some blood will be saved for later resistance testing.  
 
At the Week 2 visit we will also test the amount of CAB and RPV in your child’s blood. This is called a 
pharmacokinetic (PK) test. At this visit, we will ask you when your child took CAB or RPV in the past three days. 
[Sites: modify language as appropriate to align the three prior doses with the timing (morning or evening) of the 
Week 4b pre-dose PK sample collection.] For three days before this visit, you must be sure to give your child 
CAB and RPV on time and in the morning. This is very important. We will help you remember this before the 
visit.  
 
We will need to draw your child’s blood two times during the Week 2 visit, before and after taking CAB and 
RPV. We will remind you to not give your child CAB or RPV before coming to this visit. When you come to the 
visit, we will draw your child’s blood, then your child will take CAB and RPV, and then we will draw your 
child’s blood again, about three hours later. Each time we will draw 4mL (less than 1 teaspoon), for a total of 
8mL (about 2 teaspoons).  
 
Study staff will let you know when these procedures will occur ahead of time.  


 
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[Sites to modify] On rare occasions, we may offer some of the visit activities off-site, or by phone. The study staff 
will discuss the location and best time to visit you so that the visit is at a convenient time and the visit is done at a 
place you and your child feel comfortable and confidentiality can be maintained. 
 
10. If your child is eligible, your child will enter Cohort 2-Phase 2 (Week 4b). 
 
At the Week 4b visit, we will determine if your child is eligible for Cohort 2-Phase 2. At this visit we will: 
• 
Review your child’s medical records.  
• 
Talk with you about your child’s ARV use. 
• 
Do a physical exam. 
• 
Ask your child questions about their experience with the study drugs.  
• 
Talk with your child about preventing pregnancy.  
• 
Draw about 12mL (about 2-3 teaspoons) blood for tests. These tests will check your child’s HIV viral load. 
Some blood will be saved for later resistance testing.  
• 
Do an electrocardiogram (ECG). This is to test how well your child’s heart is working.  
• 
For girls, we will also collect urine or blood to test for pregnancy. 
• 
Remind your child to bring the oral CAB and oral RPV to the study clinic. 
• 
[Sites: modify language as appropriate to align the three prior doses with the timing (morning or evening) of 
the Week 4b pre-dose PK sample collection. Remind your child to take his/her oral CAB and oral RPV in the 
morning for the three days before this visit.]  
 
If your child is not eligible, your child will stop taking oral CAB and oral RPV and go back to taking their usual 
ARVs. If your child did not participate in Cohort 1, they will complete a final study visit about 4 weeks after their 
last oral CAB and RPV dose (see #14 for more information). If your child also participated in Cohort 1 and 
received shots of CAB or RPV but is not eligible to get the shots of CAB and RPV in Cohort 2, they will stop 
taking oral CAB and oral RPV and will enter into Cohort 2-Phase 3 long-term follow-up (see #15 below). 
 
If your child is eligible, your child will take their last dose of oral CAB and oral RPV at the Week 4b visit. At this 
visit, we will also give your child the first shot of CAB and the first shot of RPV. We will remind you not to give 
your child oral CAB and RPV before coming to this visit. Your child will take oral CAB and RPV at the study 
clinic before the first shot of CAB and the first shot of RPV.  
 
At this visit, we will also look closely at the amount of CAB and RPV in your child’s blood. To do this, we will 
need to draw your child’s blood two times during the visit, before taking oral CAB and RPV and after getting a 
shot of CAB and a shot of RPV. When you come to the visit, we will draw your child’s blood, then your child 
will take their oral CAB and RPV and get a shot of CAB and RPV, and then we will draw your child’s blood 
again, about two hours later. Each time we will draw 4mL (less than 1 teaspoon) for a total of 8mL (about 2 
teaspoons). At this visit, about 2 hours after your child gets a shot of CAB and a shot of RPV, we will also do an 
ECG to look at your child’s heart. 
 
[Sites to include if combined Week 4a and Week 4b visits are planned.] This visit may be combined with the 
previous study visit (Week 4a). 
 
11. Your child will have 14 more visits (Weeks 5-96) in Cohort 2-Phase 2.  
 
The first visit in Cohort 1-Phase 2 will be the Week 4b visit, which is described in #10 above. After that visit, 
your child will have 14 more visits in this phase.  Most of these visits will take place about 8 weeks apart, and 
some of these visits will take place 1 week apart. [Sites to modify] Each visit will take about 1-3 hours. At each of 
these visits, we will: 


 
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• 
Review your child’s medical records. 
• 
Talk with your child about preventing pregnancy.  
• 
Do a physical exam. At two of these visits (Weeks 24 and 96), this exam will include examination of your 
child’s genitals to see the stage of development. For girls, this will also include looking at the breasts. 
 
At 12 of these visits (Weeks 8-24 and 32-96) your child will:  
• 
Get a shot of CAB and a shot of RPV. 
• 
For girls, we will also collect urine or blood to check for pregnancy.  
 
At 13 of these visits (Weeks 5, 8-24, and 32- 96) we will draw about 5mL of blood (about 1 teaspoon) for tests. 
These tests will check: 
• 
Your child’s blood cells 
• 
How well your child’s liver and kidneys are working 
 
At 9 of these visits (Weeks 8-24, 32-48, 64, 80, and 96) we will draw about 12mL of blood (about 2-3 teaspoons) 
for tests. These tests will check: 
• 
Your child’s HIV viral load.  
• 
Some blood will be saved for later resistance testing.  
 
At 12 of these visits (Weeks 5, 8-48, 64, 80, 88and 96), we will also draw about 4mL of blood (less than 1 
teaspoon) of blood to look at the amount of CAB and RPV in the blood. 
 
At 4 of these visits (Weeks 24, 48, 72 and 96) we will draw about 3mL of blood (about 1 teaspoon) to check your 
child’s CD4 count.  
 
At 4 of these visits (Weeks 8, 24, 48, and 96) we will ask your child questions about getting the shots of CAB and 
RPV.  
 
At 5 of these visits (Weeks 8, 24, 48, 72, and 96) we may also talk with you and your child about how your child 
is doing with the visit schedule.  
 
If your child cannot come to the clinic to receive the CAB and RPV shots, then your child may have the option to 
take the CAB and RPV pills until they are able to get the shots again.  If this happens, your child may need more 
frequent CAB and RPV shots outside of the scheduled visit days for a few months. If your child cannot return to 
the clinic to get the CAB and RPV shots soon, then your child may need to stop taking the study ARVs and enter 
the long-term safety follow-up phase (see #15 below). This is not preferred, and it is important to get the shots on 
the scheduled visit day and not miss any CAB and RPV shots. 
 
Study staff will let you know when these procedures will occur ahead of time.  
 
12. In-depth phone interviews [for U.S. sites only] 
 
We are very interested to understand what adolescents think about getting their ARV’s as shots. Your child may 
be asked if they would like to complete an in-depth phone interview. If your child would like to take part in the 
interview, then your child may be contacted to have the interview after getting the fourth shot of CAB and RPV. 
Not all participants will be contacted for the interview. Your child does not have to do the interview to take part in 
this study. 
 
If contacted, an interviewer will talk to your child for about 1-2 hours and will ask your child how they feel about 
having shots of CAB and RPV. This information will help us understand if CAB shots and RPV shots have any 


 
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side effects for adolescents. It will also help us understand how adolescents and families feel about the shots. The 
interview may take place at or in between the Week 24 through 96 visits or during the long-term follow-up safety 
phase. The interview will only take place once. The interview will be audio recorded and written down in a report. 
Your child’s name will not be included in the report. 
 
We may also ask you to complete an in-depth interview. This interview would ask you how you felt about your 
child having shots of CAB and RPV. 
 
13. Adolescents may have an extra visit if their HIV is not controlled. 
 
Participants will have viral load tests at almost all visits to check the amount of HIV in the blood. If tests show 
that the viral load is higher than expected (above 200 copies/mL) your child will have repeat testing. This may 
occur as part of another study visit or may occur as an extra study visit.  
 
The extra visit will take about 1-2 hours. At this visit we will: 
• 
Review your child’s medical records. 
• 
Do a physical exam.  
• 
Draw about 16mL (about 3 teaspoons) of blood for tests. The tests will: 
o Check your child’s HIV viral load.  
o Check the amount of CAB and RPV in the blood.  
o We will save some blood for later resistance testing. 
• 
Talk with your child about preventing pregnancy.  
• 
For girls, we will also collect urine or blood to check for pregnancy.  
 
If the repeat test also shows an increased amount of HIV in your child’s blood, your child will stop taking the 
study product and start taking their previous ARVs again. If your child was getting shots of CAB and RPV, your 
child will enter long-term safety follow-up (more information in #15 below).   
 
14. If your child is not eligible to receive shots of CAB and RPV your child will stop the study early.  
 
If your child is not eligible to receive shots of CAB and RPV in Cohort 2-Phase 2, your child will stop taking oral 
CAB and oral RPV and will complete a final study visit about 4 weeks after their last oral dose.  
During this visit, we will:  
• 
Review your child’s medical records.  
• 
Do a physical exam. This will include looking at your child’s genitals to see the stage of development. For 
girls, this will also include looking at the breasts. 
• 
Draw blood for tests. This would be about 15-20mL of blood (about 3-4 teaspoons) for these tests. These tests 
will check:  
o Your child’s blood cells.  
o How well your child’s liver and kidneys are working. 
o Your child’s HIV viral load.  
o Some blood will also be saved for later resistance testing. 
• 
Talk with your child about preventing pregnancy.  
• 
For girls, we will also collect urine or blood to check for pregnancy.  
• 
Ask your child questions about what it is like for them to take the oral CAB and oral RPV.  
• 
We will also talk with you about your child’s ARV use.  
 


 
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If your child also participated in Cohort 1 and received shots of CAB or RPV in Cohort 1-Phase 2, but is not 
eligible to get the shots of CAB and RPV in Cohort 2-Phase 2, they will stop taking oral CAB and oral RPV and 
will enter into Cohort 2-Phase 3 long-term safety follow-up (see #15 below). 
 
15. If your child stops the shots of CAB and RPV early or after the Week 96 study visit, your child will enter Cohort 2-
Phase 3 (long-term safety follow-up phase). 
 
Your child will enter Cohort 2-Phase 3 (long-term safety follow-up phase) after the last shot of study product if 
your child: 
• 
Stops the shots of CAB and RPV early, or  
• 
Does not continue to get the shots of CAB and RPV after the final Cohort 2-Phase 2 visit (Week 96).  
 
If your child becomes pregnant, she will enter this phase of the study after her positive confirmatory pregnancy 
test result, whether she is taking the pill or the shot.  
 
During the long-term safety follow-up phase, your child will stop getting shots of CAB and RPV. Your child will 
start taking their previous ARVs again. There will be 4visits during the long-term safety follow-up phase.  
 
These visits will be scheduled 8, 24, 36 and 48 weeks after your child’s last shot of CAB and RPV (or after a 
positive confirmatory pregnancy test result). [Sites to modify] Each of these visits will take about 1-3 hours. At 
these visits, we will:  
• 
Review your child’s medical records.  
• 
Do a physical exam. At the final long-term safety follow-up visit, this will include examination of your 
child’s genitals to see the stage of development. For girls, this will also include looking at the breasts. 
• 
Talk with your child about preventing pregnancy.  
• 
Draw blood for tests. This would be about 21mL of blood (about 4 teaspoons) for these tests. These tests will 
check:  
o Your child’s blood cells.  
o How well your child’s liver and kidneys are working. 
o Your child’s HIV viral load.  
o The amount of CAB and RPV in the blood.  
o Some blood will also be saved for future resistance testing. 
• 
For girls, we will also collect urine or blood to check for pregnancy.  
• 
At two of these visits (8 weeks and 48 weeks after your child’s last shot of CAB and RPV) we will talk with 
you about your child’s ARV use.  
• 
At two of the visits (8 weeks and 48 weeks after your child’s last shot of CAB and RPV), we will also ask 
your child questions about getting shots of CAB and RPV.  
 
16. Different tests will be done at different laboratories. 
 
We will do most of the tests of blood or urine here at our laboratory. We will give you and your child the results 
of most of these tests at the next scheduled visit, or sooner, if necessary. We will explain the results and give you 
counseling and referrals for your child as needed.  
 
We will also draw blood to check the amount of CAB and RPV in your child’s blood. This is called a 
pharmacokinetic (PK) test. The PK test will be done at a laboratory in the United States. We will not usually give 
you the results of this test during the study.  
 
If your child needs a test for resistance (see #13 above), that test will be done at a laboratory in the United States.  
You and your child will be given the results of this resistance test and referrals if needed.  


 
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17. We may take your child off of the study. 
 
We may take your child off the study ARVs if: 
• 
Your child is not able to come to the study visits or we determine that your child cannot meet the study 
requirements. 
• 
Your child is not able to take the study ARVs. 
• 
The study ARVs are not controlling the HIV in your child’s blood. 
• 
Continuing the study ARVs may be harmful to your child. 
• 
You or your child request to stop the study ARVs for your child. 
• 
Your child is not able to follow the birth control requirements of this study. 
• 
Your child becomes pregnant 
 
If your child stops the oral study ARVs early, we will ask you to come back to the clinic with your child about 
four weeks after your child stops the oral study ARVs (see #14 above). Your child will not have any other visits 
after this. 
 
If your child stops the ARV shots early, we will ask you to come back to the clinic with your child for four 
additional study visits for long-term follow-up (see #15 above). Your child will not have any other visits after 
these four visits. 
 
We may also take your child off the study early if the study is stopped for any reason.  
 
The study cannot provide other types of ARVs, but we will give you and your child information, counseling, and 
referrals to where your child can get care and treatment needed. We will help make sure your child can get ARVs 
from outside of the study. If the study stops early, every effort will be made to make certain that there is no 
interruption in your child’s therapy.  
 
18. Please tell us if you or your child want to leave the study. 
 
Your child is free to leave the study at any time for any reason. The care that your child receives at this clinic will 
not be affected, but it is important for us to know about your and your child’s decision.  
 
If your child stops the study ARVs, we may ask you to return to the study clinic with your child for additional 
study visits described in #14 and #15 above. If your child stops the study early, we may ask you to return to the 
study clinic with your child for one final study visit, like the last study visit described in #15 above. 
 
We will answer any questions you or your child may have and give you information on how to contact us in the 
future, if you wish. 
 
After the study 
 
19. Receiving the study ARVs after the study is over.  
 
As your child comes to the end of the study, we will work with you to plan for your child’s care and treatment 
outside the study. It is important that we plan for this in advance, so that there is no gap in your child taking 
ARVs as they finish the study. Taking ARVs without interruption is the best known way for your child to stay 
healthy.  
 


 
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We will tell you where your child can go to receive needed care and treatment after they finish the study. If your 
child is gaining benefit from the injection ARVs given in the study, the companies that are providing these ARVs 
(ViiV Healthcare and Janssen Pharmaceuticals) will try to provide these injection ARVs to your child. They will 
be provided until they are otherwise available locally, until your child is no longer gaining benefit, or if the 
company decides to stop studying the ARVs. However, there is no guarantee this will be possible. If this is not 
possible, your child will need to switch to other oral ARVs that are available locally. We will explain the options 
to you and help ensure your child’s access to ARVs outside the study. We will also contact you again within the 
first four or eight weeks after your child finishes the study to confirm that your child is getting ARVs.  
 
Risks of the study 
 
Taking part in this study may involve some risks and discomfort. The risks are different for each phase of the 
study. Cohort 2-Phase 1 risks include: risks from blood draws, risks from the study pills (CAB and RPV), risks of 
switching ARVs, and risks to your child’s privacy.  
 
Cohort 2-Phase 2 risks include: risks from blood draws, risks from receiving the injection, risks from the study 
pills (CAB and RPV) and the study shots (long-acting CAB and RPV), and risks to your child’s privacy.  
 
Cohort 2-Phase 3 risks include: risks from blood draws, risks of switching ARVs, and risks to your child’s 
privacy. 
 
20. Risk from blood draws  
 
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted. Rarely, drawing blood 
can cause fainting or infection. 
 
21. Risk from receiving the injection  
 
People in other studies who have received the CAB and RPV shots said they had pain, skin irritation, skin 
redness, bumps, swelling, itching, bruising at the spot where they got the shot. Most reactions go away in a week 
or less but sometimes they can last longer. Most people usually do well with them and rarely need to stop the 
drug.  
 
The shots will be given in the muscles of your child’s buttocks. The injection could be given too deeply or not 
deeply enough, missing the muscle and entering your skin, blood, or a nerve.  
 
The risks of this are not well understood but could make CAB or RPV levels too low or too high. If too low, the 
drug may not work against your child’s HIV. If RPV is too high, there could be a change in your child’s 
heartbeat, which in severe cases can be life-threatening. In rare cases, symptoms such as feeling lightheaded, 
numbness or tingling, difficulty breathing, chest or stomach discomfort, sweating, nausea and/or feeling anxious 
have occurred after an injection with RPV LA. In these cases, high blood levels of RPV have been observed, 
which may be due to an accidental injection of part of the medication into a blood vessel instead of the muscle. 
Not all patients in whom an accidental injection in a blood vessel was suspected reported such symptoms. Most of 
the symptoms resolved within minutes. Your child’s doctor may need to administer treatment to help resolve 
these symptoms. Everything possible will be done to decrease this risk, including watching your child for 
problems during the study. If your child’s doctor thinks that the injection was not given the right way, your child 
might be asked to stay in the clinic up to [sites to modify] 2 hours after the injection to watch how your child is 
doing and extra tests may be needed to be sure your child is safe. If you or your child are worried about this risk, 
talk to your child’s doctor. 
 


 
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Receiving injections can cause some people to feel lightheaded or feel like they might pass out. Fainting can also 
occur. This reaction, called a ‘vasovagal reaction’, has been reported with other injectable medicines, and resolves 
quickly. 
 
22. There are risks from the study ARVs 
 
All ARVs can cause side effects. This includes the ARVs your child is currently taking and the ARVs that are 
given in the study. Some side effects are minor; others can be severe. Some side effects are common; others are 
rare. Some people who take ARVs have some of the side effects. Other people have different side effects, or no 
side effects.  
 
The most common and most serious side effects of the study ARVs, CAB and RPV, are listed below. This is 
based on what we know now about CAB and RPV used in adults. There may be other side effects that we do not 
know about now. This may be especially true for adolescents, because this is the first study of CAB and RPV in 
adolescents.  
 
This form does not list all possible side effects of all ARVs. If your child joins the study, we will tell you more 
about the ARVs your child will be taking. At each study visit, we will check on whether the ARVs may be 
causing side effects. We will also tell you what to do if your child has side effects. If you or your child have 
questions or concerns at any time, please tell us.  
 
23. Some side effects from the CAB pills and the CAB shot 
 
Many people have received CAB pills or the CAB shot in other studies. The table below lists side effects from 
other studies of CAB with people who have HIV. It is not known if CAB, other drugs or the patient’s other health 
problems caused or affected these. Some of these are the same side effects as RPV (see #24 below).  
 


 
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Common Side Effects of CAB 
Very Common Side Effects of CAB 
Common Side Effects of CAB 
• Headache 
• Fever 
• Injection Site Reactions 
 
• Rash 
• Itching  
• Vomiting (being sick) 
• Nausea (feeling sick) 
• Stomach pain and discomfort  
• Problems sleeping  
• Abnormal dreams/nightmares 
• Anxiety 
• Feeling lightheaded 
• Depression 
• Passing gas or wind 
• Diarrhea 
• Muscle pain 
• Lack of energy 
• Increase in the level of enzymes produced 
in the muscles (creatine phosphokinase) 
• Weight increased 
 
The following effects have also been seen in some of the people who received CAB pills or the CAB shot in other 
studies: 
 
Abnormal liver tests: 
 
A small number of people across all studies (just over 1% of 1644 participants as of April 2017) had abnormal 
liver tests requiring them to stop CAB. Some abnormal liver tests were explained by other health conditions such 
as a new virus infection, like Hepatitis A, B or C.  A small number of people did not have health conditions that 
could explain the abnormal test, so it is possible that a mild form of liver damage happened from taking CAB. 
The liver tests got better after stopping CAB, showing that any damage was temporary. 
 
Blood tests to check the health of your child’s liver will be done during the study. Your child’s study doctor will 
tell you if your child needs to stop taking the study drugs or if other actions are needed. If your child stops taking 
the study drug, they may be able to re-start the study drug or they may need to change their usual ARVs.  
 
Seizures/convulsions: 
 
Seizures have been seen (rarely) in people with and without HIV who have taken CAB. They are not thought to 
be caused by CAB, but the study staff will ask you about them.  
 
In other studies, two people without HIV had a history of seizures (epilepsy), and had a seizure about 3 months 
and 9 months after starting CAB. One other person with HIV but without a history of seizures, had seizures about 


 
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one year after starting CAB. This participant had a long period of seizures without medical treatment and died. It 
is not known if CAB was part of the reason for seizures in these people. If your child has a history of seizures, 
please let your child’s study doctor know. 
 
24. Some side effects from the RPV pills and the RPV shot 
 
Oral RPV (Edurant) is a marketed drug which many people throughout the world have received to manage HIV. 
We know more about the side effects of Edurant than we do about CAB or RPV shots. The following side effects 
have been seen in studies in people with HIV taking RPV.  
 
Common Side Effects of RPV 
Common Side Effects of RPV 
Uncommon Side Effects of RPV 
• 
Problems sleeping, insomnia  
• 
Headache 
• 
Feeling lightheaded (dizziness) 
• 
Rash 
• 
Nausea (feeling sick to the stomach) 
• 
Vomiting 
• 
Abdominal (belly) pain 
• 
Increase in the level of liver enzymes 
• 
Decreased appetite 
• 
Depression 
• 
Abnormal dreams 
• 
Fatigue (tiredness, lack of energy) 
• 
Dry mouth 
• 
Anxiety 
• 
Stomach pain 
 
• 
Sleepiness (somnolence) 
• 
Depressed mood 
• 
Stomach discomfort  
• 
Immune reconstitution syndrome (this can be 
an overreaction of the body’s recovering 
defense system to a previously present 
infection, or problems in the immune system) 
• 
Hepatotoxicity 
• 
Weight increased 
 
The following effects have also been seen in some people who received RPV in other studies: 
 
Abnormal blood tests: 
 
Other changes in blood tests have also been observed. People with Hepatitis B or C or who have possible liver 
damage before starting RPV may have worse liver tests while taking RPV. A few cases of liver problems were 
found in people taking RPV who did not already have any liver problems. 
 
Sometimes allergic reactions can affect body organs, like the liver, and cause liver problems which can lead to 
liver failure. Contact your child’s study doctor right away if your child has any of the following signs or 
symptoms of liver problems: 
• 
Yellowing of the skin or whites of the eyes 


 
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• 
Dark or tea colored urine 
• 
Pale colored stools/bowel movements 
• 
Nausea/vomiting 
• 
Loss of appetite 
• 
Pain, aching or tenderness on the right side below the ribs 
• 
Itchy skin  
 
Blood tests to check the health of your child’s liver will be done regularly during the study. Your child’s study 
doctor will tell you if your child needs to stop taking the study drugs or if other action is needed. If your child 
stops taking the study drug, they may be able to re-start the study drug or they may need to change their usual 
ARVs.  
 
Skin Rash: 
 
Most rashes were mild or moderate, and happened within the first 4 weeks of taking RPV. Most of rashes got 
better after one week, and the people did not need to stop taking RPV. However, the study ARVs will need to be 
stopped for some types of moderate rash and all types of severe rash, which can be life-threatening. If this 
happens to your child, they will need to come for extra study visits to monitor their health. Some people with rash 
may also have other signs and symptoms of allergic reaction. 
 
If your child has any type of rash or other skin problems during the study you must tell your child’s study doctor 
right away, and the doctor may tell your child to stop taking CAB and/or RPV. 
 
25. There may be other possible risks from the study ARVs. 
 
The study ARV shots stay in your body for a long time 
 
The shots your child gets in this study are long acting, meaning they stay in your child’s body for a long time. In 
most people, the drugs will no longer be in the body one year after an injection, while in some people low levels 
of CAB and RPV may still be in the body after one year. If your child develops a side effect to the study drug 
after the shot, there will be no way to remove the drug from your child’s body. If your child gets a shot of CAB or 
RPV, we will monitor their health for 48 weeks after their last shot. If your child develops a symptom from these 
drugs while the drugs are still in their body, every effort will be made to treat the side effects. The amount of drug 
will decrease overtime and will eventually disappear. 
 
While the amount of study drugs in your child’s body decrease slowly over time after they stop getting shots, the 
study drugs could stop working against your child’s HIV. When stopping long acting HIV drugs, it will be very 
important to start taking other HIV medications, as your child’s study doctor tells you, so your child’s HIV 
medications do not stop working against their HIV. 
 
Risk of switching ARVs 
 
If your child joined this study, your child will stop taking the ARVs they are currently taking and start taking 
ARVs given by the study. The study ARVs could cause side effects that your child would not have from the 
ARVs you are currently taking. The study ARVs also may not work as well as the ARVs your child is currently 
taking. For example, the study ARVs may not work as well to control the amount of HIV in your child’s body. 
We will test your child’s HIV viral load at most study visits to check on this. If your child’s viral load is higher 
than expected, your child will have repeat testing, and their use of the study ARVs may be stopped (see #13 
above).  
 


 
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Risk of resistance 
 
By stopping their previous ARVs and switching to the study ARVs, your child could develop resistance. This 
could happen if the study ARVs don’t work as well to control the amount of HIV in your child’s body. Resistance 
means that the ARVs may not work against HIV if these ARVs are taken again in the future. To stop resistance, it 
is important that your child takes and/or receives the ARVs as instructed and does not miss any doses. 
 
Mental illness or depression 
 
Some people with HIV sometimes have feelings of depression or may feel sad or hopeless, feel anxious or 
restless, or may have thoughts of hurting or killing themselves (suicide). A small number of people being treated 
with drugs called integrase inhibitors [INIs] for HIV like CAB, have had suicidal thoughts and actions, 
particularly patients with a prior history of depression or mental health illness.  
 
Tell the study doctor if your child has a history of mental health illness. If your child has thoughts of hurting or 
killing their self or have any other unusual or uncomfortable thoughts or feelings during this study, you should tell 
the study doctor or go to the nearest hospital right away.  
 
Possible effects on pregnancy or unborn babies 
 
HIV and ARVs may lead to some pregnancy complications, like early delivery or low weight of the baby at birth. 
We do not know if some ARVs are more likely to cause these effects than others. We do not yet know if CAB is 
safe in pregnancy. RPV does not appear to be a risk to pregnancy and the developing baby based on the 
information we know now, but additional data are still being collected. 
 
There are few data from humans on the effects of CAB in pregnancy. Most of the information we have comes 
from animal studies. In studies done in pregnant rats and their newborns, using very high amounts of CAB, there 
were more baby rats that died when they were born or right after they were born. This did not happen to the baby 
rats when the mother got lower amounts of the drug, or no drug. The amount of CAB that we are giving in this 
study is expected to be more than 7-times lower than the amount given to the pregnant rats. Birth defects have not 
been found in any animal studies of CAB so far. We do not know whether what happened to the baby rats has any 
impact on what will happen in pregnant humans taking this drug. 
 
Early results from one large study in Botswana showed that the ARV called dolutegravir (DTG) may increase the 
risk of serious birth defects of the brain or spine in the new baby. The increased risk was seen among babies 
whose mothers were taking DTG when they became pregnant. These birth defects happen during the first few 
weeks of pregnancy, before mothers may know they are pregnant. These birth defects have not been seen among 
babies whose mothers started taking DTG later in pregnancy.  
 
CAB is not the same drug as DTG. We do know that CAB and DTG belong to the same class of medications and 
work in a similar way to treat HIV infection. We do not know if CAB can cause brain or spine defects in babies.  
 
Girls who are able to become pregnant must agree to use certain effective methods of birth control to be in this 
study (see #6 above). If your child becomes pregnant during the study, please let us know right away. 
 
Immune reconstitution syndrome 
 
In some people with advanced HIV infection, signs and symptoms from other infections or certain diseases (for 
example a liver condition called autoimmune hepatitis) may occur soon after starting combination ARVs but can 
also occur later. Some of these symptoms may be life threatening. If your child starts having new symptoms, or if 


 
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you notice that any of your child’s existing symptoms are getting worse after starting the ARVs, tell your child’s 
doctor immediately. 
 
Abnormal placement of body fat and wasting  
 
The use of potent antiretroviral drug combinations may be associated with an abnormal placement of body fat and 
wasting. Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 
• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement 
   
26. There could be risks of disclosure of your child’s information. 
 
We will make every effort to keep your child’s information private and confidential. Study records and specimens 
will be kept in secure, locked locations. All specimens and most records will be labeled only with a code number. 
However, your child’s name will be written on some records.  
 
Despite our best efforts to keep your child’s information private, it is possible that the information could be 
obtained by someone who should not have it. If this were to happen, your child could be treated badly or unfairly. 
Your child could feel stress or embarrassment.  
 
To help us protect your child’s privacy, we have obtained a Certificate of Confidentiality that protects us from 
being forced to release information that may identify your child, such as by the courts or police. The certificate 
cannot be used in all situations, but it can be used to resist demands for information that would identify your 
child. The certificate does not protect against requests for information from the US federal government or from 
the US Food and Drug Administration. Regardless of the certificate, you can release information about your 
child’s participation in the study to others, if you wish. 
 
Information collected for this study may be used for other research in the future. For example, researchers may 
use information from this study to try to answer different questions about children or adolescents with HIV. Any 
future research done with the information from this study must be approved by the IMPAACT Network. If any 
future research is done, information about your child may be used but your child’s name will not be shared. 
 
Benefits of the study 
 
27. There may be a direct benefit to your child from being in the study. 
 
By joining the study, your child will be part of the search for ARVs that may be better for adolescents. We do not 
know if being in the study will benefit your child in any way. There may be a direct benefit to your child by 
taking part in this study, but no guarantee can be made. For example, if your child gets shots of CAB and RPV, 
they might prefer having monthly shots instead of taking daily pills. The study ARVs may have fewer side effects 
than the previous ARVs your child was taking. There may also be a benefit if the results from this study lead to a 
safe and effective dose of the study drugs for adolescents. It is also possible that your child may receive no direct 
benefit from this study. Information learned from this study may help other adolescents who have HIV. 
 
Your child will have regular visits here and frequent checks on your child’s health, including tests for amount of 
HIV in your child’s blood, called viral load. It is possible that the study ARVs will slow your child’s HIV 
infection. Information learned from this study may help other adolescents with HIV. 
 


 
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Other information about the study 
 
28. There are no costs from being in the study. 
 
There are no costs to you for study visits, CAB, RPV or procedures.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits. For each visit, you will be given (specify amount).] 
 
29. Study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include:  
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your child’s name or identify your child personally.  
 
A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify your child. At most, the website will include a summary of the results. You 
can search this website at any time. 
 
Your child’s study information may be given to other authorities if required by law. [Sites add more specific 
detail here as needed; example follows:] For example, we are required to report any significant risk of harm to 
your child or others.  
 
30. If your child gets sick or injured, contact us immediately. 
 
Your child’s health is important to us. We will make every effort to protect your child’s well-being and minimize 
risks. It is possible, however, that your child could have an illness or injury that is study-related. This means that 
the illness or injury occurred as a direct result of the study procedures.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage available 
through clinical trial insurance obtained by the site should be included if applicable; the statement regarding no 
program for compensation through the NIH may not be removed.]  If a study-related illness or injury occurs, we 
will treat your child or tell you were your child can get treatment. The cost for this treatment may be charged to 
you or your insurance company. There is no program for compensation either through [site name or] the U.S. 
National Institutes of Health.  
 


 
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Whom to contact 
 
31. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about your child’s rights as research participants or concerns about how your child is 
being treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 
 
• 
If your child has any health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you want your child to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
 
 


 
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Signatures 
 
If you agree to allow your child to participate in this study, please sign or make your mark below. 
Before deciding whether to allow your child to participate in this study, make sure you have read this form, or had 
it read to you, and that all of your questions have been answered. You should feel that you understand the study, 
its risks and benefits, and what is expected of your child if you decide to allow your child to join.  
 
If you decide to allow your child to join, we will tell you any new information from this study or other studies that 
may affect your child’s health, welfare, or willingness to stay in the study. You are welcome to ask questions or 
request more information at any time. If you want the results from this study, please tell the study staff. 
 
You do not give up any rights by signing this form. 
 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
 
 
 
 
 
 
 
Name of Participant (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Parent/Guardian/ 
 
Signature of Parent/Guardian  
 
Date 
Legally Authorized Representative 
Legally Authorized Representative 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
(as appropriate; print) 
 
 


 
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Appendix II-C:  Sample Parental Informed Consent Form for Specimen Storage and Future Use 
for parents/guardians of adolescents who cannot provide independent informed consent for study participation 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 3.0, dated 13 August 2020 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
You have decided to allow your child to join the study named above. As part of the study, your child will have 
blood and urine collected. After these samples are tested for the study, some samples may be left over. We call 
these extra samples. The IMPAACT Network would like to keep these extra samples and use them for other 
research in the future. 
 
This form gives information about use of extra samples. Please read it, or have it read to you, and ask any 
questions you may have. After we discuss the information with you, you will record your decisions on use of 
extra samples at the end of the form.  
 
1. It is your decision whether or not to allow the extra samples to be used.  
 
You are free to say yes or no, and to change your mind at any time. Your decision will not affect your child’s 
participation in the study. If you say no, all extra samples will be destroyed.  
 
2. If you agree, your child’s extra samples will be kept in a repository.  
 
A repository is a secure facility that is used to store samples. The IMPAACT Network repository is in the United 
States. If you agree to have extra samples stored, the samples will be kept in this repository. There is no limit on 
how long the samples will be kept [sites may insert time limits or additional site-specific requirements here if 
required by local authorities]. 
 
3. Extra samples could be used for different types of research.  
 
Extra samples may be used for research on HIV, the immune system, and other diseases. The research may be 
done in the United States or in other locations.  
 
If you agree, the extra samples could also be used for research that looks at your child’s genes. Genes are passed 
to children from their birth parents. They affect how people look and how their bodies work. Differences in 
people’s genes can help explain why some people get a disease while others do not. Your child’s samples would 
only be used to look at genes related to HIV and the immune system. Testing of all your child’s genes, which is 
sometimes called whole genome sequencing, will not be done.  
 
Any research done with the extra samples must be reviewed and approved by the IMPAACT Network. The 
research must also be approved by an ethics committee. The role of an ethics committee is to review the research 
plan and protect the rights and well-being of the people whose samples will be used.  
 


 
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The research done with extra samples is not expected to give any information relevant to your child’s health. 
Therefore, the results will not be given to the study staff or to you. The results also will not be placed in your 
child’s study records. 
 
4. There is little risk to your child.  
 
When extra samples are used for research, they are labeled with a code number only. To protect your child’s 
privacy, no names are used. However, information such as age, sex, HIV status, and other health information may 
be linked to the samples. Information on the ARVs your child received in the study may also be linked to the 
samples. The only link between the code number and your child’s name is kept here at [site name]. Your child’s 
name will not be given to other researchers. 
 
There may be some risks from tests of your child’s genes. If others found out the results of these tests, they could 
treat your child badly or unfairly. However, this is almost impossible because the results will not be given to the 
study staff, or to you, or to your child and will not be in your child’s study records. 
 
5. There may be no benefit to your child.  
 
By allowing extra samples to be used for research, your child will be part of the search for new information that 
may benefit people with HIV in the future. However, the research done with the extra samples is not expected to 
directly benefit your child in any way.  
 
6. You will not be paid for use of your child’s samples. 
 
There is no cost to you for use of your child’s extra samples. The samples will not be sold, and you will not be 
paid for use of the samples. It is possible that research done with the samples could lead to a new discovery or a 
new product. If this happens, there is no plan to share any money with you or your child.  
 
7. Information from research using extra samples may be reviewed by groups that oversee the research. 
 
These groups include:   
• 
The IMPAACT Network  
• 
The ethics committees that review and approve the research  
• 
Government and other agencies that pay for the research  
• 
Government and other agencies that monitor the research  
• 
Other local, US, or international regulatory entities 
 
The people who do research with the extra samples and the groups listed above are required to make efforts to 
keep information private and confidential. 
 
The results of research done with the extra samples may be presented publicly or published. However, no 
presentation or publication will use your child’s name or identify your child personally.  
 
8. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about use of your child’s extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you later change your mind about use of your child’s extra samples:  
[insert name and telephone number of investigator or other study staff].  


 
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• 
If you have questions about your child’s rights as a research participant or concerns about how your child is 
being treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization].  
 
Signatures 
 
Before deciding whether to allow your child’s extra samples to be used for research, make sure you have read this 
form, or had it read to you. Make sure all of your questions have been answered. You should feel that you 
understand your options and the possible risks and benefits before making your decision. 
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies and the IRB/EC determination if the level 
of risk to children in the categories specified in 45 CFR 46.404-407. Separate consent decisions must be 
documented for genetic testing]. 
 
For YOUR CHILD’s extra samples, write your initials or make your mark next to your choice.  
 
__________ 
I allow my child’s extra samples to be used for research on HIV, the immune system, ARVs, and 
other diseases. I also allow my child’s samples to be used for tests of his or her genes.  
 
__________ 
I allow my child’s extra samples to be used for research on HIV, the immune system, ARVs, and 
other diseases. I do not allow my child’s samples to be used for tests of his or her genes.  
 
__________ 
I do not allow my child’s extra samples to be used for any research.  
 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
 
 
 
 
 
 
 
Name of Participant (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Parent/Guardian/ 
 
Signature of Parent/Guardian  
 
Date 
Legally Authorized Representative 
Legally Authorized Representative 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
(as appropriate; print) 
 
 


 
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Appendix III: Sample Informed Consent Forms 
  
Appendix III-A:  Sample Informed Consent Form for Participation in Cohort 1 
for adolescents who can provide independent informed consent for study participation 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 3.0, dated 13 August 2020 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
Introduction 
 
You are being asked to take part in the research study named above. 
 
This form gives information about the study. Please read it, or have it read to you, and ask any questions you may 
have. We will take as much time as needed for you to fully understand the study. We will ask you questions to see 
if we have explained the study clearly. 
 
Here is a summary of important information about the study: 
 
• 
The study is testing two anti-HIV medicines (ARVs), Cabotegravir (CAB) and Rilpivirine (RPV), taken as 
pills and given as long-acting shots in adolescents 12 to less than 18 years of age.  
• 
The RPV pills are approved for adolescents in Botswana, Uganda, United States and for adults in Botswana, 
South Africa, Thailand, Uganda, United States. The CAB pills, and the CAB and RPV shots are now being 
tested in adults with HIV but have not yet been tested in adolescents.  
• 
There are two parts to this study, Cohort 1 and Cohort 2. This form is about Cohort 1. Adolescents who 
participate in Cohort 1 may qualify for Cohort 2 of the study after completing Cohort 1. 
• 
Participants in Cohort 1 will be in this part of the study for at least 4 months and up to 16 months. 
• 
Adolescents in Cohort 1 will continue taking their usual ARVs while also taking the study medicine. After 
entering the study, adolescents will take daily CAB or RPV pills for 4 to 6 weeks while taking their usual 
ARVs. Adolescents will then switch to getting CAB or RPV shots 4 weeks apart (for a total of 2 shots) while 
continuing to take their usual ARVs.  
• 
After the last shot, adolescents will be followed for up to 1 year for long-term safety follow-up. During this 
time, adolescents will not take any study medicine (shots or pills) but will continue taking their usual ARVs.   
• 
While in the study, adolescents will have clinic visits with physical examinations and blood draws for 
laboratory tests. Some visits will include a review of adolescents’ medical records and ECG tests to look at 
the adolescent’s heart. Female participants will also be tested for pregnancy.  
• 
If interested, participants in the U.S. may be eligible to do one in-depth phone interview where they will talk 
about their experience getting their ARV’s as shots. 
• 
There are some possible risks for adolescents in the study. One possible risk is that the pills or shots being 
tested could cause side effects.  The most severe side effects include allergic reaction, liver problems, and 
mental health problems.  These side effects are uncommon. 


 
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• 
There are some possible benefits for adolescents in the study. One possible benefit is a better understanding 
of your health and HIV care.  Another possible benefit is early access to the Cohort 2 part of the study, if you 
qualify.  
• 
Your decision on your participation in the study will have no effect on the medical care you receive at this 
clinic. Your access to services, and the benefits and rights you normally have, will not be affected. You may 
choose to leave the study at any time.  
 
More information is given in this form about the study, its risks and benefits. You should feel that you understand 
the study before deciding whether to participate. If you decide to participate, you will be asked to sign or make 
your mark on this form. You will be offered a copy to keep. 
 
About the study 
 
This study is being done by the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
(IMPAACT) and [insert site name]. The person in charge of the study at [insert site name] is [insert name of 
IoR].  
 
The study is being done to test two anti-HIV medicines (antiretrovirals or ARVs) in adolescents 12 to less than 18 
years old who have HIV. The study ARVs are called cabotegravir (CAB) and rilpivirine (RPV). HIV is the virus 
that can lead to AIDS.  
 
The study will include up to 155 adolescents from the United States, Botswana, South Africa, Thailand and 
Uganda. There will be two groups of adolescents, called Cohort 1 and Cohort 2. This form is about Cohort 1. 
Participants in Cohort 1 will be in the study for at least 16 weeks (4 months) and then up to an additional 48 
weeks (12 months) as part of long-term follow-up, for a total of 64 weeks (16 months).  
 
The United States National Institutes of Health and the companies that make CAB and RPV, ViiV Healthcare and 
Janssen Pharmaceuticals, are paying for this study.  
 
1. The study is testing CAB and RPV in adolescents. 
 
People with HIV usually take a combination of ARVs daily to stay healthy. There are not as many ARVs 
available for adolescents as for adults because many ARVs have not yet been tested in adolescents. ARVs can be 
made in different forms, such as liquids, pills, and injections (shots). The study will test CAB and RPV when 
taken as pills and when given as shots in adolescents. The pills are taken every day. The shots can be given every 
4 weeks or every 8 weeks. The shots are being developed because it can be difficult to take pills every day, and 
some people may prefer to have the shots rather than taking pills.  
 
RPV pills (25mg taken once daily) have been shown to be safe and effective for both adults and adolescents 12 
years and older with HIV. The RPV pills are already approved by the US Food and Drug Administration (FDA) 
for adults and adolescents with HIV.  The FDA is the part of the government that regulates medicines in the 
United States. The RPV pills have also been approved for use for adults and adolescents in Cambodia, Canada, 
China, Ethiopia, the European Union, Gabon, Ghana, Hong Kong, Ivory Coast, Japan, Kazakhstan, Kenya, 
Malawi, Mali, Namibia, Nigeria, Russia, Taiwan, Tanzania, Ukraine and Zimbabwe. 
 
RPV shots (600mg and 900mg), CAB pills (30mg), and CAB shots (400mg and 600mg) are now being tested in 
adults with HIV. The FDA is asking for more information on how these medicines are made before they can 
approve them in adults.  The FDA has no safety concerns regarding these medicines. RPV shots, CAB pills and 
CAB shots have been approved in Canada for monthly dosing. 
 


 
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This will be the first study of these ARVs in adolescents.  So far, the testing in adults has shown that RPV shots, 
CAB pills, and CAB shots work as well as other ARVs that are approved. However, because these ARVs are still 
being tested, there may be some effects that we do not know about yet.  
 
This study will test the effects of these ARVs in adolescents. The study will look at whether these ARVs:  
• 
Are being given at the correct dose for adolescents  
• 
Are safe and well-tolerated in adolescents 
• 
Can control HIV in adolescents as well as other ARVs 
 
The study will also look at how willing adolescents are to take these ARVs.  
 
Cohort 1 of this study will be done first to test CAB and RPV pills when taken for about 1 month followed by 
CAB and RPV shots. Adolescents in Cohort 1 will take either CAB pills followed by CAB shots or RPV pills 
followed by RPV shots. They will keep taking their usual ARVs (see #4 below for more information). 
 
Some adolescents have already taken part in Cohort 1 of this study. They received the study pills for about 1 
month followed by 3 study shots given over 2 months. The RPV shots given at that time were 900mg for the first 
and second shots and then 600mg for the third RPV shot. The CAB shots given at that time were 600mg for the 
first and second shots and then 400mg for the third CAB shot.  
 
For adolescents now entering Cohort 1, the study pills will be taken for about 1 month and followed by 2 study 
shots given 1 month apart. There will now only be 2 study shots given in Cohort 1. Both RPV study shots will be 
900mg, while both CAB study shots will be 600mg. This is because the testing in adults has shown that fewer 
study shots can be given with these amounts. 
 
If the results from Cohort 1 show that CAB pills, CAB shots and RPV shots are safe and that the dose is correct, 
Cohort 2 will start. Cohort 2 will test whether CAB and RPV pills taken together, followed by CAB and RPV 
shots taken together are safe and can control HIV when adolescents stop taking their previous ARVs. Some 
adolescents from Cohort 1 may be eligible to also take part in Cohort 2.  
 
More information about the study, Cohort 1, and CAB and RPV is given in the rest of this form. 
 
2. Only adolescents who are eligible can participate in the study. 
 
If you decide to join the study, we will first do some tests to find out if you are eligible. More information about 
the tests is given in #5 (see below). If you are eligible, you will be entered in the study. If you are not eligible, you 
cannot be entered in the study.  
 
3. It is your decision whether or not you join the study. 
 
Deciding to join the study is voluntary (your choice). You may choose to join or not join. If you choose to join, 
you can change your mind and leave the study. Your choices will have no effect on the medical care you would 
normally receive. Your access to services, and the benefits and rights you normally have, will not be affected.  
 
Take your time and consider your decision carefully. If you wish, you can talk to other people about the study. 
You can bring other people here to learn about the study with you. 
 
No matter what you decide about the study, it is important for you to keeping taking ARVs. This is the best known 
way for you to stay healthy. 
 
 


 
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4. There are three phases in Cohort 1.  
 
For participants in Cohort 1, there are three phases of the study. All participants will take part in Cohort 1-Phase 
1. Only those who are eligible will take part in Cohort 1-Phase 2. Participants who take part in Cohort 1-Phase 2 
will also take part in Cohort 1-Phase 3, called the long-term safety follow-up phase. 
 
In Cohort 1-Phase 1, you will keep taking your usual ARVs. You will also take either the CAB or the RPV pills. 
The type of usual ARVs you take will determine whether you will take CAB or RPV in this study. The pills must 
be swallowed whole. They cannot be broken or crushed. They should be taken with a meal. This phase lasts for 
about 4-6 weeks. After the study entry visit (see #8 below), you will have 2 more visits during Phase 1. At these 
visits, we will check to see how you are doing while taking the pills (see #9 for more information). We will also 
check to see if you are eligible for Cohort 1-Phase 2. 
 
If you are eligible for Cohort 1-Phase 2, you will keep taking your usual ARVs. You will stop taking the CAB 
or RPV pills and start getting either the CAB or the RPV shots. The study ARV you get in the shot will be the 
same study ARV you were taking by pill. The shots are long-acting, meaning the medicine stays in the body for a 
long time. This phase lasts about 12 weeks. You will have 6 visits during this time, and you will get shots at two 
of these visits. Each shot is about 3mL (about 1 teaspoon). The shots are given in the buttocks (bottom “cheeks”). 
At each of these two visits, you will be given one shot of CAB or one shot of RPV. At all of the Phase 2 visits, we 
will check on how you are doing while getting the shots (see #11 for more information). 
 
After Cohort 1-Phase 2, you will take part in the long-term safety follow-up phase of the study. This phase lasts 
about 48 weeks. You child will keep taking your usual ARVs. There will be 3 or 4 visits during long-term follow-
up (see #16 for more information). 
 
Finding out if you are eligible for Cohort 1 
 
5. We will ask questions, examine you, and discuss the study requirements with you. 
 
To find out if you are eligible for the study, we will: 
 
• 
Review your medical records. 
• 
Ask questions about you, your health, and the medications you take.  
• 
Talk with you about birth control (ways to prevent pregnancy).  
• 
Talk with you about the study requirements and if you are able to meet these requirements. 
• 
Do a physical exam. This will include looking at your genitals to see your stage of development. For girls, 
this will also include looking at your breasts. 
• 
Do an electrocardiogram (ECG). This is to test how well your heart is working.  
• 
Draw between 11-17mL (about 2-3 teaspoons) of blood for tests. The tests will: 
o Check your blood cells. 
o Check how well your liver and kidneys are working. 
o Confirm that you have HIV. There are certain HIV tests that are required for this study. If the required 
tests are not in the medical records, we will do the tests that are needed. 
o Check the amount of HIV in your blood. This is called the HIV viral load.  
 
These procedures will take about 4 hours [here and throughout this form, sites may modify the expected visit 
duration as needed]. 
 
 


 
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6. For girls, we will also test for pregnancy. 
 
Girls in this study cannot be pregnant. Girls should not join this study if they are pregnant or intend to become 
pregnant within 30 days after stopping the study ARV pills or within 48 weeks after stopping the study shots. 
Because the effects of the study ARVs on unborn babies are unknown, you should not become pregnant while in 
this study. For all girls in the study, we will collect urine or blood to test for pregnancy. 
 
There are certain effective methods of birth control that girls who are able to become pregnant must use while in 
this study. These effective methods must be continued for 30 days after stopping the study ARV pills, or for at 
least 48 weeks after stopping the study ARV shots. Girls who are able to become pregnant, must agree to use 
these methods in order to take part in the study. We will help make sure you can get effective methods by 
providing them here in the clinic or offering a referral. At study visits when you will receive study medicines 
(either the pill or shot), we will need to confirm that you are using effective birth control before giving you the 
study medicines. 
 
Girls who become pregnant during the study will stop taking the study medicines and enter the long-term safety 
follow-up phase of the study (see #16 below). You must continue taking your usual ARVs. We will contact you 
to find out the outcome of the pregnancy even if the outcome occurs after leaving the study. 
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure of 
pregnancy results to parents or guardians: As soon as the pregnancy test result is available, we will go over it 
with you in private, without your parents/guardians present. You must give us permission before we can share 
these results with your parents/guardians. If the test shows that you are pregnant, we will give you information on 
where medical care and other services can be received.] 
 
If you are pregnant, your doctor may report your pregnancy to the Antiretroviral Pregnancy 
Registry. The Antiretroviral Pregnancy Registry assists patients and doctors in gauging potential benefits 
and risks of treatment; however, the registry does not collect any identifying information about you, such as your 
name, initials, contact information, or date of birth.  
 
7. We will tell you if you are eligible. 
 
We will give you the results of all procedures and explain the results to you. We will tell you about getting care, 
treatment and any other services you may need. While waiting for the results, it is important for you to keep 
taking your usual ARVs. 
 
If you are not eligible for the study for any reason, we will tell you this. You will not be entered in the study. You 
can and should continue to receive medical care and treatment outside of the study. We will tell you more about 
getting this care and treatment and any other services you may need.  
 
If you do not enter the study, we will still use some information collected about you (for example age, sex, and 
race). We will use this information to look at patterns or common reasons for not entering the study. 
 
If you are eligible for the study, you will be entered into the study.  
 
Entering the study 
 
8. If you are eligible, you will enter the study. 
 
On the day you enter the study we will:   
• 
Review your medical records.  


 
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• 
Talk with you about your ARV use 
• 
Talk with you about preventing pregnancy 
• 
Ask you questions about what you think about CAB or RPV 
• 
Do a physical exam.  
• 
Draw about 18mL (about 4 teaspoons) of blood for tests. The tests will: 
o Check your blood cells. 
o Check how well your liver and kidneys are working. 
o Check how much the virus has affected your ability to fight the virus. This is called CD4 cell count.  
o The tests will check your HIV viral load.  
o Some blood will be saved for later testing for resistance to ARVs. This test shows whether different 
ARVs may work against the HIV in your blood. 
• 
For girls, we will collect urine or blood for a pregnancy test.  
 
At the study entry visit we may also do an ECG to look at your heart. This will only be needed if you enter the 
study more than 2 weeks after your first visit.  
 
At this visit, you will start taking CAB or RPV pills. We will give you the pills and explain how to take them. 
You will take your first dose at the visit. You will continue taking your usual ARVs. This visit will take about 4 
hours.  
 
Being in the study 
 
9. After entering the study, you will have two more visits in Cohort 1-Phase 1 (Weeks 2 and 4a).  
 
The first visit in Cohort 1-Phase 1 will be the study entry visit and is described in #8 above.  After that visit, you 
will have 2 more visits in Cohort 1-Phase 1.  These visits will be scheduled 2 weeks apart. [Sites to modify] Each 
visit will take about 1-3 hours. At each of these visits, we will:  
 
• 
Review your medical records.  
• 
Talk with you about your ARV use 
• 
Do a physical exam. 
• 
For girls, we will also collect urine or blood to test for pregnancy.  
• 
Talk with you about preventing pregnancy.  
• 
Remind you to bring the oral CAB or oral RPV to the study clinic. 
 
At two of these visits (Week 2 and Week 4a), we will draw about 5mL (about 1 teaspoon) of blood for tests. 
These tests will check your blood cells and how well your liver and kidneys are working.  
 
At the second visit (Week 2), we will also draw about 12mL (about 2-3 teaspoons) blood for tests. This test will 
check your HIV viral load. Some blood will be saved for later resistance testing.  
 
At the second visit (Week 2), we will also do an intensive pharmacokinetic (PK) test. This is a test to look at the 
amount of CAB or RPV in your blood. At this visit, we will ask you when you took CAB or RPV in the past three 
days. [Sites: modify language as appropriate to align the three prior doses with the timing (morning or evening) 
of the Week 4b pre-dose PK sample collection.] For three days before this visit, you must be sure to take CAB or 
RPV on time and in the morning. This is very important. We will help you remember this before the visit. 
 
If you are taking oral CAB, we will need to draw your blood six times during the visit, one time before and five 
times after taking CAB. We will also remind you not to take CAB before coming to this visit. When you come to 
the visit, we will draw your blood, then you will take CAB, and then we will draw your blood 5 more times, about 


 
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1, 2, 3, 4, and 8 hours later. Each time we will draw 2mL (less than 1 teaspoon), for a total of 12mL (about 3 
teaspoons).  
 
If you are taking oral RPV, we will need to draw your blood three times during the visit, before and after taking 
RPV. We will remind you not to take RPV before coming to this visit. When you come to the visit, we will draw 
your blood, then you will take RPV, and then we will draw your blood 2 more times, about 4, and 8 hours later. 
Each time we will draw 2mL (less than 1 teaspoon), for a total of 6mL (about 1 teaspoon). 
 
[Sites: modify language as appropriate to indicate procedures for the intensive PK collection. For the intensive 
PK tests, a small plastic tube will be placed in your arm to draw blood samples. This tube is attached to a plastic 
needle so that we can draw blood several times. We will not need to stick you with a needle each time. The plastic 
tube may stay in place for the blood draws.]  
 
[Sites: modify language as appropriate to indicate procedures for intensive PK visit and overnight stays – You 
may need to stay at the clinic or hospital for up to 8 hours. If the study clinic is able, you may be allowed to stay 
at the clinic the night before and during your first PK visit.] 
 
[Sites to modify] On rare occasions, we may offer some of the visit activities off-site, or by phone. The study staff 
will discuss the location and best time to visit you so that the visit is at a convenient time and the visit is done at a 
place you feel comfortable and confidentiality can be maintained. 
 
10. If you are eligible, you will enter Cohort 1-Phase 2 (Week 4b). 
 
At the Week 4b visit, we will determine if you are eligible for Cohort 1-Phase 2. At this visit, we will:  
• 
Review your medical records.  
• 
Talk with you about your ARV use. 
• 
Do a physical exam. 
• 
Ask you questions about their experience with the study drug.  
• 
Talk with you about preventing pregnancy.  
• 
Draw about 12mL (about 2-3 teaspoons) blood for tests. These tests will check your HIV viral load. Some 
blood will be saved for later resistance testing.  
• 
For girls, we will also collect urine or blood to test for pregnancy. 
• 
Remind you to bring the oral CAB or oral RPV to the study clinic. 
• 
[Sites: modify language as appropriate to align the three prior doses with the timing (morning or evening) of 
the Week 4b pre-dose PK sample collection. Remind you to take your oral CAB or oral RPV in the morning 
for the three days before this visit.]  
 
If you are not eligible, you will stop taking oral CAB or oral RPV and will complete a final study visit about 4 
weeks after your last oral dose (see #15 for more information). 
 
If you are eligible for Cohort 1-Phase 2, you will continue taking your usual ARVs. You will take your last dose 
of oral CAB or oral RPV at the Week 4b visit. We will also give you the first shot of CAB or the first shot of RPV 
at the Week 4b visit. We will remind you not to take oral CAB or oral RPV before coming to this visit. You will 
take oral CAB or oral RPV at the study clinic before the first shot of CAB or the first shot of RPV.  
 
At this visit, we will also look closely at the amount of CAB or RPV in your blood. To do this, we will need to 
draw your blood two times during the visit, before taking oral CAB or RPV and after getting a shot of CAB or 
RPV. When you come to the visit, we will draw your blood, then you will take your oral CAB or RPV and get a 
shot of CAB or RPV, and then we will draw your blood again, about two hours later. Each time we will draw 
2mL (less than 1 teaspoon), for a total of 4mL (less than 1 teaspoon).  


 
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[Sites to include if combined Week 4a and Week 4b visits are planned.] This visit may be combined with the 
previous study visit (Week 4a). 
 
11. You will have 5 visits (Weeks 5-16) in Cohort 1-Phase 2.  
 
The first visit in Cohort 1-Phase 2 will be the Week 4b visit, which is described in #10 above. After that visit, you 
will have 5 more visits in this phase.  These visits will take place 1-4 weeks apart. [Sites to modify] Each visit will 
take about 1-3 hours.  
 
At each of these visits, we will:  
• 
Review your medical records.  
• 
Talk with you about preventing pregnancy. 
• 
Do a physical exam. At the Week 16 visit, this will include looking at your genitals to see your stage of 
development. For girls, this will also include looking at your breasts 
• 
Draw about 2mL of blood (less than 1 teaspoon) to look at the amount of CAB or RPV in your blood. 
 
At 3 of these visits (Weeks 5, 8, and 16) we will also draw about 5mL of blood (about 1 teaspoon) to check your 
blood cells and how well your liver and kidneys are working.  
 
At 2 of these visits (Weeks 8 and 16) we will also draw about 12mL of blood (about 2-3 teaspoons) to check your 
HIV viral load. Some blood will be saved for later resistance testing.  
 
At 1 of these visits (Week 16), we will also draw about 3mL of blood (less than 1 teaspoon) for tests. These tests 
will check your blood cells and CD4 count. 
 
At 2 of these visits (Weeks 9 and 16) we will also do an ECG to look at your heart.  
 
At 1 of these visits (Week 8) we will also give you a shot of either CAB or RPV. 
 
At 2 of these visits (Weeks 8 and 16) we will also talk with you about your experience with study ARVs.  
 
For girls, at 2 of these visits (Weeks 8 and 16) we will also collect urine or blood to test for pregnancy.  
 
12. In-depth phone interview [for U.S. sites only] 
 
We are very interested to understand what adolescents think about getting their ARV’s as shots. You may be 
asked if you would like to complete an in-depth phone interview. If you would like to take part in the interview, 
then you may be contacted to have the interview after getting the first shot of CAB or RPV. Not all participants 
will be contacted for the interview. You do not have to do the interview to take part in this study.  
 
If contacted, an interviewer will talk to you for about 1-2 hours and will ask how you feel about having shots of 
CAB or RPV. This information will help us understand if CAB shots and RPV shots have any side effects for 
adolescents. It will also help us understand how adolescents and families feel about the shots. The interview may 
take place at or in between the Week 4b, 5, 6, 8, and 12 study visits, or during the long-term follow-up safety 
phase. The interview will only take place once. The interview will be audio recorded and written down in a report. 
Your name will not be included in the report.  
 
We may also ask your parent or caregiver to complete an in-depth interview. This interview would ask them how 
they felt about you having shots of CAB or RPV.  


 
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13. We will tell you if you are eligible for Cohort 2. 
 
After your last visit in Cohort 1-Phase 2, we will tell you if are eligible for Cohort 2 or if you need additional tests 
to see if you qualify for Cohort 2.  
 
If you are not eligible for Cohort 2, or if Cohort 2 is not ready to take participants, you will stop getting shots of 
CAB or RPV and will enter Cohort 1-Phase 3, also called the long-term safety follow-up phase (see #16 below for 
more information). We will let you know when Cohort 2 is ready and if you need additional tests to see if you 
qualify for Cohort 2. 
 
If you are eligible for Cohort 2 and Cohort 2 is ready to take participants, you can enter into Cohort 2.  
 
14. Adolescents may have an extra visit if their HIV is not controlled. 
 
Participants will have viral load tests at almost all visits to check the amount of HIV in the blood. If tests show 
that the viral load is higher than expected (above 200 copies/mL) you will have repeat testing. This may occur as 
part of another study visit or may occur as an extra study visit.  
 
The extra visit will take about 1-2 hours. At this visit we will: 
• 
Review your medical records. 
• 
Do a physical exam.  
• 
Draw about 14mL (about 3 teaspoons) of blood for tests. The tests will: 
o Check your HIV viral load.  
o Check the amount of CAB or RPV in the blood.  
o We will save some blood for later resistance testing. 
• 
Talk with you about preventing pregnancy.  
• 
For girls, we will also collect urine or blood to check for pregnancy.  
 
If the repeat test also shows an increased amount of HIV in your blood, you will stop taking the study product. If 
you were getting shots of CAB or RPV, you will enter long-term follow-up (more information in #16 below).   
 
15. If you are not eligible to receive shots of CAB or RPV you will stop the study early. 
 
If you are not eligible to get shots of CAB or RPV in Cohort 1-Phase 2, you will stop taking oral CAB or oral 
RPV and will complete a final study visit about 4 weeks after your last oral dose.  
During this visit, we will:  
• 
Review your medical records.  
• 
Do a physical exam. This will include looking at your genitals to see the stage of development. For girls, this 
will also include looking at the breasts.  
• 
Draw blood for tests. This would be about 15-20mL of blood (about 3-4 teaspoons) for these tests. These tests 
will check:  
o Your blood cells.  
o How well your liver and kidneys are working. 
o Your HIV viral load.  
o Some blood will be saved for future resistance testing. 
• 
Talk with you about preventing pregnancy.  
• 
For girls, we will also collect urine or blood to check for pregnancy.  
• 
Ask you questions about what it is like taking CAB or RPV.  
• 
We will also talk with you about your ARV use.  


 
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16. If you stop the shots of CAB or RPV early, or if you are not eligible to enroll in Cohort 2, or if Cohort 2 is not yet 
ready, you will enter Cohort 1-Phase 3 (long-term safety follow-up phase). 
 
You will enter Cohort 1-Phase 3 (long-term safety follow-up phase) after the last shot of study product, if you: 
• 
Stop the shots of CAB or RPV during Cohort 1-Phase 2 early, or 
• 
Are not eligible to enroll in Cohort 2, or 
• 
If Cohort 2 is not yet ready for participants 
 
For females, if you become pregnant, you will enter this phase of the study after your positive confirmatory 
pregnancy test result, whether you are taking the pill or the shot.  
 
You will keep taking your usual ARVs. There will be 3 or 4 visits during the long-term safety follow-up phase. 
These visits will be scheduled 8, 24, 36 and 48 weeks after your last shot of CAB or RPV (or after a positive 
confirmatory pregnancy test result). [Sites to modify] Each of these visits will take about 1-3 hours. At these 
visits, we will:  
• 
Review your medical records.  
• 
Do a physical exam. At the final long-term follow-up visit, this will include examination of your genitals to 
see the stage of development. For girls, this will also include looking at your breasts. 
• 
Talk with you about preventing pregnancy. 
• 
Draw blood for tests. This would be about 19mL of blood (about 4 teaspoons) for these tests. These tests will 
check:  
o Your blood cells.  
o How well your liver and kidneys are working. 
o Your HIV viral load.  
o The amount of CAB or RPV in the blood.  
o Some blood will also be saved for future resistance testing. 
• 
For girls, we will also collect urine or blood to check for pregnancy.  
• 
At two of these visits (8 weeks and 48 weeks after your last shot of CAB or RPV) we will talk with you about 
your ARV use. 
• 
At two of the visits (8 weeks and 48 weeks after your last shot of CAB or RPV), we will also ask you 
questions about getting shots of CAB or RPV.  
 
For participants who complete the Week 16 visit in Cohort 1-Phase 2, the first long-term follow-up visit will be 
skipped entirely. The Week 16 visit and the first long-term follow-up visit are very similar and do not need to be 
conducted twice. 
 
17. Different tests will be done at different laboratories. 
 
We will do most of the tests of blood or urine here at our laboratory. We will give you the results of most of these 
tests at the next scheduled visit, or sooner, if necessary. We will explain the results and give you counseling and 
referrals as needed.  
 
We will also draw blood to check the amount of CAB or RPV in your blood. This is called a pharmacokinetic 
(PK) test. The PK test will be done at a laboratory in the United States. We will not usually give you the results of 
this PK test during the study.   
 
If you need a test for resistance (see #14 above), that test will be done at a laboratory in the United States.  You 
will be given the results of this resistance test and referrals if needed.  
 
 


 
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18. We may take you off of the study. 
 
We may take you off the study ARVs if: 
• 
You are not able to come to the study visits or we determine that you cannot meet the study requirements. 
• 
You are not able to take the study ARVs. 
• 
The study ARVs are not controlling the HIV in your blood. 
• 
Continuing the study ARVs may be harmful to you. 
• 
You request to stop the study ARVs. 
• 
You are not able to follow the birth control requirements of this study. 
• 
You become pregnant. 
 
If you stop the oral study ARVs early, we will ask you to come back to the clinic about four weeks after you stop 
the oral study ARVs (see #15 above). You will not have any other visits after this. 
 
If you stop the ARV shots early, we will ask you to come back to the clinic for four additional study visits for 
long-term safety follow-up (see #16 above). You will not have any other visits after these four visits. 
 
We may also take you off the study early if the study is stopped for any reason.  
 
The study cannot provide other types of ARVs, but we will give you information, counseling, and referrals to 
where you can get care and treatment needed. We will help make sure you can get ARVs from outside of the 
study. If the study stops early, every effort will be made to make certain that there is no interruption in your 
therapy.  
 
19. Please tell us if you want to leave the study. 
 
You are free to leave the study at any time for any reason. The care that you receive at this clinic will not be 
affected, but it is important for us to know about your decision.  
 
If you stop the study ARVs, we may ask you to return to the study clinic for additional study visits described in 
#15 and #16 above. If you stop the study early, we may ask you to return to the study clinic for one final study 
visit, like the last study visit described in #16 above. 
 
We will answer any questions you may have and give you information on how to contact us in the future, if you 
wish. 
 
Risks of the study 
 
Taking part in this study may involve some risks and discomfort. The risks are different for each phase of the 
study. Cohort 1-Phase 1 risks include: risks from blood draws, risk from the study pills (CAB or RPV), and risks 
to your privacy.  
 
Cohort 1-Phase 2 risks include: risks from blood draws, risks from receiving the injection, risks from the study 
pills (CAB or RPV) and the study shots (long-acting CAB or RPV) and risks to your privacy.  
 
Cohort 1-Phase 3 risks include: risks from blood draws, and risks to your privacy.  
 
 


 
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20. Risk from blood draws  
 
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted. Rarely, drawing blood 
can cause fainting or infection.  
 
21. Risk from receiving the injection  
 
People in other studies who have received the CAB and RPV shots said they had pain, skin irritation, skin 
redness, bumps, swelling, itching, bruising at the spot where they got the shot. Most reactions go away in a week 
or less but sometimes they can last longer. Most people usually do well with them and rarely need to stop the 
drug.  
 
The shots will be given in the muscles of your buttocks. The injection could be given too deeply or not deeply 
enough, missing the muscle and entering your skin, blood, or a nerve.  
 
The risks of this are not well understood but could make CAB or RPV levels too low or too high. If too low the 
drug may not work against your HIV. If RPV is too high, there could be a change in your heartbeat, which in 
severe cases can be life-threatening. In rare cases, symptoms such as feeling lightheaded, numbness or tingling, 
difficulty breathing, chest or stomach discomfort, sweating, nausea and/or feeling anxious have occurred after an 
injection with RPV LA. In these cases, high blood levels of RPV have been observed, which may be due to an 
accidental injection of part of the medication into a blood vessel instead of the muscle. Not all patients in whom 
an accidental injection in a blood vessel was suspected reported such symptoms. Most of the symptoms resolved 
within minutes. Your doctor may need to administer treatment to help resolve these symptoms.  Everything 
possible will be done to decrease this risk, including watching you for problems during the study. If your doctor 
thinks that the injection was not given the right way, you might be asked to stay in the clinic up to [sites to 
modify] 2 hours after the injection to watch how you are doing and extra tests may be needed to be sure you are 
safe. If you are worried about this risk, talk to your doctor. 
 
Receiving injections can cause some people to feel lightheaded or feel like they might pass out. Fainting can also 
occur. This reaction, called a ‘vasovagal reaction’, has been reported with other injectable medicines, and resolves 
quickly. 
 
22. There are risks from the study ARVs 
 
All ARVs can cause side effects. This includes the ARVs you are currently taking and the ARVs that are given in 
the study. Some side effects are minor; others can be severe. Some side effects are common; others are rare. Some 
people who take ARVs have some of the side effects. Other people have different side effects, or no side effects.  
 
The most common and most serious side effects of the study ARVs, CAB and RPV, are listed below. This is 
based on what we know now about CAB and RPV used in adults. There may be other side effects that we do not 
know about now. This may be especially true for adolescents, because this is the first study of CAB and RPV in 
adolescents.  
 
This form does not list all possible side effects of all ARVs. If you join the study, we will tell you more about the 
ARVs you will be taking. At each study visit, we will check on whether the ARVs may be causing side effects. 
We will also tell you what to do if you have side effects. If you have questions or concerns at any time, please tell 
us.  
 
 


 
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23. Some side effects from the CAB pills and the CAB  
 
Many people have received CAB pills or the CAB shot in other studies. The table below lists side effects from 
other studies of CAB with people who have HIV. It is not known if CAB, other drugs or the patient’s other health 
problems caused or affected these. Some of these are the same side effects as RPV (see #24 below).  
 
Common Side Effects of CAB 
Very Common Side Effects of CAB 
Common Side Effects of CAB 
• Headache 
• Fever 
• Injection Site Reactions 
 
• Rash 
• Itching  
• Vomiting (being sick) 
• Nausea (feeling sick) 
• Stomach pain and discomfort  
• Problems sleeping  
• Abnormal dreams/nightmares 
• Anxiety 
• Feeling lightheaded 
• Depression 
• Passing gas or wind 
• Diarrhea 
• Muscle pain 
• Lack of energy 
• Increase in the level of enzymes produced 
in the muscles (creatine phosphokinase) 
• Weight increased 
 
The following effects have also been seen in some of the people who received CAB pills or the CAB shot in other 
studies: 
 
Abnormal liver tests: 
 
A small number of people across all studies (just over 1% of 1644 participants as of April 2017) had abnormal 
liver tests requiring them to stop CAB. Some abnormal liver tests were explained by other health conditions such 
as a new virus infection, like Hepatitis A, B or C. A small number of people did not have health conditions that 
could explain the abnormal test, so it is possible that a mild form of liver damage happened from taking CAB. 
The liver tests got better after stopping CAB, showing that any damage was temporary. 
 
Blood tests to check the health of your liver will be done during the study. Your study doctor will tell you if you 
need to stop taking the study drugs or if other actions are needed. If you stop taking the study drug, you may be 
able to re-start the study drug or you may need to change your usual ARVs.  
 
 


 
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Seizures/convulsions: 
 
Seizures have been seen (rarely) in people with and without HIV who have taken CAB. They are not thought to 
be caused by CAB, but the study staff will ask you about them.  
 
In other studies, two people without HIV had a history of seizures (epilepsy), and had a seizure about 3 months 
and 9 months after starting CAB. One other person with HIV but without a history of seizures, had seizures about 
one year after starting CAB. This participant had a long period of seizures without medical treatment and died. It 
is not known if CAB was part of the reason for seizures in these people. If you have a history of seizures, please 
let your study doctor know. 
 
24. Some side effects from the RPV pills and the RPV shot 
 
Oral RPV (Edurant) is a marketed drug which many people throughout the world have received to manage HIV. 
We know more about the side effects of Edurant than we do about CAB or RPV shots. The following side effects 
have been seen in studies in people with HIV taking RPV.  
 
Common Side Effects of RPV 
Common Side Effects of RPV 
Uncommon Side Effects of RPV 
• 
Problems sleeping, insomnia  
• 
Headache 
• 
Feeling lightheaded (dizziness) 
• 
Rash 
• 
Nausea (feeling sick to the stomach) 
• 
Vomiting 
• 
Abdominal (belly) pain 
• 
Increase in the level of liver enzymes 
• 
Decreased appetite 
• 
Depression 
• 
Abnormal dreams 
• 
Fatigue (tiredness, lack of energy) 
• 
Dry mouth 
 
• 
Sleepiness (somnolence) 
• 
Depressed mood 
• 
Stomach discomfort  
• 
Immune reconstitution syndrome (this can be 
an overreaction of the body’s recovering 
defense system to a previously present 
infection, or problems in the immune system) 
 
The following effects have also been seen in some people who received RPV in other studies: 
 
Abnormal blood tests: 
 
Other changes in blood tests have also been observed. People with Hepatitis B or C or who have possible liver 
damage before starting RPV may have worse liver tests while taking RPV. A few cases of liver problems were 
found in people taking RPV who did not already have any liver problems. 
 


 
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Sometimes allergic reactions can affect body organs, like the liver, and cause liver problems which can lead to 
liver failure. Contact your study doctor right away if you have any of the following signs or symptoms of liver 
problems: 
• 
Yellowing of the skin or whites of the eyes 
• 
Dark or tea colored urine 
• 
Pale colored stools/bowel movements 
• 
Nausea/vomiting 
• 
Loss of appetite 
• 
Pain, aching or tenderness on the right side below the ribs 
• 
Itchy skin  
 
Blood tests to check the health of your liver will be done regularly during the study. Your study doctor will tell 
you if you need to stop taking the study drugs or if other action is needed. If you stop taking the study drug, you 
may be able to re-start the study drug or you may need to change your usual ARVs.  
 
Skin Rash: 
 
Most rashes were mild or moderate, and happened within the first 4 weeks of taking RPV. Most of rashes got 
better after one week, and the people did not need to stop taking RPV. However, the study ARVs will need to be 
stopped for some types of moderate rash and all types of severe rash, which can be life-threatening. If this 
happens to you, you will need to come for extra study visits to monitor your health. Some people with rash may 
also have other signs and symptoms of allergic reaction. 
 
If you have any type of rash or other skin problems during the study you must tell your study doctor right away, 
and the doctor may tell you to stop taking CAB and/or RPV. 
 
25. There may be other possible risks from the study ARVs. 
 
The study ARV shots stay in your body for a long time 
 
The shots you get in this study are long acting, meaning they stay in your body for a long time. In most people the 
drugs will no longer be in the body one year after an injection, while in some people low levels of CAB and RPV 
may still be in the body after one year. If you develop a side effect to the study drug after the shot, there will be no 
way to remove the drug from your body. If you get a shot of CAB or RPV, we will monitor your health for 48 
weeks after your last shot. If you develop a symptom from these drugs while the drugs are still in your body, 
every effort will be made to treat the side effects. The amount of drug will decrease overtime and will eventually 
disappear. 
 
While the amount of study drugs in your body decrease slowly over time after you stop getting shots, the study 
drugs could stop working against your HIV. When stopping long acting HIV drugs, it will be very important to 
start taking other HIV medications, as your study doctor tells you, so your HIV medications do not stop working 
against your HIV. 
 
Risk of resistance 
 
All ARVs can cause some resistance if not taken correctly. Resistance means that the ARVs may not work against 
HIV if these ARVs are taken again in the future. To stop resistance, it is important that you take and/or receive the 
ARVs as instructed, and do not miss any doses. 
 
 


 
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Effects on other ARVs 
 
We do not expect the study ARVs to change the way other ARVs work in the body. For example, if you were to 
join the study, we would expect the ARVs you are currently taking to keep working to control the amount of HIV 
in your body. We also do not expect the study ARVs to cause more or worse side effects from other ARVs. 
However, this study is being done to learn more about these kinds of possible effects. 
 
Mental illness or depression 
 
Some people with HIV sometimes have feelings of depression or may feel sad or hopeless, feel anxious or 
restless, or may have thoughts of hurting or killing themselves (suicide). A small number of people being treated 
with drugs called integrase inhibitors [INIs] for HIV like CAB, have had suicidal thoughts and actions, 
particularly patients with a prior history of depression or mental health illness.  
 
Tell the study doctor if you have a history of mental health illness. If you have thoughts of hurting or killing 
yourself or have any other unusual or uncomfortable thoughts or feelings during this study, you should tell the 
study doctor or go to the nearest hospital right away.  
 
Possible effects on pregnancy or unborn babies 
 
HIV and ARVs may lead to some pregnancy complications, like early delivery or low weight of the baby at birth. 
We do not know if some ARVs are more likely to cause these effects than others. We do not yet know if CAB is 
safe in pregnancy. RPV does not appear to be a risk to pregnancy and the developing baby based on the 
information we know now, but additional data are still being collected. 
 
There are few data from humans on the effects of CAB in pregnancy. Most of the information we have comes 
from animal studies. In studies done in pregnant rats and their newborns, using very high amounts of CAB, there 
were more baby rats that died when they were born or right after they were born. This did not happen to the baby 
rats when the mother got lower amounts of the drug, or no drug. The amount of CAB that we are giving in this 
study is expected to be more than 7-times lower than the amount given to the pregnant rats. Birth defects have not 
been found in any animal studies of CAB so far. We do not know whether what happened to the baby rats has any 
impact on what will happen in pregnant humans taking this drug. 
 
Early results from one large study in Botswana showed that the ARV called dolutegravir (DTG) may increase the 
risk of serious birth defects of the brain or spine in the new baby. The increased risk was seen among babies 
whose mothers were taking DTG when they became pregnant. These birth defects happen during the first few 
weeks of pregnancy, before mothers may know they are pregnant. These birth defects have not been seen among 
babies whose mothers started taking DTG later in pregnancy.  
 
CAB is not the same drug as DTG. We do know that CAB and DTG belong to the same class of medications and 
work in a similar way to treat HIV infection. We do not know if CAB can cause brain or spine defects in babies.  
 
Girls who are able to become pregnant must agree to use certain effective methods of birth control to be in this 
study (see #6 above). If you become pregnant during the study, please let us know right away. 
 
Immune reconstitution syndrome 
 
In some people with advanced HIV infection, signs and symptoms from other infections or certain diseases (for 
example a liver condition called autoimmune hepatitis) may occur soon after starting combination ARVs but can 
also occur later. Some of these symptoms may be life threatening. If you start having new symptoms, or if you 
notice that any existing symptoms are getting worse after starting the ARVs, tell your doctor immediately. 


 
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Abnormal placement of body fat and wasting 
 
The use of potent antiretroviral drug combinations may be associated with an abnormal placement of body fat and 
wasting. Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 
• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement 
 
26. There could be risks of disclosure of your information. 
 
We will make every effort to keep your information private and confidential. Study records and specimens will be 
kept in secure, locked locations. All specimens and most records will be labeled only with a code number. 
However, your name will be written on some records.  
 
Despite our best efforts to keep your information private, it is possible that the information could be obtained by 
someone who should not have it. If this were to happen, you could be treated badly or unfairly. You could feel 
stress or embarrassment.  
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality that protects us from being 
forced to release information that may identify you, such as by the courts or police. The certificate cannot be used 
in all situations, but it can be used to resist demands for information that would identify you. The certificate does 
not protect against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your participation in the study to 
others, if you wish. 
 
Information collected for this study may be used for other research in the future. For example, researchers may 
use information from this study to try to answer different questions about children or adolescents with HIV. Any 
future research done with the information from this study must be approved by the IMPAACT Network. If any 
future research is done, information about you may be used, but your name will not be shared. 
 
Benefits of the study 
 
27. There may be a direct benefit to you from being in the study. 
 
By joining the study, you will be part of the search for ARVs that may be better for adolescents. We do not know 
if being in the study will benefit you in any way. There may be a direct benefit to you by taking part in this study, 
but no guarantee can be made. For example, you may gain a better understanding of your health and HIV care.  
Another possible benefit is early access to the Cohort 2 part of the study, if you qualify. There may also be benefit 
if the results from this study lead to a safe and effective dose of the study drugs for adolescents. It is also possible 
that you may receive no direct benefit from this study. Information learned from this study may help other 
adolescents who have HIV. 
 
You will have regular visits here and frequent checks on your health, including tests for amount of HIV in your 
blood, called viral load. It is possible that the study ARVs will slow your HIV infection. Information learned from 
this study may help other adolescents with HIV. 
 
 


 
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Other information about the study 
 
28. There are no costs from being in the study. 
 
There are no costs to you for study visits, CAB, RPV or procedures.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits. For each visit, you will be given (specify amount).] 
 
29. Study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include:  
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your name or identify you personally.  
 
A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify you. At most, the website will include a summary of the results. You can 
search this website at any time. 
 
Your study information may be given to other authorities if required by law. [Sites add more specific detail here 
as needed; example follows:] For example, we are required to report any significant risk of harm to you or others.  
 
30. If you get sick or injured, contact us immediately. 
 
Your health is important to us. We will make every effort to protect your well-being and minimize risks. It is 
possible, however, that you could have an illness or injury that is study-related. This means that the illness or 
injury occurred as a direct result of the study procedures.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage available 
through clinical trial insurance obtained by the site should be included if applicable; the statement regarding no 
program for compensation through the NIH may not be removed.]  If a study-related illness or injury occurs, we 
will treat you or tell you where you can get treatment. The cost for this treatment may be charged to you or your 
insurance company. There is no program for compensation either through [site name or] the U.S. National 
Institutes of Health.  
 


 
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Whom to contact 
 
31. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about your rights as research participants or concerns about how you are being treated 
in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 
 
• 
If you have any health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you want to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
 
Signatures 
 
If you agree to participate in this study, please sign or make your mark below. 
Before deciding whether to participate in this study, make sure you have read this form, or had it read to you, and 
that all of your questions have been answered. You should feel that you understand the study, its risks and 
benefits, and what is expected of you if you decide to join.  
 
If you decide to join, we will tell you any new information from this study or other studies that may affect your 
willingness to stay in the study. You are welcome to ask questions or request more information at any time. If you 
want the results from this study, please tell the study staff. 
 
You do not give up any rights by signing this form. 
[Insert signature blocks as required by site IRB/EC policies.] 
 
 
 
Signature blocks for participants of legal age to provide independent informed consent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 


 
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Appendix III-B:  Sample Informed Consent Form for Participation in Cohort 2 
for adolescents who can provide independent informed consent for study participation 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 3.0, dated 13 August 2020 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
Introduction 
 
You are being asked to take part in the research study named above. 
 
This form gives information about the study. Please read it, or have it read to you, and ask any questions you may 
have. We will take as much time as needed for you to fully understand the study. We will ask you questions to see 
if we have explained the study clearly. 
 
Here is a summary of important information about the study: 
 
• 
The study is testing two anti-HIV medicines (ARVs), Cabotegravir (CAB) and Rilpivirine (RPV), taken as 
pills and given as long-acting shots in adolescents 12 to less than 18 years of age.  
• 
The RPV pills are approved for adolescents in Botswana, Uganda, United States and for adults in Botswana, 
South Africa, Thailand, Uganda, United States. The CAB pills, and the CAB and RPV shots are now being 
tested in adults with HIV but have not yet been tested in adolescents.  
• 
There are two parts to this study, Cohort 1 and Cohort 2. This form is about Cohort 2.  
• 
Adolescents in Cohort 2 will be in this part of the study for at least 2 years up to 3 years.  
• 
Adolescents in Cohort 2 will switch from their usual ARVs to the study medicine. After entering the study, 
adolescents will stop taking their usual ARVs and start taking daily CAB and RPV pills for 4 to 6 weeks. 
Adolescents will then switch to CAB and RPV shots every 8 weeks for about 2 years.  
• 
After the 2 years of getting the CAB and RPV shots, adolescents might be able to continue getting the same 
CAB and RPV shots outside of the study. We will explain the options to you and help ensure your access to 
ARVs outside the study. 
• 
Adolescents who stop taking the CAB and RPV shots may be followed for up to 1 year for long-term safety 
follow-up. During this time, adolescents will not take any study medicine (shots or pills) but will take ARVs.   
• 
While in the study, adolescents will have clinic visits with physical examinations and blood draws for 
laboratory tests. Some visits will include a review of adolescents’ medical records and ECG tests to look at 
the adolescent’s heart. Female participants will also be tested for pregnancy.  
• 
If interested, participants in the U.S. may be eligible to do one in-depth phone interview where they will talk 
about their experience getting their ARVs as shots.  
• 
There are some possible risks for adolescents in the study. One possible risk is that the pills or shots being 
tested could cause side effects. The most severe side effects include allergic reaction, liver problems, and 
mental health problems.  These side effects are uncommon. 
• 
There are some possible benefits for adolescents in the study. One possible benefit is not taking daily pills 
while getting the CAB and RPV shots.  Another possible benefit is that the shots being tested will be better 
for your health and HIV care than the usual ARV pills.  


 
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• 
Your decision on your participation in the study will have no effect on the medical care you receive at this 
clinic. Your access to services, and the benefits and rights you normally have, will not be affected. You may 
choose to leave the study at any time. 
 
More information is given in this form about the study, its risks and benefits. You should feel that you understand 
the study before deciding whether you will participate. If you decide to participate, you will be asked to sign or 
make your mark on this form. You will be offered a copy to keep. 
 
About the study 
 
This study is being done by the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
(IMPAACT) and [insert site name]. The person in charge of the study at [insert site name] is [insert name of 
IoR].  
 
The study is being done to test two anti-HIV medicines (antiretrovirals or ARVs) in adolescents 12 to less than 18 
years old who have HIV. The study ARVs are called cabotegravir (CAB) and rilpivirine (RPV). HIV is the virus 
that can lead to AIDS.  
 
The study will include up to 155 adolescents from the United States, Botswana, South Africa, Thailand and 
Uganda. There will be two groups of adolescents, called Cohort 1 and Cohort 2. This form is about Cohort 2. 
Participants in Cohort 2 will be in the study for 2 to 3 years. In Cohort 2, participants will get study product for 96 
weeks (about 2 years). After 96 weeks, participants may continue getting the study medicines outside of the study. 
If you continue getting the study medicines outside of the study, you will not have any additional study visits. If 
you choose to stop getting the study medicines, you will enter long-term safety follow-up and continue having 
study visits for an additional 48 weeks (about 1 year). 
 
The United States National Institutes of Health and the companies that make CAB and RPV, ViiV Healthcare and 
Janssen Pharmaceuticals, are paying for this study.  
 
1. The study is testing CAB and RPV in adolescents. 
 
People with HIV usually take a combination of ARVs daily to stay healthy. There are not as many ARVs 
available for adolescents as for adults because many ARVs have not yet been tested in adolescents. ARVs can be 
made in different forms, such as liquids, pills, and injections (shots). The study will test CAB and RPV when 
taken as pills and when given as shots in adolescents. The pills are taken every day. The shots can be given every 
4 weeks or every 8 weeks. The shots are being developed because it can be difficult to take pills every day, and 
some people may prefer to have the shots rather than taking pills.  
 
RPV pills (25mg taken once daily) have been shown to be safe and effective for both adults and adolescents 12 
years and older with HIV. The RPV pills are already approved by the US Food and Drug Administration (FDA) 
for adults and adolescents with HIV. The FDA is the part of the government that regulates medicines in the 
United States. The RPV pills have also been approved for use for adults and adolescents in Cambodia, Canada, 
China, Ethiopia, the European Union, Gabon, Ghana, Hong Kong, Ivory Coast, Japan, Kazakhstan, Kenya, 
Malawi, Mali, Namibia, Nigeria, Russia, Taiwan, Tanzania, Ukraine and Zimbabwe. 
 
RPV shots (600mg and 900mg), CAB pills (30mg), and CAB shots (400mg and 600mg) are now being tested in 
adults with HIV. The FDA is asking for more information on how these medicines are made before they can 
approve them in adults.  The FDA has no safety concerns regarding these medicines. RPV shots, CAB pills and 
CAB shots have been approved in Canada for monthly dosing. 
 


 
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This will be the first study of these ARVs in adolescents. So far, the testing in adults has shown that RPV shots, 
CAB pills, and CAB shots work as well as other ARVs that are approved. However, because these ARVs are still 
being tested, there may be some effects that we do not know about yet.  
 
This study will test the effects of these ARVs in adolescents. The study will look at whether these ARVs:  
• 
Are being given at the correct dose for adolescents  
• 
Are safe and well-tolerated in adolescents 
• 
Can control HIV in adolescents as well as other ARVs 
The study will also look at how willing adolescents are to take these ARVs.  
 
Cohort 1 of this study was done first to test CAB and RPV pills when taken for about 1 month followed by 2 or 3 
CAB and RPV shots when taken 1 month apart. Cohort 2 is now being done to test CAB and RPV pills taken 
together for about 1 month, followed by CAB and RPV shots taken together. Both CAB and RPV shots will be 
given together about every 8 weeks for up to two years. Each time the shots are given, the RPV shot will be 
900mg and the CAB shot will be 600mg. Cohort 2 will look at whether these study ARVs are safe and can control 
HIV when adolescents stop taking their previous ARVs.  
 
More information about the study, Cohort 2, and CAB and RPV is given in the rest of this form. 
 
2. Only adolescents who are eligible can participate in the study. 
 
If you decide to join the study, we will first do some tests to find out if you are eligible. More information about 
the tests is given in #5 (see below). If you are eligible, you will be entered in the study. If you are not eligible, you 
cannot be entered in the study.  
 
3. It is your decision whether or not you join the study. 
 
Deciding to join the study is voluntary (your choice). You may choose to join or not join. If you choose to join, 
you can change your mind and leave the study. Your choices will have no effect on the medical care you would 
normally receive. Your access to services, and the benefits and rights you normally have, will not be affected.  
 
Take your time and consider your decision carefully. If you wish, you can talk to other people about the study. 
You can bring other people here to learn about the study with you. 
 
No matter what you decide about the study, it is important for you to keeping taking ARVs. This is the best known 
way for you to stay healthy. 
 
4. There are three phases in Cohort 2.  
 
For participants in Cohort 2, there are three phases of the study. All participants will take part in Cohort 2-Phase 
1. Only those who are eligible will take part in Cohort 2-Phase 2. Some participants who take part in Cohort 2-
Phase 2 will also take part in Cohort 2-Phase 3, called the long-term safety follow-up phase. 
 
In Cohort 2-Phase 1, you will stop taking your usual ARVs and take CAB and RPV pills. The pills must be 
swallowed whole. They cannot be broken or crushed. They should be taken with a meal. This phase lasts for 
about 4-6 weeks. After the study entry visit (see #8 below), you will have 2 more visits during Phase 1. At these 
visits, we will check to see how you are doing while taking the pills (see #9 for more information). We will also 
check to see if you are eligible for Cohort 2-Phase 2.  
 
If you are eligible for Cohort 2-Phase 2, you will stop taking the CAB and the RPV pills and start getting CAB 
and RPV shots. This phase lasts 2-3 years. You will have 15 visits over about two years and will get shots at 13 of 


 
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these visits. At each of these 13 visits, you will be given one shot of CAB and one shot of RPV. Each shot is 
about 3mL (about 1 teaspoon). The shots are given in the buttocks (bottom “cheeks”). The shots may be given on 
the same side of the buttocks or on different sides. The shots are long-acting, meaning the medicine stays in your 
body for a long time. The first two visits with the CAB and RPV shots are 4 weeks apart. Then the CAB and RPV 
shots are given every 8 weeks. At all of these study visits, we will check on how you are doing while getting the 
shots (see #11 for more information). 
 
After Cohort 2-Phase 2, you might have the option to continue getting the long-acting injections (see #19 for more 
information). If you no longer want to get the injections, you will take part in Cohort 2-Phase 3, the long-term 
safety follow-up phase of the study. This phase lasts about 48 weeks. You will also go back to taking your usual 
(pre-study) ARVs. There will be 3 or 4 visits during long-term follow up (see #15 for more information). 
 
Finding out if you are eligible for Cohort 2 
 
5. We will ask questions, examine you, and discuss the study requirements with you. 
 
To find out if you are eligible for the study, we will: 
 
• 
Review your medical records. 
• 
Ask questions about you, your health, and the medications you take.  
• 
Talk with you about birth control (ways to prevent pregnancy). 
• 
Talk with you about the study requirements and if you are able to meet these requirements. 
• 
Do a physical exam. This will include looking at your genitals to see your stage of development. For girls, 
this will also include looking at your breasts. 
• 
Do an electrocardiogram (ECG). This is to test how well your heart is working.  
• 
Draw about 11-17mL (about 2-3 teaspoons) of blood for tests. The tests will: 
o Check your blood cells. 
o Check how well your liver and kidneys are working. 
o Confirm that you have HIV. There are certain HIV tests that are required for this study. If the required 
tests are not in the medical records, we will do the tests that are needed. 
o Check the amount of HIV in your blood. This is called your HIV viral load.  
 
These procedures will take about 4 hours [here and throughout this form, sites may modify the expected visit 
duration as needed]. 
 
6. For girls, we will also test for pregnancy. 
 
Girls in this study cannot be pregnant. Girls should not join this study if they are pregnant or intend to become 
pregnant within 30 days after stopping the study ARV pills or within 48 weeks after stopping the study shots. 
Because the effects of the study ARVs on unborn babies are unknown, you should not become pregnant while in 
this study. For all girls in the study, we will collect urine or blood to test for pregnancy.  
 
There are certain effective methods of birth control that girls who are able to become pregnant must use while in 
this study. These effective methods must be continued for 30 days after stopping the study ARV pills, or for at 
least 48 weeks after stopping the study ARV shots. Girls who are able to become pregnant, must agree to use 
these methods in order to take part in the study. We will help make sure you can get effective methods by 
providing them here in the clinic or offering a referral. At study visits when you will receive study medicines 
(either the pill or shot), we will need to confirm that you are using effective birth control before giving you the 
study medicines. 
 


 
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Girls who become pregnant during the study will stop taking the study medicines and enter the long-term safety 
follow-up phase of the study (see #15 below). They must continue taking their usual ARVs. We will also 
contact you to find out the outcome of the pregnancy even if the outcome occurs after leaving the study. 
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure of 
pregnancy results to parents or guardians: As soon as the pregnancy test result is available, we will go over it 
with you in private, without your parents/guardians present. You must give us permission before we can share 
these results with your parents/guardians. If the test shows that you are pregnant, we will give you information on 
where medical care and other services can be received.] 
 
If you are pregnant, your doctor may report your pregnancy to the Antiretroviral Pregnancy 
Registry. The Antiretroviral Pregnancy Registry assists patients and doctors in gauging potential benefits 
and risks of treatment; however, the registry does not collect any identifying information about you, such as your 
name, initials, contact information, or date of birth.  
 
7. We will tell you if you are eligible. 
 
We will give you the results of all procedures and explain the results to you. We will tell you about getting care, 
treatment and any other services you may need. While waiting for the results, it is important for you to keep 
taking your usual ARVs. 
 
If you are not eligible for the study for any reason, we will tell you this. You will not be entered in the study. You 
can and should continue to receive medical care and treatment outside of the study. We will tell you more about 
getting this care and treatment and any other services you may need.  
 
If you do not enter the study, we will still use some information collected about you (for example age, sex, and 
race). We will use this information to look at patterns or common reasons for not entering the study. 
 
If you are eligible for the study, you will be entered into the study.  
 
Entering the study 
 
8. If you are eligible, you will enter the study 
 
On the day you enter the study we will:  
• 
Review your medical records.  
• 
Talk with you about your ARV use. 
• 
Talk with you about preventing pregnancy. 
• 
Ask you questions about what you think about CAB and RPV 
• 
Do a physical exam.  
• 
Draw about 18mL (about 4 teaspoons) of blood for tests. The tests will: 
o Check your blood cells. 
o Check how well your liver and kidneys are working. 
o Check how much the virus has affected your ability to fight the virus. This is called CD4 cell count. 
o The tests will check your HIV viral load.  
o Some blood will be saved for later testing for resistance to ARVs. This test shows whether different 
ARVs may work against the HIV in your blood. 
• 
For girls we will collect urine or blood for a pregnancy test  
 


 
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At the study entry visit we may also do an ECG to look at your heart. This will only be needed if you enter the 
study more than 2 weeks after your first visit. 
 
At this visit, you will stop taking your usual ARVs and start taking CAB and RPV pills. We will give you the pills 
and explain how to take them. You will take your first dose at the visit.  
 
This visit will take about 4 hours.  
 
Being in the study 
 
9. After entering the study, you will have two more visits in Cohort 2-Phase 1 (Weeks 2 and 4a).  
 
The first visit in Cohort 2-Phase 1 will be the study entry visit and is described in #7 above.  After that visit, you 
will have 2 more visits in Cohort 2-Phase 1.  These visits will be scheduled 2 weeks apart. [Sites to modify] Each 
visit will take about 1-3 hours. At each of these visits, we will:  
 
• 
Review your medical records.  
• 
Talk with you about your ARV use 
• 
Do a physical exam. 
• 
Talk with you about preventing pregnancy.  
• 
For girls, we will collect urine or blood to test for pregnancy.  
• 
Remind you to bring the oral CAB and oral RPV to the study clinic. 
 
At two of these visits (Week 2 and Week 4a), we will draw about 5mL (about 1 teaspoon) of blood for tests. 
These tests will check your blood cells and how well your liver and kidneys are working.  
 
At the second visit (Week 2), we will draw about 12mL (about 2-3 teaspoons) blood for tests. This test will check 
your HIV viral load. Some blood will be saved for later resistance testing.  
 
At the Week 2 visit we will also test the amount of CAB and RPV in your blood. This is called a pharmacokinetic 
(PK) test. At this visit, we will ask you when you took CAB or RPV in the past three days. [Sites: modify 
language as appropriate to align the three prior doses with the timing (morning or evening) of the Week 4b pre-
dose PK sample collection.] For three days before this visit, you must be sure to take CAB and RPV on time and 
in the morning. This is very important. We will help you remember this before the visit. 
 
We will need to draw your blood two times during the Week 2 visit, before and after taking CAB and RPV. We 
will remind you to not to take CAB or RPV before coming to this visit. When you come to the visit, we will draw 
your blood, then you will take CAB and RPV, and then we will draw your blood again, about three hours later. 
Each time we will draw 4mL (less than 1 teaspoon), for a total of 8mL (about 2 teaspoons).  
 
Study staff will let you know when these procedures will occur ahead of time.  
 
[Sites to modify] On rare occasions, we may offer some of the visit activities off-site, or by phone. The study staff 
will discuss the location and best time to visit you so that the visit is at a convenient time and the visit is done at a 
place you feel comfortable and confidentiality can be maintained. 
 
10. If you are eligible, you will enter the Cohort 2-Phase 2 (Week 4b). 
 
At the Week 4b visit, we will determine if you are eligible for Cohort 2-Phase 2. At this visit we will:  


 
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• 
Review your medical records.  
• 
Talk with you about your ARV use. 
• 
Do a physical exam. 
• 
Ask you questions about your experience with the study drugs.  
• 
Talk with you about preventing pregnancy.  
• 
Draw about 12mL (about 2-3 teaspoons) blood for tests. These tests will check your HIV viral load. Some 
blood will be saved for later resistance testing.  
• 
Do an electrocardiogram (ECG). This is to test how well your heart is working.  
• 
For girls, we will also collect urine or blood to test for pregnancy. 
• 
Remind you to bring the oral CAB and oral RPV to the study clinic. 
• 
[Sites: modify language as appropriate to align the three prior doses with the timing (morning or evening) of 
the Week 4b pre-dose PK sample collection. Remind you to take the oral CAB and oral RPV in the morning 
for the three days before this visit.]  
 
If you are not eligible, you will stop taking oral CAB and oral RPV and will start taking your previous ARVs 
again. If you did not participate in Cohort 1, you will complete a final study visit about 4 weeks after your last 
oral CAB and RPV dose (see #14 for more information). If you also participated in Cohort 1 and received shots of 
CAB or RPV in Cohort 1-Phase 2 but are not eligible to get the shots of CAB and RPV in Cohort 2, you will stop 
taking oral CAB and oral RPV and will enter into Cohort 2-Phase 3 long-term follow-up (see #15 below). 
 
If you are eligible, you will take your last dose of oral CAB and oral RPV at the Week 4b visit. At this visit, we 
will also give you the first shot of CAB and the first shot of RPV. We will remind you not to take oral CAB and 
RPV before coming to this visit. You will take oral CAB and RPV at the study clinic before the first shot of CAB 
and the first shot of RPV.  
 
At this visit, we will also look closely at the amount of CAB and RPV in your blood. To do this, we will need to 
draw your blood two times during the visit, before taking oral CAB and RPV and after getting a shot of CAB and 
a shot of RPV. When you come to the visit, we will draw your blood, then you will take oral CAB and RPV and 
get a shot of CAB and RPV, and then we will draw your blood again, about two hours later. Each time we will 
draw 4mL (less than 1 teaspoon) for a total of 8mL (about 2 teaspoons). At this visit, about 2 hours after you get a 
shot of CAB and a shot of RPV, we will also do an ECG to look at your heart. 
 
[Sites to include if combined Week 4a and Week 4b visits are planned.] This visit may be combined with the 
previous study visit (Week 4a). 
 
11. You will have 14 more visits (Weeks 5-96) in Cohort 2-Phase 2.  
 
The first visit in Cohort 1-Phase 2 will be the Week 4b visit, which is described in #10 above. After that visit, you 
will have 14 more visits in this phase. Most of these visits will take place about 8 weeks apart, and some of these 
visits will take place 1 week apart. [Sites to modify] Each visit will take about 1-3 hours. At each of these visits, 
we will: 
• 
Review your medical records.  
• 
Talk with you about preventing pregnancy.  
• 
Do a physical exam. At two of these visits (Weeks 24 and 96), this exam will include examination of your 
genitals to see the stage of development. For girls, this will also include looking at the breasts. 
 
At 12 of these visits (Weeks 8-24 and 32-96) you will:  
• 
Get a shot of CAB and a shot of RPV. 
• 
For girls, we will also collect urine or blood to check for pregnancy.  
 


 
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At 13 of these visits (Weeks 5, 8-24, and 32-96) we will draw about 5mL of blood (about 1 teaspoon) for tests. 
These tests will check: 
• 
Your blood cells 
• 
How well your liver and kidneys are working 
 
At 9 of these visits (Weeks 8-24, 32-48, 64, 80, and 96) we will draw about 12mL of blood (about 2-3 teaspoons) 
for tests. These tests will check: 
• 
Your HIV viral load.  
• 
Some blood will be saved for later resistance testing.  
 
At 12 of these visits (Weeks 5, 8-48, 64, 80, 88, and 96), we will also draw about 4mL of blood (less than 1 
teaspoon) of blood to look at the amount of CAB and RPV in the blood. 
 
At 4 of these visits (Weeks 24, 48, 72 and 96) we will draw about 3mL of blood (about 1 teaspoon) to check your 
CD4 count.  
 
At 4 of these visits (Weeks 8, 24, 48, and 96) we will ask you questions about getting the shots of CAB and RPV.  
 
At 5 of these visits (Weeks 8, 24, 48, 72, and 96) we may also talk with you about how you are doing with the 
visit schedule.  
 
If you cannot come to the clinic to receive the CAB and RPV shots, then you may have the option to take the 
CAB and RPV pills until you are able to get the shots again.  If this happens, your child may need more frequent 
CAB and RPV shots outside of the scheduled visit days for a few months. If you cannot return to the clinic to get 
the CAB and RPV shots soon, then you may need to stop taking the study ARVs and enter the long-term safety 
follow-up phase (see #15 below). This is not preferred, and it is important to get the shots on the scheduled visit 
day and not miss any CAB and RPV shots. 
 
Study staff will let you know when these procedures will occur ahead of time.  
 
12. In-depth phone interviews [for U.S. sites only] 
 
We are very interested to understand what adolescents think about getting their ARV’s as shots. You may be 
asked if you would like to complete an in-depth phone interview. If you would like to take part in the interview, 
then you may be contacted to have the interview after getting the fourth shot of CAB and RPV. Not all 
participants will be contacted for the interview. You do not have to do the interview to take part in this study. 
 
If contacted, an interviewer will talk to you for about 1-2 hours and will ask how you feel about having shots of 
CAB and RPV. This information will help us understand if CAB shots and RPV shots have any bad side effects 
for adolescents. It will also help us understand how adolescents and families feel about the shots. The interview 
may take place at or in between the Week 24 through 96 visits or during the long-term follow-up safety phase. 
The interview will only take place once. The interview will be audio recorded and written down in a report. Your 
name will not be included in the report.  
 
We may also ask your parent or caregiver to complete an in-depth interview. This interview would ask them how 
they felt about you having shots of CAB and RPV.  
 
 


 
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13. Adolescents may have an extra visit if their HIV is not controlled. 
 
Participants will have viral load tests at almost all visits to check the amount of HIV in the blood. If tests show 
that the viral load is higher than expected (above 200 copies/mL) you will have repeat testing. This may occur as 
part of another study visit or may occur as an extra study visit.  
 
The extra visit will take about 1-2 hours. At this visit we will: 
• 
Review your medical records. 
• 
Do a physical exam.  
• 
Draw about 16mL (about 3 teaspoons) of blood for tests. The tests will: 
o Check your HIV viral load.  
o Check the amount of CAB and RPV in the blood.  
o We will save some blood for later resistance testing. 
• 
Talk with you about preventing pregnancy. 
• 
For girls, we will also collect urine or blood to check for pregnancy.  
 
If the repeat test also shows an increased amount of HIV in your blood, you will stop taking the study product and 
start taking your previous ARVs again. If you were getting shots of CAB and RPV, you will enter long-term 
safety follow-up (more information in #15 below).   
 
14. If you are not eligible to receive shots of CAB and RPV you will stop the study early.  
 
If you are not eligible to get shots of CAB and RPV in Cohort 2-Phase 2, you will stop taking oral CAB and oral 
RPV and will complete a final study visit about 4 weeks after your last oral dose.  
During this visit, we will:  
• 
Review your medical records.  
• 
Do a physical exam. This will include looking at your genitals to see the stage of development. For girls, this 
will also include looking at the breasts. 
• 
Draw blood for tests. This would be about 15-20mL of blood (about 3-4 teaspoons) for these tests. These tests 
will check:  
o Your blood cells.  
o How well your liver and kidneys are working. 
o Your HIV viral load.  
o Some blood will also be saved for later resistance testing. 
• 
Talk with you about preventing pregnancy.  
• 
For girls, we will also collect urine or blood to check for pregnancy.  
• 
Ask you questions about what it is like to take the oral CAB and oral RPV.  
• 
We will talk with you about your ARV use.  
 
If you also participated in Cohort 1 and received shots of CAB or RPV in Cohort 1-Phase 2, but are not eligible to 
get the shots of CAB and RPV in Cohort 2-Phase 2, you will stop taking oral CAB and oral RPV and will enter 
into Cohort 2-Phase 3 long-term safety follow-up (see #15 below). 
 
15. If you stop the shots of CAB and RPV early or after the Week 96 study visit, you will enter Cohort 2-Phase 3 
(long-term safety follow-up phase). 
 
You will enter Cohort 2-Phase 3 (long-term safety follow-up phase) after the last shot of study product if you: 
• 
Stop the shots of CAB and RPV early, or  
• 
Do not continue to get the shots of CAB and RPV after the final Cohort 2-Phase 2 visit (Week 96)  


 
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For females, if you become pregnant, you will enter this phase of the study after your positive confirmatory 
pregnancy test result, whether you are taking the pill or the shot.  
 
During the long-term safety follow-up phase, you will stop getting shots of CAB and RPV. You will start taking 
your previous ARVs again. There will be 4 visits during the long-term safety follow-up phase.  
 
These visits will be scheduled 8, 24, 36 and 48 weeks after your last shot of CAB and RPV (or after a positive 
confirmatory pregnancy test result). [Sites to modify] Each of these visits will take about 1-3 hours. At these 
visits, we will:  
• 
Review your medical records.  
• 
Talk with you about preventing pregnancy.  
• 
Do a physical exam. At the final long-term safety follow-up visit, this will include examination of your 
genitals to see the stage of development. For girls, this will also include looking at your breasts. 
• 
Draw blood for tests. This would be about 21mL of blood (about 4 teaspoons) for these tests. These tests will 
check:  
o Your blood cells.  
o How well your liver and kidneys are working. 
o Your HIV viral load.  
o The amount of CAB and RPV in the blood.  
o Some blood will also be saved for future resistance testing. 
• 
For girls, we will also collect urine or blood to check for pregnancy.  
• 
At two of these visits (8 weeks and 48 weeks after your last shot of CAB and RPV) we will talk with you 
about your ARV use.  
• 
At two of these visits (8 weeks and 48 weeks after your last shot of CAB and RPV), we will also ask you 
questions about getting shots of CAB and RPV.  
 
16. Different tests will be done at different laboratories. 
 
We will do most of the tests of blood or urine here at our laboratory. We will give you the results of most of these 
tests at the next scheduled visit, or sooner, if necessary. We will explain the results and give you counseling and 
referrals as needed.  
 
We will also draw blood to check the amount of CAB and RPV in your blood. This is called a pharmacokinetic 
(PK) test. The PK test will be done at a laboratory in the United States. We will not usually give you the results of 
this test during the study.  
 
If you need a test for resistance (see #13 above), that test will be done at a laboratory in the United States.  You 
will be given the results of this resistance test and referrals if needed.  
 
17. We may take you off of the study. 
 
We may take you off the study ARVs if: 
• 
You are not able to come to the study visits or we determine that you cannot meet the study requirements. 
• 
You are not able to take the study ARVs. 
• 
The study ARVs are not controlling the HIV in your blood. 
• 
Continuing the study ARVs may be harmful to you. 
• 
You request to stop the study ARVs. 
• 
You are not able to follow the birth control requirements of this study. 
• 
For females, if they become pregnant 


 
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If you stop the oral study ARVs early, we will ask you to come back to the clinic about four weeks after you stop 
the oral study ARVs (see #14 above). You will not have any other visits after this. 
 
If you stop the ARV shots early, we will ask you to come back to the clinic for four additional study visits for 
long-term follow-up (see #15 above). You will not have any other visits after these four visits. 
 
We may also take you off the study early if the study is stopped for any reason.  
 
The study cannot provide other types of ARVs, but we will give you information, counseling, and referrals to 
where you can get care and treatment needed. We will help make sure you can get ARVs from outside of the 
study. If the study stops early, every effort will be made to make certain that there is no interruption in your 
therapy.  
 
18. Please tell us if you want to leave the study. 
 
You are free to leave the study at any time for any reason. The care that you receive at this clinic will not be 
affected, but it is important for us to know about your decision.  
 
If you stop the study ARVs, we may ask you to return to the study clinic for additional study visits described in 
#14 and #15 above. If you stop the study early, we may ask you to return to the study clinic for one final study 
visit, like the last study visit described in #15 above. 
 
We will answer any questions you may have and give you information on how to contact us in the future, if you 
wish. 
 
After the study 
 
19. Receiving the study ARVs after the study is over.  
 
As you come to the end of the study, we will work with you to plan for your care and treatment outside the study. 
It is important that we plan for this in advance, so that there is no gap in your taking ARVs as you finish the 
study. Taking ARVs without interruption is the best known way for you to stay healthy.  
 
We will tell you where you can go to receive needed care and treatment after you finish the study. If you are 
gaining benefit from the injection ARVs given in the study, the companies that are providing these ARVs (ViiV 
Healthcare and Janssen Pharmaceuticals) will try to provide these injection ARVs to you. They will be provided 
until they are otherwise available locally, until you are no longer gaining benefit, or if the company decides to 
stop studying the ARVs. However, there is no guarantee this will be possible. If this is not possible, you will need 
to switch to other oral ARVs that are available locally. We will explain the options to you and help ensure your 
access to ARVs outside the study. We will also contact you again within the first four or eight weeks after you 
finish the study to confirm that you are getting ARVs. 
 
Risks of the study 
 
Taking part in this study may involve some risks and discomfort. The risks are different for each phase of the 
study. Cohort 2-Phase 1 risks include: risks from blood draws, risks from the study pills (CAB and RPV), risks of 
switching ARVs, and risks to your privacy.  
 
Cohort 2-Phase 2 risks include: risks from blood draws, risks from receiving the injection, risks from the study 
pills (CAB and RPV) and the study shots (long-acting CAB and RPV), and risks to your privacy.  
 


 
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Cohort 2-Phase 3 risks include: risks from blood draws, risks of switching ARVs, and risks to your privacy. 
 
20. Risk from blood draws  
 
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted. Rarely, drawing blood 
can cause fainting or infection. 
 
21. Risk from receiving the injection  
 
People in other studies who have received the CAB and RPV shots said they had pain, skin irritation, skin 
redness, bumps, swelling, itching, bruising at the spot where they got the shot. Most reactions go away in a week 
or less but sometimes they can last longer. Most people usually do well with them and rarely need to stop the 
drug.  
 
The shots will be given in the muscles of your buttocks. The injection could be given too deeply or not deeply 
enough, missing the muscle and entering your skin, blood, or a nerve.  
 
The risks of this are not well understood but could make CAB or RPV levels too low or too high. If too low the 
drug may not work against your HIV. If RPV is too high, there could be a change in your heartbeat, which in 
severe cases can be life-threatening. In rare cases, symptoms such as feeling lightheaded, numbness or tingling, 
difficulty breathing, chest or stomach discomfort, sweating, nausea and/or feeling anxious have occurred after an 
injection with RPV LA. In these cases, high blood levels of RPV have been observed, which may be due to an 
accidental injection of part of the medication into a blood vessel instead of the muscle. Not all patients in whom 
an accidental injection in a blood vessel was suspected reported such symptoms. Most of the symptoms resolved 
within minutes. Your doctor may need to administer treatment to help resolve these symptoms. Everything 
possible will be done to decrease this risk, including watching you for problems during the study. If your doctor 
thinks that the injection was not given the right way, you might be asked to stay in the clinic up to [sites to 
modify] 2 hours after the injection to watch how you are doing and extra tests may be needed to be sure you are 
safe. If you are worried about this risk, talk to your doctor. 
 
Receiving injections can cause some people to feel lightheaded or feel like they might pass out. Fainting can also 
occur. This reaction, called a ‘vasovagal reaction’, has been reported with other injectable medicines, and resolves 
quickly. 
 
22. There are risks from the study ARVs 
 
All ARVs can cause side effects. This includes the ARVs you are currently taking and the ARVs that are given in 
the study. Some side effects are minor; others can be severe. Some side effects are common; others are rare. Some 
people who take ARVs have some of the side effects. Other people have different side effects, or no side effects.  
 
The most common and most serious side effects of the study ARVs, CAB and RPV, are listed below. This is 
based on what we know now about CAB and RPV used in adults. There may be other side effects that we do not 
know about now. This may be especially true for adolescents, because this is the first study of CAB and RPV in 
adolescents.  
 
This form does not list all possible side effects of all ARVs. If you join the study, we will tell you more about the 
ARVs you will be taking. At each study visit, we will check on whether the ARVs may be causing side effects. 
We will also tell you what to do if you have side effects. If you have questions or concerns at any time, please tell 
us.  
 


 
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23. Some side effects from the CAB pills and the CAB shot 
 
Many people have received CAB pills or the CAB shot in other studies. The table below lists side effects from 
other studies of CAB with people who have HIV. It is not known if CAB, other drugs or the patient’s other health 
problems caused or affected these. Some of these are the same side effects as RPV (see #24 below).  
 
Common Side Effects of CAB 
Very Common Side Effects of CAB 
Common Side Effects of CAB 
• Headache 
• Fever 
• Injection Site Reactions 
 
• Rash 
• Itching  
• Vomiting (being sick) 
• Nausea (feeling sick) 
• Stomach pain and discomfort  
• Problems sleeping  
• Abnormal dreams/nightmares 
• Anxiety 
• Feeling lightheaded 
• Depression 
• Passing gas or wind 
• Diarrhea 
• Muscle pain 
• Lack of energy 
• Increase in the level of enzymes produced 
in the muscles (creatine phosphokinase) 
• Weight increased 
 
The following effects have also been seen in some of the people who received CAB pills or the CAB shot in other 
studies: 
 
Abnormal liver tests: 
 
A small number of people across all studies (just over 1% of 1644 participants as of April 2017) had abnormal 
liver tests requiring them to stop CAB. Some abnormal liver tests were explained by other health conditions such 
as a new virus infection, like Hepatitis A, B or C. A small number of people did not have health conditions that 
could explain the abnormal test, so it is possible that a mild form of liver damage happened from taking CAB. 
The liver tests got better after stopping CAB, showing that any damage was temporary. 
 
Blood tests to check the health of your liver will be done during the study. Your study doctor will tell you if you 
need to stop taking the study drugs or if other actions are needed. If you stop taking the study drug, you may be 
able to re-start the study drug or you may need to change your usual ARVs.  
 
 


 
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Seizures/convulsions: 
 
Seizures have been seen (rarely) in people with and without HIV who have taken CAB. They are not thought to 
be caused by CAB, but the study staff will ask you about them.  
 
In other studies, two people without HIV had a history of seizures (epilepsy), and had a seizure about 3 months 
and 9 months after starting CAB. One other person with HIV but without a history of seizures, had seizures about 
one year after starting CAB. This participant had a long period of seizures without medical treatment and died. It 
is not known if CAB was part of the reason for seizures in these people. If you have a history of seizures, please 
let your study doctor know. 
 
24. Some side effects from the RPV pills and the RPV shot 
 
Oral RPV (Edurant) is a marketed drug which many people throughout the world have received to manage HIV. 
We know more about the side effects of Edurant than we do about CAB or RPV shots. The following side effects 
have been seen in studies in people with HIV taking RPV.  
 
Common Side Effects of RPV 
Common Side Effects of RPV 
Uncommon Side Effects of RPV 
• 
Problems sleeping, insomnia  
• 
Headache 
• 
Feeling lightheaded (dizziness) 
• 
Rash 
• 
Nausea (feeling sick to the stomach) 
• 
Vomiting 
• 
Abdominal (belly) pain 
• 
Increase in the level of liver enzymes 
• 
Decreased appetite 
• 
Depression 
• 
Abnormal dreams 
• 
Fatigue (tiredness, lack of energy) 
• 
Dry mouth 
• 
Anxiety 
• 
Stomach pain 
 
• 
Sleepiness (somnolence) 
• 
Depressed mood 
• 
Stomach discomfort  
• 
Immune reconstitution syndrome (this can be 
an overreaction of the body’s recovering 
defense system to a previously present 
infection, or problems in the immune system) 
• 
Hepatotoxicity 
• 
Weight increased 
 
The following effects have also been seen in some people who received RPV in other studies: 
 
Abnormal blood tests: 
 
Other changes in blood tests have also been observed. People with Hepatitis B or C or who have possible liver 


 
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damage before starting RPV may have worse liver tests while taking RPV. A few cases of liver problems were 
found in people taking RPV who did not already have any liver problems. 
 
Sometimes allergic reactions can affect body organs, like the liver and cause liver problems which can lead to 
liver failure. Contact your study doctor right away if you have any of the following signs or symptoms of liver 
problems: 
• 
Yellowing of the skin or whites of the eyes 
• 
Dark or tea colored urine 
• 
Pale colored stools/bowel movements 
• 
Nausea/vomiting 
• 
Loss of appetite 
• 
Pain, aching or tenderness on the right side below the ribs 
• 
Itchy skin  
 
Blood tests to check the health of your liver will be done regularly during the study. Your study doctor will tell 
you if you need to stop taking the study drugs or if other action is needed. If you stop taking the study drug, you 
may be able to re-start the study drug or you may need to change your usual ARVs.  
 
Skin Rash: 
Most rashes were mild or moderate, and happened within the first 4 weeks of taking RPV. Most of rashes got 
better after one week, and the people did not need to stop taking RPV. However, the study ARVs will need to be 
stopped for some types of moderate rash and all types of severe rash, which can be life-threatening. If this 
happens to you, you will need to come for extra study visits to monitor your health. Some people with rash may 
also have other signs and symptoms of allergic reaction. 
 
If you have any type of rash or other skin problems during the study you must tell your study doctor right away, 
and the doctor may tell you to stop taking CAB and/or RPV. 
 
25. There may be other possible risks from the study ARVs. 
 
The study ARV shots stay in your body for a long time 
 
The shots you get in this study are long acting, meaning they stay in your body for a long time. In most people the 
drugs will no longer be in the body one year after an injection, while in some people low levels of CAB and RPV 
may still be in the body after one year. If you develop a side effect to the study drug after the shot, there will be no 
way to remove the drug from your body. If you get a shot of CAB or RPV, we will monitor your health for 48 
weeks after your last shot. If you develop a symptom from these drugs while the drugs are still in your body, 
every effort will be made to treat the side effects. The amount of drug will decrease overtime and will eventually 
disappear. 
 
While the amount of study drugs in your body decrease slowly over time after you stop getting shots, the study 
drugs could stop working against your HIV. When stopping long acting HIV drugs, it will be very important to 
start taking other HIV medications, as your study doctor tells you, so your HIV medications do not stop working 
against your HIV. 
 
Risk of switching ARVs 
 
If you join this study, you will stop taking the ARVs you are currently taking, and start taking ARVs given by the 
study. The study ARVs could cause side effects that you would not have from the ARVs you are currently taking. 
The study ARVs also may not work as well as the ARVs you are currently taking. For example, the study ARVs 


 
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may not work as well to control the amount of HIV in your body. We will test your HIV viral load at most study 
visits to check on this. If your viral load is higher than expected, you will have repeat testing, and your use of the 
study ARVs may be stopped (see #13 above).  
 
Risk of resistance 
 
By stopping your previous ARVs and switching to the study ARVs, you could develop resistance. This could 
happen if the study ARVs don’t work as well to control the amount of HIV in your body. Resistance means that 
the ARVs may not work against HIV if these ARVs are taken again in the future. To stop resistance, it is 
important that you take and/or receive the ARVs as instructed, and do not miss any doses. 
 
Mental illness or depression 
 
Some people with HIV sometimes have feelings of depression or may feel sad or hopeless, feel anxious or 
restless, or may have thoughts of hurting or killing themselves (suicide). A small number of people being treated 
with drugs called integrase inhibitors [INIs] for HIV like CAB, have had suicidal thoughts and actions, 
particularly patients with a prior history of depression or mental health illness.  
 
Tell the study doctor if you have a history of mental health illness. If you have thoughts of hurting or killing 
yourself or have any other unusual or uncomfortable thoughts or feelings during this study, you should tell the 
study doctor or go to the nearest hospital right away.  
 
Possible effects on pregnancy or unborn babies 
 
HIV and ARVs may lead to some pregnancy complications, like early delivery or low weight of the baby at birth. 
We do not know if some ARVs are more likely to cause these effects than others. We do not yet know if CAB is 
safe in pregnancy. RPV does not appear to be a risk to pregnancy and the developing baby based on the 
information we know now, but additional data are still being collected. 
 
There are few data from humans on the effects of CAB in pregnancy. Most of the information we have comes 
from animal studies. In studies done in pregnant rats and their newborns, using very high amounts of CAB, there 
were more baby rats that died when they were born or right after they were born. This did not happen to the baby 
rats when the mother got lower amounts of the drug, or no drug. The amount of CAB that we are giving in this 
study is expected to be more than 7-times lower than the amount given to the pregnant rats. Birth defects have not 
been found in any animal studies of CAB so far. We do not know whether what happened to the baby rats has any 
impact on what will happen in pregnant humans taking this drug. 
 
Early results from one large study in Botswana showed that the ARV called dolutegravir (DTG) may increase the 
risk of serious birth defects of the brain or spine in the new baby. The increased risk was seen among babies 
whose mothers were taking DTG when they became pregnant. These birth defects happen during the first few 
weeks of pregnancy, before mothers may know they are pregnant. These birth defects have not been seen among 
babies whose mothers started taking DTG later in pregnancy.  
 
CAB is not the same drug as DTG. We do know that CAB and DTG belong to the same class of medications and 
work in a similar way to treat HIV infection. We do not know if CAB can cause brain or spine defects in babies.  
 
Girls who are able to become pregnant must agree to use certain effective methods of birth control to be in this 
study (see #6 above). If you become pregnant during the study, please let us know right away. 
 


 
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Immune reconstitution syndrome 
 
In some people with advanced HIV infection, signs and symptoms from other infections or certain diseases (for 
example a liver condition called autoimmune hepatitis) may occur soon after starting combination ARVs but can 
also occur later. Some of these symptoms may be life threatening. If you start having new symptoms, or if you 
notice that any existing symptoms are getting worse after starting the ARVs, tell your doctor immediately. 
 
Abnormal placement of body fat and wasting 
 
The use of potent antiretroviral drug combinations may be associated with an abnormal placement of body fat and 
wasting. Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 
• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement 
 
26. There could be risks of disclosure of your information. 
 
We will make every effort to keep your information private and confidential. Study records and specimens will be 
kept in secure, locked locations. All specimens and most records will be labeled only with a code number. 
However, your name will be written on some records.  
 
Despite our best efforts to keep your information private, it is possible that the information could be obtained by 
someone who should not have it. If this were to happen, you could be treated badly or unfairly. You could feel 
stress or embarrassment.  
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality that protects us from being 
forced to release information that may identify you, such as by the courts or police. The certificate cannot be used 
in all situations, but it can be used to resist demands for information that would identify you. The certificate does 
not protect against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your participation in the study to 
others, if you wish. 
 
Information collected for this study may be used for other research in the future. For example, researchers may 
use information from this study to try to answer different questions about children or adolescents with HIV. Any 
future research done with the information from this study must be approved by the IMPAACT Network. If any 
future research is done, information about you may be used but your name will not be shared. 
 
Benefits of the study 
 
27. There may be a direct benefit to you from being in the study. 
 
By joining the study, you will be part of the search for ARVs that may be better for adolescents. We do not know 
if being in the study will benefit you in any way. There may be a direct benefit to you by taking part in this study, 
but no guarantee can be made. For example, if you get shots of CAB and RPV, you might prefer having monthly 
shots instead of taking daily pills. The study ARVs may have fewer side effects than the previous ARVs you were 
taking. There may also be benefit if the results from this study lead to a safe and effective dose of the study drugs 
for adolescents. It is also possible that you may receive no direct benefit from this study. Information learned 
from this study may help other adolescents who have HIV. 
 


 
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You will have regular visits here and frequent checks on your health, including tests for amount of HIV in your 
blood, called viral load. It is possible that the study ARVs will slow your HIV infection. Information learned from 
this study may help other adolescents with HIV. 
 
Other information about the study 
 
28. There are no costs from being in the study. 
 
There are no costs to you for study visits, CAB, RPV or procedures.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits. For each visit, you will be given (specify amount).] 
 
29. Study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include:  
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your name or identify you personally.  
 
A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify you. At most, the website will include a summary of the results. You can 
search this website at any time. 
 
Your study information may be given to other authorities if required by law. [Sites add more specific detail here 
as needed; example follows:] For example, we are required to report any significant risk of harm to you or others.  
 
30. If you get sick or injured, contact us immediately. 
 
Your health is important to us. We will make every effort to protect your well-being and minimize risks. It is 
possible, however, that you could have an illness or injury that is study-related. This means that the illness or 
injury occurred as a direct result of the study procedures.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage available 
through clinical trial insurance obtained by the site should be included if applicable; the statement regarding no 
program for compensation through the NIH may not be removed.]  If a study-related illness or injury occurs, we 
will treat you or tell you where you can get treatment. The cost for this treatment may be charged to you or your 


 
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insurance company. There is no program for compensation either through [site name or] the U.S. National 
Institutes of Health.  
 
Whom to contact 
 
31. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about your rights as research participants or concerns about how you are being treated 
in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 
 
• 
If you have any health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you want to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
 
Signatures 
 
If you agree to participate in this study, please sign or make your mark below. 
Before deciding whether to participate in this study, make sure you have read this form, or had it read to you, and 
that all of your questions have been answered. You should feel that you understand the study, its risks and 
benefits, and what is expected of you if you decide to join.  
 
If you decide to join, we will tell you any new information from this study or other studies that may affect your 
health, welfare, or willingness to stay in the study. You are welcome to ask questions or request more information 
at any time. If you want the results from this study, please tell the study staff. 
 
You do not give up any rights by signing this form. 
 [Insert signature blocks as required by site IRB/EC policies.] 
 
 


 
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Signature blocks for participants of legal age to provide independent informed consent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 


 
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Appendix III-C:  Sample Informed Consent Form for Specimen Storage and Future Use 
for adolescents who can provide independent informed consent for study participation 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 3.0, dated 13 August 2020 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
You have decided to join the study named above. As part of the study, you will have blood and urine collected. 
After these samples are tested for the study, some samples may be left over. We call these extra samples. The 
IMPAACT Network would like to keep these extra samples and use them for other research in the future. 
 
This form gives information about use of extra samples. Please read it, or have it read to you, and ask any 
questions you may have. After we discuss the information with you, you will record your decisions on use of 
extra samples at the end of the form.  
 
1. It is your decision whether or not to allow the extra samples to be used.  
 
You are free to say yes or no, and to change your mind at any time. Your decision will not affect your 
participation in the study. If you say no, all extra samples will be destroyed.  
 
2. If you agree, your extra samples will be kept in a repository.  
 
A repository is a secure facility that is used to store samples. The IMPAACT Network repository is in the United 
States. If you agree to have extra samples stored, the samples will be kept in this repository. There is no limit on 
how long the samples will be kept [sites may insert time limits or additional site-specific requirements here if 
required by local authorities]. 
 
3. Extra samples could be used for different types of research.  
 
Extra samples may be used for research on HIV, the immune system, and other diseases. The research may be 
done in the United States or in other locations.  
 
If you agree, the extra samples could also be used for research that looks at your genes. Genes are passed to 
children from their birth parents. They affect how people look and how their bodies work. Differences in people’s 
genes can help explain why some people get a disease while others do not. Your samples would only be used to 
look at genes related to HIV and the immune system. Testing of all your genes, which is sometimes called whole 
genome sequencing, will not be done.  
 
Any research done with the extra samples must be reviewed and approved by the IMPAACT Network. The 
research must also be approved by an ethics committee. The role of an ethics committee is to review the research 
plan and protect the rights and well-being of the people whose samples will be used.  
 
The research done with extra samples is not expected to give any information relevant to your health. Therefore, 
the results will not be given to the study staff or to you. The results also will not be placed in your study records. 


 
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4. There is little risk to you.  
 
When extra samples are used for research, they are labeled with a code number only. To protect your privacy, no 
names are used. However, information such as age, sex, HIV status, and other health information may be linked to 
the samples. Information on the ARVs you received in the study may also be linked to the samples. The only link 
between the code number and your name is kept here at [site name]. Your name will not be given to other 
researchers. 
 
There may be some risks from tests of your genes. If others found out the results of these tests, they could treat 
you badly or unfairly. However, this is almost impossible because the results will not be given to the study staff, 
or to you, and will not be in your study records. 
 
5. There may be no benefit to you.  
 
By allowing extra samples to be used for research, you will be part of the search for new information that may 
benefit people with HIV in the future. However, the research done with the extra samples is not expected to 
directly benefit you in any way.  
 
6. You will not be paid for use of your samples. 
 
There is no cost to you for use of your extra samples. The samples will not be sold, and you will not be paid for 
use of the samples. It is possible that research done with the samples could lead to a new discovery or a new 
product. If this happens, there is no plan to share any money with you.  
 
7. Information from research using extra samples may be reviewed by groups that oversee the research. 
 
These groups include:   
• 
The IMPAACT Network  
• 
The ethics committees that review and approve the research  
• 
Government and other agencies that pay for the research  
• 
Government and other agencies that monitor the research  
• 
Other local, US, or international regulatory entities  
 
The people who do research with the extra samples and the groups listed above are required to make efforts to 
keep information private and confidential. 
 
The results of research done with the extra samples may be presented publicly or published. However, no 
presentation or publication will use your name or identify you personally.  
 
8. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about use of your extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you later change your mind about use of your extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you have questions about your rights as a research participant or concerns about how you are being treated 
in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization].  


 
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Signatures 
 
Before deciding whether your extra samples to be used for research, make sure you have read this form, or had it 
read to you. Make sure all of your questions have been answered. You should feel that you understand your 
options and the possible risks and benefits before making your decision. 
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies and the IRB/EC determination if the level 
of risk to children in the categories specified in 45 CFR 46.404-407. Separate consent decisions must be 
documented for genetic testing]. 
 
For YOUR extra samples, write your initials or make your mark next to your choice.  
 
__________ 
I allow my extra samples to be used for research on HIV, the immune system, ARVs, and other 
diseases. I also allow my samples to be used for tests of my genes.  
 
__________ 
I allow my extra samples to be used for research on HIV, the immune system, ARVs, and other 
diseases. I do not allow my samples to be used for tests of my genes.  
 
__________ 
I do not allow my extra samples to be used for any research.  
 
 
Signature blocks for participants of legal age to provide independent informed consent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 


 
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Appendix IV: Sample Informed Assent Forms  
 
Appendix IV-A: Sample Informed Assent Form for Participation in Cohort 1 
for adolescents who cannot provide independent informed consent for study participation 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 3.0, dated 13 August 2020 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
Introduction 
 
You are being asked to take part in a research study. To take part in this study, you must give your permission. 
Your parent/guardian must also give their permission.  
 
This form gives information about the study. Please read it, or have it read to you, and ask any questions you may 
have. We will take as much time as you need to understand the study. We will ask you questions to see if we have 
explained the study clearly. 
 
After you understand the study, if you decide to take part, you will sign or make your mark on this form. You will 
be offered a copy to keep.  
 
About the study 
 
This study is for 12 to 17-year-olds who have HIV. The study will test two anti-HIV medicines (antiretrovirals or 
ARVs). The ARVs are called cabotegravir (CAB) and rilpivirine (RPV).  
 
People with HIV take a combination of ARVs to stay healthy. There are not as many ARVs available for children 
and teenagers as for adults, because many ARVs have only been tested in adults. ARVs can be made in different 
forms, such as liquids, pills, and injections (shots). The study will test CAB and RPV pills and shots. The pills are 
taken every day. The shots are given every 4 or 8 weeks. The shots are being developed because it can be difficult 
to take pills every day, and some people may prefer having shots instead of taking pills.  
 
The RPV pills are already approved by the US Food and Drug Administration (FDA) for adults and adolescents 
with HIV. The FDA is the part of the government that regulates medicines in the United States. RPV shots, CAB 
pills, and CAB shots are now being tested in adults with HIV. 
 
There will be two groups in the study, called Cohort 1 and Cohort 2. This form is about Cohort 1.  
 
What happens in the study 
 
If you decide to take part in the study, we will check your medical records and examine you to see if you qualify. 
This will include looking at your genitals to see how developed you are. We will ask you and your 
parent/guardian questions about your health and the medications you take. We will collect blood for tests. We will 
also do a test of your heart called an ECG. 


 
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For girls, we will do a pregnancy test. If you are pregnant, you cannot take part in the study. Girls who are able to 
become pregnant must agree to use certain methods of birth control in order to take part in the study. If you 
become pregnant during the study, you will stop getting CAB or RPV pills or shots and will enter the long-term 
follow-up safety phase of the study. We will also contact you to find out the outcome of the pregnancy, even if the 
outcome occurs after leaving the study. 
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure of 
pregnancy results to parents or guardians: As soon as the pregnancy test result is available, we will go over it 
with you in private, without your parents/guardians present. We will not share these results with your 
parents/guardians unless you tell us it is okay to share the results. If the test shows that you are pregnant, we will 
give you information on where medical care and other services can be received.] 
 
We give you your test results and explain them to you. If you qualify, you can join the study. If you do not join 
the study, we will still use some information collected about you (for example age, sex, and race). We will use 
this information to look at patterns or common reasons for not entering the study. 
 
First phase of the study 
 
The study has three phases. If you join, you will start in the first phase. You will be given CAB or RPV pills to 
take in addition to the other ARVs you are already taking. The RPV pills should be taken with a meal. It is 
important to keep taking all your ARVs as instructed.  
 
You will have 3 study visits over 4-6 weeks (about one month). At these visits, we will: 
 
• 
Collect information from your medical records. 
• 
Ask questions about your health, ARVs, and other medications. 
• 
Give you a physical exam. 
• 
Collect blood for tests. This will be done using a needle in your arm. 
• 
For girls, collect blood or urine for a pregnancy test.  
• 
At the first visit, we may do an ECG test to look at your heart. 
 
Each visit will take about 1-3 hours.  
 
At the second visit, we will look very closely at the amount of CAB or RPV in your blood. To do this, we will 
collect your blood different times over 8 hours (one full day). If you are taking CAB, we will collect your blood 6 
times. If you are taking RPV, we will collect your blood 3 times. [Sites: modify language as appropriate to 
indicate procedures for the intensive PK collection: A small tube will be placed in your arm and attached to a 
plastic needle to draw your blood, so we do not need to stick you with a needle each time. The plastic tube may 
stay in place for 8 hours. You may need to stay at the clinic or hospital for up to 8 hours. If the study clinic is able, 
you may be able to stay at the clinic the night before and during this visit.] 
 
Second phase of the study 
 
At the fourth study visit, we will review all your test results to see if you qualify for the second phase of the study. 
This visit could be combined with your third visit. 
 
• 
If you do not qualify, you will stop taking CAB or RPV pills. You will have one more visit about 4 weeks 
later. This visit will be like the other visits described above. 
• 
If you qualify, you can enter the second phase of the study 
 


 
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In the second phase of the study you will have 5 more study visits over 12 weeks (about 3 months). At these 
visits, we will:  
• 
Collect information from your medical records. 
• 
Ask questions about your health, ARVs, and other medications. 
• 
Give you a physical exam. At the last visit, we will also look at your genitals again to see how developed you 
are.  
• 
Collect blood for tests. This will be done using a needle in your arm.  
• 
For girls, collect blood or urine for a pregnancy test.  
• 
At two of these visits, we may do an ECG test to look at your heart. 
 
Each visit will take about 1-3 hours. 
 
During the second phase of the study, you will not take CAB or RPV pills. Instead, you will be given shots of 
CAB or RPV. The shots will be given 2 times (4 weeks apart). You will get one shot in the buttocks (bottom, 
“cheeks”) each time. You will keep taking your other ARVs while getting the shots.  
 
[U.S. sites only] You may also be contacted to answer questions over the phone about how you feel about the 
shots.  
 
After 12 weeks, we will review your tests to see if you are eligible for Cohort 2.  
• 
If you do not qualify, or if Cohort 2 isn’t ready yet, you will stop getting shots of CAB or RPV. You will 
enter into the third phase, which is also called the long-term safety follow-up phase of the study. This is 
described below. 
• 
If you qualify, and when Cohort 2 is ready, you can enter Cohort 2. 
 
[Sites to modify] Some visit activities may be offered off-site or by phone. This might only happen if you are 
unable to come the clinic. The study staff will discuss this with you if it is an option.  They will also discuss the 
location and time to visit you so that the visit is at a time and place when you feel comfortable and confidentiality 
can be maintained. 
 
Long-term safety follow-up phase of the study 
 
You will have 3 or 4 study visits over 48 weeks (about 1 year). The visits will be like the visits described above.  
 
You will not be given CAB or RPV pills or shots. You will keep taking your other ARVs.  
 
Risks of the study 
 
Having blood collected may cause pain, bleeding, bruising, swelling, or infection where the needle goes in your 
arm.  
 
Having shots of CAB or RPV may cause pain, irritation, redness, bumps, swelling, itching, or bruising on the 
buttocks (where the shot is given). When CAB and RPV are given as shots, they stay in the body for much longer 
than when CAB and RPV are taken as pills.  
 
The shots will be given in the muscles of your buttocks. The shot could be given too deeply or not deeply enough, 
missing the muscle and entering your skin, blood, or a nerve. The side effects of shot missing the muscle are not 
well understood but could make CAB or RPV levels too low or too high. If too low the drug may not work against 
your HIV. If RPV is too high, there could be a change in your heartbeat, which in severe cases can be life-
threatening. In rare cases, symptoms such as feeling lightheaded, numbness or tingling, difficulty breathing, chest 


 
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or stomach discomfort, sweating, nausea and/or feeling anxious have occurred after RPV shot. Not all patients 
reported such symptoms. Most of the symptoms resolved within minutes. Your doctor may need to administer 
treatment to help resolve these symptoms.  Everything possible will be done to decrease this risk, including 
watching you for problems during the study. 
 
CAB and RPV can cause other side effects. These side effects are common, but not everyone will have them. You 
may have pain, feel sick to your stomach, or vomit (throw up). You may have diarrhea. You may have a 
headache, fever, runny nose, sore throat, dry mouth, or rash. You may have trouble sleeping or a lack of energy. 
You may not want to eat as much as you usually do. You may feel lightheaded or sad. You may have problems in 
other parts of the body, such as your liver.  
 
We do not yet know if CAB or RPV are safe in pregnancy. Early results from one study showed that the ARV 
called dolutegravir (DTG) may increase the risk of serious birth defects in the new baby. These mothers were 
taking the drug before they knew they were pregnant. The birth defects have not been seen when mothers started 
taking DTG later in pregnancy. CAB is not the same drug as DTG. We do not know if CAB can cause the same 
defects in babies. 
 
Girls who are able to become pregnant must agree to use certain methods of birth control to be in this study. If 
you become pregnant during the study, please let us know right away. 
 
We will check for side effects at each study visit. Please tell us if you have any side effects or don’t feel well. We 
will also check the amount of HIV in your blood. If you have side effects, or if the amount of HIV in your blood 
is higher than expected, you may have extra visits. We will talk with you and your parent/guardian about this, and 
tell you what to do about any side effects. We will also tell you if you can keep taking CAB or RPV. In some 
cases, you may have to stop taking CAB or RPV.  
 
All information collected for this study will be kept private and confidential. However, it is possible that 
information could be obtained by someone who should not have it. If this were to happen, you could be treated 
badly or unfairly. You could feel stressed or embarrassed. 
 
Other information about the study 
 
Study records may be reviewed by study staff and groups that oversee the study. Groups that oversee the study 
include:  
 
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your name or identify you personally.  


 
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A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify you. At most, the website will include a summary of the results. You can 
search this website at any time. 
 
[Sites may modify this paragraph to reflect local reporting requirements and legal statues: Your study 
information may be shared with other authorities if required by law. Public health authorities are required by law 
to receive information for the prevention or control of disease, injury or disability. (We must follow laws 
requiring the reporting of suspected child abuse and neglect).]   
 
Benefits of the study 
 
By joining the study, you will be part of the search for new ARVs for adolescents. The information learned in this 
study could someday lead to better ARVs for adolescents. However, being in this study may not be of any benefit 
to you. 
 
Your rights  
 
Taking part in this study is voluntary. You can say yes or no. If you say yes now, you can change your mind later. 
Your decision will have no effect on the medical care you normally receive. 
 
Who to contact 
 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
If you have questions about your rights or how you are treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 
 
If you have problems related to being in the study:  
[insert name and telephone number of investigator or other study staff] 
 
If you want to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
 


 
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Signatures 
 
If you want to take part in this study, sign or make your mark below. 
 
Before deciding whether to take part in this study, make sure you have read this form, or had it read to you. Make 
sure all your questions have been answered. You should feel that you understand the study, its risks and benefits, 
and what is expected of you if you decide to take part.  
 
We will tell you and your parent/guardian any new information that may affect your willingness to stay in the 
study. You can ask questions or ask for more information at any time.  
 
You do not give up any rights by signing this form. 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Participant (print) 
 
Signature of Participant   
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Assent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
(as appropriate; print) 
 
 


 
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Appendix IV-B:  Sample Informed Assent Form for Participation in Cohort 2 
for adolescents who cannot provide independent informed consent for study participation 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 3.0, dated 13 August 2020 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
Introduction 
 
You are being asked to take part in a research study. To take part in this study, you must give your permission. 
Your parent/guardian must also give their permission.  
 
This form gives information about the study. Please read it, or have it read to you, and ask any questions you may 
have. We will take as much time as you need to understand the study. We will ask you questions to see if we have 
explained the study clearly. 
 
After you understand the study, if you decide to take part, you will sign or make your mark on this form. You will 
be offered a copy to keep.  
 
About the study 
 
This study is for 12 to 17-year-olds who have HIV. The study will test two anti-HIV medicines (antiretrovirals or 
ARVs). The ARVs are called cabotegravir (CAB) and rilpivirine (RPV).  
 
People with HIV take a combination of ARVs to stay healthy. There are not as many ARVs available for children 
and teenagers as for adults, because many ARVs have only been tested in adults. ARVs can be made in different 
forms, such as liquids, pills, and injections (shots). The study will test CAB and RPV pills and shots. The pills are 
taken every day. The shots are given every 4 or 8 weeks. The shots are being developed because it can be difficult 
to take pills every day, and some people may prefer having shots instead of taking pills.  
 
The RPV pills are already approved by the US Food and Drug Administration (FDA) for adults and adolescents 
with HIV. The FDA is the part of the government that regulates medicines in the United States. RPV shots, CAB 
pills, and CAB shots are now being tested in adults with HIV. 
 
There will be two groups in the study, called Cohort 1 and Cohort 2. This form is about Cohort 2.  
 
What happens in the study 
 
If you decide to take part in the study, we will check your medical records and examine you to see if you qualify. 
This will include looking at your genitals to see how developed you are. We will ask you and your 
parent/guardian questions about your health and the medications you take. We will collect blood for tests. We will 
also do a test of your heart called an ECG. 
 


 
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For girls, we will do a pregnancy test. If you are pregnant, you cannot take part in the study. Girls who are able to 
become pregnant must agree to use certain methods of birth control in order to take part in the study. If you 
become pregnant during the study, you will stop getting CAB and RPV pills or shots and will enter the long-term 
follow-up safety phase of the study. We will also contact you to find out the outcome of the pregnancy, even if the 
outcome occurs after leaving the study. 
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure of 
pregnancy results to parents or guardians: As soon as the pregnancy test result is available, we will go over it 
with you in private, without your parents/guardians present. We will not share these results with your 
parents/guardians unless you tell us it is okay to share the results. If the test shows that you are pregnant, we will 
give you information on where medical care and other services can be received.] 
 
We give you your test results and explain them to you. If you qualify, you can join the study. If you do not join 
the study, we will still use some information collected about you (for example age, sex, and race). We will use 
this information to look at patterns or common reasons for not entering the study. 
 
First phase of the study 
 
The study has three phases. If you join, you will start in the first phase. You will be given CAB and RPV pills to 
start taking. The pills should be taken with a meal. You will stop taking the other ARVs you were taking before.  
 
You will have 3 study visits over 4-6 weeks (about one month). At these visits, we will: 
 
• 
Collect information from your medical records. 
• 
Ask questions about your health, ARVs, and other medications. 
• 
Give you a physical exam. 
• 
Collect blood for tests. This will be done using a needle in your arm. 
• 
For girls, collect blood or urine for a pregnancy test.  
• 
At the first visit, we may also do an ECG test of your heart. 
 
Each visit will take about 1-3 hours.  
 
At the second visit, we will look at the amount of CAB and RPV in your blood. To do this, we will collect your 
blood once before you take CAB and RPV and again about 3 hours after you have taken CAB and RPV. [Sites: 
modify language as appropriate to indicate procedures for the intensive PK collection: A small tube will be 
placed in your arm and attached to a plastic needle to draw your blood, so we do not need to stick you with a 
needle each time. The plastic tube may stay in place for 3 hours.] 
 
Second phase of the study 
 
At the fourth study visit, we will review all your test results to see if you qualify for the second phase of the study. 
This visit could be combined with your third visit. 
 
• 
If you do not qualify, you will stop taking CAB or RPV pills. You will have one more visit about 4 weeks 
later. This visit will be like the other visits described above. 
• 
If you qualify, you can enter the second phase of the study 
 
In the second phase of the study, you will have 14 more study visits over about 2 years. The visits will be like the 
visits described above. At two of these visits, we will also look at your genitals again to see how developed you 
are. 


 
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During the second phase of the study, you will not take CAB and RPV pills. Instead, you will be given shots of 
CAB and RPV. The shots will be given at 13 of the study visits (4 weeks and then 8 weeks apart). You will get 
one shot of CAB and one shot of RPV each time. The shots will be in the buttocks (bottom, “cheeks”). The shots 
may be given on the same side of the buttocks or on different sides. 
 
[U.S. sites only] You may also be contacted to answer questions over the phone about how you feel about the 
shots.  
 
After you finish the study visits in Cohort 2, you might be able to keep getting shots of CAB and RPV. If you do 
not keep getting shots of CAB and RPV, or if you stop the shots early, you will enter the third phase, which is 
also called the long-term safety follow-up phase of the study. This phase is described below. 
 
[Sites to modify] Some visit activities may be offered off-site or by phone. This might only happen if you are 
unable to come the clinic. The study staff will discuss this with you if it is an option.  They will also discuss the 
location and time to visit you so that the visit is at a time and place when you feel comfortable and confidentiality 
can be maintained. 
 
If you cannot come to the clinic for a visit when you need the study shots, then you might have the option to take 
the study pills again.  You would take the study pills until you are able to come back to the clinic to get the study 
shot.  If this happens, then you may need to get the study shots 4 weeks apart and then 8 weeks apart. If you 
cannot return to the clinic to get the study shots soon, then you may need to stop taking the study ARVs and enter 
the long-term safety follow-up phase. This is not preferred, and it is important to get the study shots on the 
scheduled day and not miss any visits. 
 
Long-term safety follow-up phase of the study 
 
You will have 4 study visits over 48 weeks (about 1 year). The visits will be like the visits described above.  
 
You will not be given CAB and RPV pills or shots. You will go back to taking your other ARVs.  
 
Risks of the study 
 
Having blood collected may cause pain, bleeding, bruising, swelling, or infection where the needle goes in your 
arm.  
 
Having shots of CAB or RPV may cause pain, irritation, redness, bumps, swelling, itching, or bruising on the 
buttocks (where the shot is given). When CAB and RPV are given as shots, they stay in the body for much longer 
than when CAB and RPV are taken as pills.  
 
The shots will be given in the muscles of your buttocks. The shot could be given too deeply or not deeply enough, 
missing the muscle and entering your skin, blood, or a nerve. The side effects of shot missing the muscle are not 
well understood but could make CAB or RPV levels too low or too high. If too low the drug may not work against 
your HIV. If RPV is too high, there could be a change in your heartbeat, which in severe cases can be life-
threatening. In rare cases, symptoms such as feeling lightheaded, numbness or tingling, difficulty breathing, chest 
or stomach discomfort, sweating, nausea and/or feeling anxious have occurred after RPV shot. Not all patients 
reported such symptoms. Most of the symptoms resolved within minutes. Your doctor may need to administer 
treatment to help resolve these symptoms.  Everything possible will be done to decrease this risk, including 
watching you for problems during the study. 
 
CAB and RPV can cause other side effects. These side effects are common, but not everyone will have them. You 
may have pain, feel sick to your stomach, or vomit (throw up). You may have diarrhea. You may have a 


 
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headache, fever, runny nose, sore throat, dry mouth, or rash. You may have trouble sleeping or a lack of energy. 
You may not want to eat as much as you usually do. You may feel lightheaded or sad. You may have problems in 
other parts of the body, such as your liver.  
 
We do not yet know if CAB or RPV are safe in pregnancy. Early results from one study showed that the ARV 
called dolutegravir (DTG) may increase the risk of serious birth defects in the new baby. These mothers were 
taking the drug before they knew they were pregnant. The birth defects have not been seen when mothers started 
taking DTG later in pregnancy. CAB is not the same drug as DTG. We do not know if CAB can cause the same 
defects in babies.  
 
Girls who are able to become pregnant must agree to use certain methods of birth control to be in this study. If 
you become pregnant during the study, please let us know right away. 
  
We will check for side effects at each study visit. Please tell us if you have any side effects or don’t feel well. 
There is also a risk that the CAB and RPV pills and shots won’t control the HIV as well as the ARVs you were 
taking before. We will check the amount of HIV in your blood at each study visit. If you have side effects, or if 
the amount of HIV in your blood is higher than expected, you may have extra visits. We will talk with you and 
your parent/guardian about this, and tell you what to do about any side effects. We will also tell you if you can 
keep taking CAB and RPV. In some cases, you may have to stop taking CAB and RPV.  
 
All information collected for this study will be kept private and confidential. However, it is possible that 
information could be obtained by someone who should not have it. If this were to happen, you could be treated 
badly or unfairly. You could feel stressed or embarrassed. 
 
Other information about the study 
 
Study records may be reviewed by study staff and groups that oversee the study. Groups that oversee the study 
include:  
 
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your name or identify you personally.  
 
A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify you. At most, the website will include a summary of the results. You can 
search this website at any time. 
 


 
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[Sites may modify this paragraph to reflect local reporting requirements and legal statues: Your study 
information may be shared with other authorities if required by law. Public health authorities are required by law 
to receive information for the prevention or control of disease, injury or disability. (We must follow laws 
requiring the reporting of suspected child abuse and neglect).]   
 
Benefits of the study 
 
By joining the study, you will be part of the search for new ARVs for adolescents. The information learned in this 
study could someday lead to better ARVs for adolescents. However, being in this study may not be of any benefit 
to you. 
 
Your rights  
 
Taking part in this study is voluntary. You can say yes or no. If you say yes now, you can change your mind later. 
Your decision will have no effect on the medical care you normally receive. 
 
Who to contact 
 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
If you have questions about your rights or how you are treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 
 
If you have problems related to being in the study:  
[insert name and telephone number of investigator or other study staff] 
 
If you want to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
 
 


 
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Signatures 
 
If you want to take part in this study, sign or make your mark below. 
 
Before deciding whether to take part in this study, make sure you have read this form, or had it read to you. Make 
sure all your questions have been answered. You should feel that you understand the study, its risks and benefits, 
and what is expected of you if you decide to take part.  
 
We will tell you and your parent/guardian any new information that may affect your willingness to stay in the 
study. You can ask questions or ask for more information at any time.  
 
You do not give up any rights by signing this form. 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Participant (print) 
 
Signature of Participant   
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Assent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
(as appropriate; print) 
 
 
 


 
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Appendix IV-C: Sample Assent Form for Specimen Storage and Future Use for Participants 
who cannot provide independent informed consent 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 3.0, dated 13 August 2020 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
Introduction 
 
As part of the study, you will have blood and urine collected. After these samples are tested for the study, some 
samples may be left over. We call these extra samples. The IMPAACT Network would like to keep these extra 
samples and use them for other research in the future. 
 
You are being asked for permission to keep your extra samples and use them for other research in the future. Your 
parent/guardian will also be asked for permission.  
 
This form gives information about extra samples. Please read it, or have it read to you, and ask any questions you 
may have. After we talk about the information with you, you will record your decisions at the end of the form. 
 
What happens with extra samples 
 
If you allow your extra samples to be kept, there is no limit on how long they will be kept.  
 
The samples may be used for research on HIV, the immune system, and other diseases.  
 
If you agree, the samples could be used for research that looks at your genes. Genes are passed to children from 
their birth parents. They affect how people look and how their bodies work. Differences in people’s genes can 
help explain why some people get a disease while others do not. Your samples would only be used to look at 
genes related to HIV and the immune system. All your genes will not be tested. 
 
The results of tests done with your samples will not be given to you or your parent/guardian. 
 
Risks and benefits 
 
When extra samples are kept for research, they are labeled with a code number only. No names are used. 
Therefore, there is very little risk to your privacy. Your name will not be given to other researchers. 
 
By allowing extra samples to be used for research, you will be part of the search for new information that may 
benefit people with HIV in the future. However, the research done with extra samples is not expected to be of 
benefit to you. 
 
Information from research using extra samples may be reviewed by groups that oversee the research 
 
These groups include:   


 
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• 
The IMPAACT Network  
• 
The ethics committees that review and approve the research  
• 
Government and other agencies that pay for the research  
• 
Government and other agencies that monitor the research  
• 
Other local, US, or international regulatory entities  
 
The people who do research with the extra samples and the groups listed above are required to make efforts to 
keep information private and confidential. 
 
The results of research done with the extra samples may be presented publicly or published. However, no 
presentation or publication will use your name or identify you personally.  
 
Your rights  
 
It is up to you and your parent/guardian to decide if your extra samples can be used for research. You can say yes 
or no. If you say yes now, you can change your mind later. Your decision will have no effect on your participation 
in the study. If you say no, all extra samples will be destroyed. 
 
Who to contact 
 
If you have questions about use of your extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
If you change your mind about use of your extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
If you have questions about your rights or how you are treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 
 
Signatures 
 
Before deciding whether to allow your extra samples to be used for research, make sure you have read this form, 
or had it read to you. Make sure all your questions have been answered. You should feel that you understand your 
choices and the possible risks and benefits before making your decision. 
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies. Separate consent decisions must be 
documented for genetic testing]. 
 
Please write your initials or make your mark next to your choices:  
 
 
__________ 
I allow my extra samples to be used for research on HIV, the immune system, and other diseases.  
 
__________ 
I allow my extra samples to be used for tests of my genes.  
 
 
__________ 
I do not allow my extra samples to be used for any research.  
 


 
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Name of Participant (print) 
 
Signature of Participant   
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Assent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
(as appropriate; print) 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix V: Parent/Caregiver Participation in Qualitative Phone Interviews  
(U.S. Sites Only) 
 
Appendix V-A: Parent/Caregiver Qualitative Phone Interviews 
 
Parents or caregivers of adolescent participants enrolled at U.S. study sites will be selected by the 
protocol interview team for enrollment into the study to conduct a single in-depth qualitative phone 
interview, with the purpose of evaluating their perceptions of adolescent acceptability and tolerability of 
CAB LA and/or RPV LA. The phone interviews with parents/caregivers will be conducted separately and 
apart from any phone interviews conducted with adolescent participants. 
 
The protocol interview team will notify sites to initiate recruitment of the selected parent/caregiver. After 
obtaining consent, sites will confirm eligibility for the parent/caregiver to take part in the interview. 
Parents/caregivers meeting eligibility criteria will be enrolled as study participants, and site staff will 
work with the protocol interview team and the enrolled parent/caregiver to schedule and conduct the 
phone interview. Further details relating to these processes and procedures are provided below. 
 
Protocol Section 11 provides information and details regarding the qualitative phone interviews with the 
adolescent participants. 
 
1 
Sample Size, and Selection Process 
 
Enrolled adolescent participants at U.S. study sites will be selected by the protocol interview team for 
their parent/caregiver to be recruited by site staff to take part in a single in-depth qualitative interview for 
a maximum of 60 completed phone interviews: 30 phone interviews completed by parents/caregivers of 
Cohort 1 adolescent participants, and 30 phone interviews completed by parents/caregivers of Cohort 2 
adolescent participants. The sample size is based on the likely number of interviews needed to achieve 
thematic saturation. Parent/caregiver selection for the interviews will continue until there is either 
saturation of themes among the parent/caregiver interview data, or the parent/caregiver maximum sample 
size is reached. See Protocol Section 11.6 regarding thematic saturation and qualitative interview data 
analyses. 
 
Parent/caregiver selection is based on the adolescent participant’s reported demographics from the 
adolescent’s Screening and Entry visits, with the goal of balancing interviewed parents/caregivers across 
female/male and older/younger adolescent participants. Additionally, parents/caregivers of participants 
who permanently discontinue injectable study product will be purposefully selected. This will ensure that 
perspectives from parents/caregivers across the range of enrolled participants are reflected in the final 
analysis. Parents/caregivers will be selected across multiple sites, but restricted to those willing and able 
to conduct the interview in English. 
 
When possible, parents/caregivers of adolescents also participating in interviews will be selected to allow 
for dyadic comparisons between the parents’/caregivers’ and adolescents’ perspectives. However, a 
parent/caregiver of an adolescent participant may be selected to take part in the qualitative phone 
interview even if their adolescent participant is not selected or does not complete a (separate) qualitative 
phone interview. 
 
The interviews must be completed within the applicable specified interview window (see Appendix V-A 
Section 2 below). Parents/caregivers will be selected on an on-going basis, and as their adolescent 
participant approaches the parent/caregiver interview procedural window. Parents/caregivers of 


 
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adolescent participants enrolling to the study early will be selected for interviews first, as their adolescent 
participant will be the first to receive the injectable study products. The selection process will continue 
until thematic saturation or the sample size is reached for each Cohort; therefore, some parents/caregivers 
may be selected after entering the interview procedure window. Parents/caregivers who complete an 
interview for Cohort 1 will not be eligible to complete an interview for Cohort 2.  
 
2 
Phone Interview Procedural Windows 
 
The qualitative phone interviews will be conducted with selected parents/caregivers of adolescent 
participants within the following timeframes:  
• 
Parents/caregivers of Cohort 1 adolescent participants: Between the adolescent participant’s 
Week 4b and Week 12 visits (inclusive), or during LSFU visits.  
 
• 
Parents/caregivers of Cohort 2 adolescent participants: Between the adolescent participant’s 
Week 24 and Week 96 visits (inclusive), or during LSFU visits.  
 
3 
Recruitment Considerations 
 
The protocol interview team will notify sites of an adolescent participant’s PID to then initiate the 
recruitment of the adolescent participant’s parent/caregiver. Recruitment of the parent/caregiver will 
generally rely on the enrolled adolescent participant identifying the potentially eligible parent/caregiver 
and referring him/her to site staff for the qualitative interview; site staff may also identify a potentially 
eligible parent/caregiver (of the selected adolescent participant) as they present to the study clinic.  
 
Sites must source document notification by the protocol interview team of adolescent participant selection 
for parent/caregiver recruitment, all attempts to contact the adolescent participant for parent/caregiver 
recruitment. Sites must follow their IRB/EC approved recruitment methods for approaching a potential 
parent/caregiver participant. Further guidance on recruitment considerations and processes is provided in 
the IMPAACT 2017 MOP. 
 
Eligibility criteria for parents/caregivers are provided in Protocol Section 4.5, and details regarding 
confirmation of eligibility criteria and the enrollment process are provided in Appendix V-A Section 5.    
 
4 
Consenting Considerations 
 
Parents/caregivers must provide consent prior to enrollment and conducting the phone interview. After 
recruitment of a selected and potentially eligible parent/caregiver, study staff will provide information, 
education, and counseling as part of the study informed consent process for the qualitative phone 
interview. The consent process will include information exchange, discussion, and assessment of 
understanding of all required elements of informed consent, including the potential risks, benefits, and 
alternatives to study participation. Study staff will also provide time to address any questions or concerns 
the parent/caregiver may have, and an assessment of understanding, before proceeding to a consenting 
decision.  
 
Obtaining informed consent from the parent/caregiver for the phone interview is ideally conducted in 
person and in writing by the parent/caregiver signing the informed consent form. Appendix V-B provides 
a sample written informed consent form for parent/caregiver study participation in the qualitative phone 
interview which sites may modify for use. If the parent/caregiver is unable to read, the process for 
consenting illiterate participants, as defined or approved by the local IRB/EC, should be followed. 
 


 
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Sites have the option of seeking a waiver from their IRB/EC of the requirement to obtain written 
documentation of the consent process for parent/caregiver participation in the qualitative phone interview. 
Consistent with DAIDS policies on the requirements for obtaining informed consent 
(https://ohsr.od.nih.gov/public/SOP_12_v5_5-22-2017.pdf), when the IRB/EC considers waiving the 
requirement to obtain written documentation of the consent process, the IRB/EC reviews a written 
description of the information that will be provided, either verbally or in writing, to the 
parents/caregivers. Appendix V-C provides a sample of a script or statement which sites may modify for 
use, should an IRB/EC grant a waiver of written documentation.  
 
Additionally, sites also have the option of seeking IRB/EC approval for obtaining parent/caregiver 
consent by telephone, rather than in person. In such instances, a witness to the consent process (e.g., 
another study or non-study staff member) must be present at the time of the study site staff obtaining 
consent from the parent/caregiver, and should ideally also listen in to the consenting discussion between 
the parent/caregiver and study staff member. Appendix V-C may be modified for use as a verbal script to 
obtain consent by telephone. If telephone consent is used and the parent/caregiver is seen at the site prior 
to conducting the phone interview, it is recommended to re-confirm the parent/caregiver’s understanding 
of the phone interview and willingness to participate through an additional, brief consent process, as 
required by the IRB. 
 
Study sites are permitted to develop a separate parent/caregiver consent form and/or script for this study, 
if required by site or IRB/EC policies and procedures. Sites must establish and maintain an informed 
consent SOP with written procedures describing standards for obtaining informed consent, and roles and 
responsibilities of study staff involved in obtaining informed consent for all the consenting options being 
utilized for the parents/caregivers (i.e., written signed consent, waiver of written consent, and/or verbal 
consent by telephone), reflective of applicable IRB/EC guidance. For sites seeking IRB/EC approval for 
obtaining consent by telephone, the site’s informed consent SOP should include procedures for 
subsequently obtaining a written signed consent form from the parent/caregiver (unless the IRB waives 
written consent), and how a copy of the consent form (or script) will be provided to the parent/caregiver.  
 
Regardless of a waiver of written consent, all the informed consent processes will be fully source 
documented, consistent with the DAIDS policies referenced in Protocol Section 12.2.  
 
5 
Eligibility Confirmation and Enrollment Process 
 
Eligibility criteria for parents/caregivers are provided in Protocol Section 4.5. Inclusion criteria include 
confirmation from both the parent/caregiver as well as the adolescent participant that the identified 
parent/caregiver has knowledge of how the adolescent participant tolerated the study product, and lives 
with or has regular supportive contact with the adolescent participant. As these inclusion criteria require 
reporting from separate individuals, parent/caregiver eligibility may be assessed at multiple timepoints 
after obtaining consent and prior to enrollment and may be assessed in-person at the study clinic or by 
telephone. It is generally expected that site staff will ascertain adolescent participant report of 
parent/caregiver eligibility during the adolescent’s study visit. Eligibility criteria must be confirmed, and 
source documented after obtaining informed consent.  
 
Eligibility determination for parents/caregivers must also be included in site SOPs, which describe how 
(whether in-person or over the phone), where and when recruitment and confirmation of eligibility criteria 
will be performed; roles and responsibilities for assessing (whether in-person or over the phone) and 
confirming eligibility; and procedures for documenting the process.  
 
The DMC system will not be used for tracking parent/caregiver screening process. However, sites will 
source document reasons for any consenting parent/caregiver found to be ineligible. For 


 
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parents/caregivers found to be eligible, enrollment into the study will occur upon successful entry of 
required eligibility data into the IMPAACT Data Management Center (DMC) Subject Enrollment System 
(SES). Successful entry into the SES will generate a study identification number (SID).  
 
The IMPAACT 2017 MOP provides further guidance on operational and logistical considerations of 
assessing and confirming eligibility, and enrolling the parent/caregiver to the study prior to the phone 
interview being conducted. 
 
6 
Scheduling and Conducting Phone Interviews 
 
Site staff will work with the protocol interview team and the parent/caregiver to schedule the phone 
interview at a time that is convenient for the parent/caregiver and within the applicable interview 
procedural window. Scheduling of the interview may occur at any point with the intention to minimize 
the number of scheduled but uncompleted interviews. Parents/caregivers must be consented, confirmed as 
eligible, and enrolled prior to conducting the phone interview. 
 
Once the phone interview is scheduled, site staff will provide the parent/caregiver with detailed 
instructions and guidance on accessing the phone interview platform. Phone interviews may be completed 
either in the study clinic during their adolescent participant’s scheduled study visit, or from a phone 
outside the study clinic. All phone interviews will be conducted by a protocol interview team member 
external to participating clinical research sites, following an interview guide, and will be audio recorded 
and transcribed.  
 
After obtaining consent, sites must source document all attempts to contact the parent/caregiver and 
interview scheduling attempts, and enter into eCRFs demographics and the date the phone interview 
occurred. Operational and logistical details regarding communication with the protocol interview team 
members and site staff are provided in the IMPAACT 2017 MOP. 
 
7 
Human Subjects Protections 
 
Protocol Section 14.1 provides information regarding IRB/EC review and approval requirements in 
relation to the IMPAACT 2017 study. Informed consent considerations are provided in Appendix V-A 
Section 4 above. 
 
There may be no direct benefit to parents/caregivers who take part in the qualitative phone interviews. 
Information learned in this study may be of benefit to adolescent participants and others in the future, 
particularly information that may lead to more treatment options for HIV-infected children and 
adolescents. Parents/caregivers may also appreciate the opportunity for themselves to contribute to HIV-
related research. 
 
Despite all efforts to maintain confidentiality, involvement in the qualitative phone interview could 
become known to others, possibly leading to unfair treatment, discrimination, or other social impacts 
(e.g., because adolescent participants could become known as having HIV). For example, adolescent 
participants could be treated unfairly or discriminated against or could have problems being accepted by 
their families and/or communities.  
 
Pending IRB/EC approval, parents/caregivers may be reimbursed for their time and any costs associated 
with completing the qualitative phone interview. Reimbursement amounts will be specified in the site-
specific consent, verbal script, or other materials if applicable per IRC/EC policies and procedures.  
 


 
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All study procedures will be conducted in private and every effort will be made to protect 
parent/caregiver privacy and confidentiality to the extent possible. Parent/caregiver information will not 
be released without written permission to do so except as necessary for review, monitoring, and/or 
auditing as described in Protocol Section 13. Refer to Protocol Section 14.7 for further information on 
privacy and confidentiality. 
 
8 
Disclosure of Harm 
 
As described above, the purpose of conducting in-depth qualitative phone interviews with 
parents/caregivers is to evaluate their perceptions of adolescent acceptability and tolerability of CAB LA 
and/or RPV LA. Conducting the interviews is not expected to increase the likelihood or risk of self-harm 
or harm to others.    
 
During the consent process, parents/caregivers will be informed that the information they provide in the 
interview will be kept confidential, with the exception of disclosures of significant risk for harm, 
including suicidality, or at risk of committing harm toward others, including abuse, violence or 
homicidality. 
 
If at any time during a qualitative phone interview, a parent/caregiver divulges that s/he is at significant 
risk for harm or at significant risk of committing harm toward the adolescent participant, or if harm is 
suspected or likely, or if the parent/caregiver states s/he is suicidal or homicidal, the following will occur: 
• 
The protocol interview team member conducting the interview will immediately contact the site 
IoR or designee and share any time-sensitive, potentially life-threatening information received 
from the parent/caregiver as part of the phone interview discussions. 
• 
The IoR or designee contacted with this information will follow local policies for management of 
such situations including engaging immediate/first responders as applicable. 
• 
The IoR or designee will also follow local reporting policies and legal statutes, including 
reporting to child protection or other appropriate agencies, as well as arranging referrals to 
appropriate support, counseling or treatment resources. 
 
For disclosure of safety concerns to the parent/caregiver, the IoR or designee will notify the CMC after 
completing the steps above. No further safety reporting of the parents/caregivers is required, and Protocol 
Section 7 Safety Assessment, Monitoring, and Reporting does not apply for the parents/caregivers.  
 
For disclosure by the parent/caregiver of safety concerns to the adolescent participant, the IoR or designee 
will notify the CMC after completing the steps above, and document and report the event as applicable 
per Protocol Section 7.  
 
To facilitate rapid communications, the IoR or designee is expected to provide up-to-date contact 
information to the protocol interview team while phone interviews are being scheduled and conducted 
with participants from the site.  
 
9 
Data Management, Clinical Site Monitoring, and Administrative Procedures 
 
Protocol Section 11.6 provides details on the qualitative phone interview data analyses, and Protocol 
Section 12 provides details on the management, handling, and record keeping of the qualitative phone 
interview data. Protocol Section 13 provides information on clinical site monitoring, and Protocol Section 
15 provides information on overarching administrative procedures for the IMPAACT 2017 study. 
 
 


 
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Appendix V-B: Parent/Caregiver Phone Interview Sample Informed Consent Form 
for parents/caregivers of adolescents enrolled in: 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 3.0, dated 13 August 2020 
 
Introduction 
 
You are being asked to take part in the research study named above.  
 
This form gives information about your role in the study. Please read it, or have it read to you, and ask any 
questions you may have. We will take as much time as needed for you to fully understand your role in the study. 
At the end, we will ask you questions to see if we have explained your role in the study clearly. 
 
After you understand your role in the study, and if you decide that you will participate, you will be asked to sign 
or make your mark on this form. You will be offered a copy to keep. 
 
It is your decision whether or not you join the study. 
 
Deciding to join the study is voluntary. You may choose to join or not join. If you choose to join, you can change 
your mind and stop the study at any time. Your choice will have no effect on your child’s medical care at this 
clinic or your child participating in the study. Access to services and the benefits and rights you and your child 
normally have will not be affected.  
 
Your role in the study 
 
If you agree, you may be asked to complete one phone interview about how you felt and how you think your child 
felt about the shots they receive in this study. Not all parents/caregivers of adolescents who receive shots will be 
asked to complete a phone interview. Some, but not all adolescents who receive shots will also be asked to 
complete a phone interview.  
 
If you are eligible and selected to complete an interview, we will help you to schedule the interview at a time that 
works for you. During the interview, you will be asked questions about how you felt about your child receiving 
shots of CAB or [and] RPV. The interview will be audio recorded. The words that you say will then be written 
down. This information will help us understand if CAB shots and RPV shots have any bad side effects for 
adolescents. It will also help us understand how adolescents and families feel about them receiving the shots.  
 
The interview may take place at or in between your child’s Week 4b, 5, 8, and 12 study visits [Week 24 through 
96 visits], in Cohort 1 [Cohort 2] or during the long-term follow-up visits. The interview could also take place at 
or in between any of the long-term follow-up visits if your child enters into long-term follow-up. You will only 
complete one interview. Your part in the study should take about 1-2 hours.  
 
 


 
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There are no costs from being in the study. 
 
There are no costs to you for this phone interview.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for your time, and 
given (specify amount).] 
 
Possible Risks 
 
There could be risks of disclosure of your information. We will make every effort to keep your information 
private and confidential. Your and your child’s names will not be included in the recording of the interview. The 
interview will only be labeled with a code number. 
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality that protects us from being 
forced to release information that may identify you, such as by the courts or police. The certificate cannot be used 
in all situations, but it can be used to resist demands for information that would identify you. The certificate does 
not protect against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your participation in the study to 
others, if you wish. 
 
Possible Benefits 
 
By joining the study, you will be part of the search for ARVs that may be better for adolescents. There may be no 
direct benefit to you from taking part in this study. There may be a benefit if the results from this study lead to a 
safe and effective dose of the study drugs for adolescents. Information learned from this study may help other 
adolescents who have HIV. 
 
Other information about the study 
 
Study records may be reviewed by study staff and groups that oversee the study. Groups that oversee the study 
include:  
 
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your child’s name or identify your child personally.  
 


 
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A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify your child. At most, the website will include a summary of the results. You 
can search this website at any time. 
 
[Sites may modify this paragraph to reflect local reporting requirements and legal statues: Your child’s study 
information may be disclosed to other authorities if required by law. Public health authorities are required by law 
to receive information for the prevention or control of disease, injury or disability. (We must comply with laws 
requiring the reporting of suspected child abuse and neglect).]   
 
Signatures 
 
If you agree to participate in this study, please sign or make your mark below. 
 
Before deciding whether to participate in this study, make sure you have read this form, or had it read to you, and 
that all of your questions have been answered. You should feel that you understand the study, its risks and 
benefits, and what is expected of you if you decide to join. You are welcome to ask questions or request more 
information at any time.  
 
You do not give up any rights by signing this form. 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
Signature blocks for participants of legal age to provide independent informed consent 
 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
 
 
 
 
 
              
 
 
 
 
 
 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix V-C: Parent/Caregiver Phone Interview Sample Informed Consent Verbal Script 
for parents/caregivers of adolescents enrolled in: 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 3.0, dated 13 August 2020 
 
Introduction 
 
You are being asked to take part in the research study named above.  
 
This form gives information about your role in the study. Please read it, or have it read to you, and ask any 
questions you may have. We will take as much time as needed for you to fully understand your role in the study. 
At the end, we will ask you questions to see if we have explained your role in the study clearly. 
 
After you understand your role in the study, and if you decide that you will participate, you will be asked to sign 
or make your mark on this form. You will be offered a copy to keep. 
 
It is your decision whether or not you join the study. 
 
Deciding to join the study is voluntary. You may choose to join or not join. If you choose to join, you can change 
your mind and stop the study at any time. Your choice will have no effect on your child’s medical care at this 
clinic or your child participating in the study. Access to services and the benefits and rights you and your child 
normally have will not be affected.  
 
Your role in the study 
 
If you agree, you may be asked to complete one phone interview about how you felt and how you think your child 
felt about the shots they receive in this study. Not all parents/caregivers of adolescents who receive shots will be 
asked to complete a phone interview. Some, but not all adolescents who receive shots will also be asked to 
complete a phone interview.  
 
If you are eligible and selected to complete an interview, we will help you to schedule the interview at a time that 
works for you. During the interview, you will be asked questions about how you felt about your child receiving 
shots of CAB or [and] RPV. The interview will be audio recorded. The words that you say will then be written 
down. This information will help us understand if CAB shots and RPV shots have any bad side effects for 
adolescents. It will also help us understand how adolescents and families feel about them receiving the shots.  
 
The interview may take place at or in between your child’s Week 4b 5, 8, and 12 study visits [Week 24 through 
96 visits] in Cohort 1 [Cohort 2], or during the long-term follow-up visits. The interview could also take place at 
or in between any of the long-term follow-up visits if your child enters into long-term follow-up. You will only 
complete one interview. Your part in the study should take about 1-2 hours.  
 
 


 
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There are no costs from being in the study. 
 
There are no costs to you for this phone interview.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for your time, and 
given (specify amount).] 
 
Possible Risks 
 
There could be risks of disclosure of your information. We will make every effort to keep your information 
private and confidential. Your and your child’s names will not be included in the recording of the interview. The 
interview will only be labeled with a code number. 
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality that protects us from being 
forced to release information that may identify you, such as by the courts or police. The certificate cannot be used 
in all situations, but it can be used to resist demands for information that would identify you. The certificate does 
not protect against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your participation in the study to 
others, if you wish. 
 
Possible Benefits 
 
By joining the study, you will be part of the search for ARVs that may be better for adolescents. There may be no 
direct benefit to you from taking part in this study. There may be a benefit if the results from this study lead to a 
safe and effective dose of the study drugs for adolescents. Information learned from this study may help other 
adolescents who have HIV. 
 
Other information about the study 
 
Study records may be reviewed by study staff and groups that oversee the study. Groups that oversee the study 
include:  
 
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your child’s name or identify your child personally.  
 


 
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A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify your child. At most, the website will include a summary of the results. You 
can search this website at any time. 
 
[Sites may modify this paragraph to reflect local reporting requirements and legal statues: Your child’s study 
information may be disclosed to other authorities if required by law. Public health authorities are required by law 
to receive information for the prevention or control of disease, injury or disability. (We must comply with laws 
requiring the reporting of suspected child abuse and neglect).]   
 
Agreement to participate  
 
Before deciding whether to participate in this study, please ask me any questions that you have. You should feel 
that you understand the study, its risks and benefits, and what is expected of you if you decide to join. You are 
welcome to ask questions or request more information at any time.  
 
You do not give up any rights by agreeing to participate.  
 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
Signature blocks for witnesses to verbal consent of parents/guardians of legal age to provide independent informed 
consent 
 
 
 
 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 
 


 
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Appendix VI:  Injectable Study Product Preparation 
 
This appendix provides requirements for injectable study product preparation for both CAB LA and RPV 
LA.  The study product regimen, administration, formulation, storage requirements, supply and other 
relevant information is described in protocol Section 5 Study Product.  The IMPAACT 2017 MOP 
provides additional details and guidance regarding study product ordering, prescribing, short-term 
storage, and administration. 
 
The investigational pharmacist(s) must be proficient in the preparation of study products using aseptic 
technique under a pharmacy biological safety cabinet (BSC) Class II or better isolator. Local regulations 
and site institutional policies and procedures for use of personal protective equipment, such as gloves, 
gowns, masks, and safety glasses, must be followed.  
 
Suggested supplies for CAB LA and RPV LA:  
 
- 
BD 5-mL syringe, Luer-Lok Tip, Reference No.: 309646, or equivalent 
- 
BD 3-mL syringe, Luer-Lok Tip, Reorder No.: 309585, 309657, or equivalent 
- 
Needle for aspiration: BD Precision Glide Needle, 21G 1 inch, Reference No.: 305165, 
or equivalent 
- 
Needle for intramuscular injection: 
▪ 
21G x 1.5" SurGuard Safety Hypodermic Needle CE MARKED Mfg Catalog 
Number: SG3-2138 (Central Supply as applicable per country) 
▪ 
23G x 1.5" SurGuard Safety Hypodermic Needle CE MARKED Mfg Catalog 
Number: SG3-2338 (Central Supply as applicable per country) 
▪ 
BD Precision Glide Needle, 23G ½", Reference No.: 305194, or equivalent 
 
NOTE: 25G needle is not permitted for administration of RPV LA.  
Variable needle lengths and/or needles with different gauge (1.5 inch, 2 inch; CAB LA: 21 to 25 gauge; 
RPV LA: 21 to 23 gauge) are permitted if needed to accommodate individual body types. 
 
 


 
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Appendix VI-A: Preparation of CAB LA 
 
1 
Preparation of CAB LA 600mg/3mL (using one 600 mg/3mL vial or two 400 mg/2 mL vials) 
 
One syringe containing 3 mL (600 mg) of CAB LA study product must be prepared using aseptic 
technique under a pharmacy BSC/isolator.  
 
1. Remove one 3-mL CAB LA vial or two 2-mL CAB LA vials (as available) from storage. If CAB LA 
vials are stored in the refrigerator (2°C to 8°C), remove vial(s) from the refrigerator and wait at least 15 
minutes to equilibrate to room temperature. 
 
2. Shake the vial(s) for 10 seconds, or alternatively, vortex the vial(s) moderately inverted for a minimum 
of 10 seconds, then upright for a minimum of 10 seconds to ensure a homogeneous suspension. 
 
3. Invert the vial(s) and inspect to ensure complete re-suspension. If sediments are observed, repeat Steps 
2-3. After re-suspending, it is recommended to use the suspension immediately. 
 
4. using aseptic technique under a pharmacy biological safety cabinet, flip off the plastic cap from the 
vial(s). Wipe the top of the vial(s) with disinfecting tissue of isopropyl alcohol 70% or similar and allow 
the alcohol to dry. 
5. Remove one 5-mL syringe and aspiration needles from the blister pouch (see suggested supplies). Take 
one aspiration needle and attach the needle to the Luer-Lok connection of the syringe. 
 
6. If using two 2-mL CAB LA vials: 
• 
Pull back on the syringe plunger to allow approximately 1 mL of air into the syringe. 
• 
Push the needle through the stopper of the first vial and inject 1 mL of air into the vial. 
• 
Withdraw 1.5 mL of suspension from the first vial and put vial aside. 
• 
Remove the needle from the syringe and attach a new aspiration needle. Repeat the steps above to 
withdraw 1.5 mL of suspension from the second vial, for a total of 3 mL from two vials. Because 
the suspension can contain some air after having shaken the vial, take out enough suspension in 
order to be able to de-aerate the syringe properly (Step 9). Record for each individual vial the 
time withdrawn into the syringe.  
 
7. If using one 3-mL CAB LA vial: 
• 
Pull back on the syringe plunger to allow approximately 1 mL of air into the syringe. 
• 
Push the needle through the stopper of the vial and inject 1mL of air into the vial. 
• 
Withdraw the entire contents of the vial into the syringe. Because the suspension can contain 
some air after having shaken the vial, take out enough suspension in order to be able to de-aerate 
the syringe properly (Step 9). Record the time withdrawn into the syringe.  
 
8. Remove the needle that was used to withdraw the suspension and discard it appropriately. Attach the 
needle for intramuscular administration to the Luer-Lok connection of the syringe or attach a syringe cap 
(per site’s SOP). Consult with clinic staff regarding the recommended needle for IM administration (see 
suggested supplies). 
 
9. De-aerate the syringe by first tapping with a finger against the syringe and then by moving the plunger 
rod carefully forward with the needle in upright position until a drop of suspension appears. Remove the 
excess suspension in order to administer the correct volume (3 mL). 
 
10. Label the syringe appropriately. 


 
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After withdrawal of the suspension from the vial(s) into a syringe, it is recommended to administer the 
suspension immediately. Do not exceed 2 hours between withdrawing the contents of the vial(s) into 
a syringe (Step 6 or Step 7) and administration to the study participant.   
 
The prepared CAB LA suspension in a syringe must be stored at controlled room temperature between 
20°C to 25°C from the time it is withdrawn into a syringe to the time it is administered. 
 
Any entered vials or expired filled syringes should be disposed of in accordance with institutional or 
pharmacy policy. 
 
2 
Preparation of CAB LA 400mg/2mL (using one 400 mg/2 mL vial) 
 
One syringe containing 2 mL (400 mg) of CAB LA study product must be prepared using aseptic 
technique under a pharmacy BSC/isolator.  
 
1. Remove one 2-mL CAB LA vial from storage. If CAB LA vials are stored in the refrigerator 
(2°C to 8°C), remove vial from the refrigerator and wait at least 15 minutes to equilibrate to room 
temperature. 
2. Shake the vial for 10 seconds, or alternatively, vortex the vial moderately inverted for a minimum 
of 10 seconds, then upright for a minimum of 10 seconds to ensure a homogeneous suspension. 
3. Invert the vial and inspect the vial to ensure complete re-suspension. If sediments are observed, 
repeat Steps 2-3. After re-suspending, it is recommended to use the suspension immediately. 
4. Using aseptic technique under a pharmacy biological safety cabinet, flip off the plastic cap from 
the vial. Wipe the top of the vial with a 70% isopropyl alcohol pad or similar and allow the 
alcohol to dry. 
5. Remove one 3-mL syringe and one aspiration needle from the blister pouch (see suggested 
supplies). Attach the needle to the Luer-Lok connection of the syringe. 
6. Pull the syringe plunger rod to allow approximately 1 mL of air into the syringe. 
7. Push the needle through the stopper of the vial and inject 1 mL of air into the vial.  
8. Withdraw the entire contents from the vial. Since the suspension can contain some air after 
shaking, take out all suspension in order to be able to de-aerate the syringe properly (Step 10). 
Record the time that the suspension is withdrawn into the syringe.  
9. Remove the needle that was used to withdraw the suspension and discard it appropriately. Attach 
the needle for intramuscular administration to the Luer-Lok connection of the syringe or attach a 
syringe cap (per site’s SOP). Consult with clinic staff regarding the recommended needle for IM 
administration (see suggested supplies). 
10. De-aerate the syringe by first tapping with a finger against the syringe and then by moving the 
plunger rod carefully forward with the needle in upright position until a drop of suspension 
appears. Remove the excess suspension in order to administer the correct volume (2 mL).   
11. Label the syringe appropriately. 
  
After withdrawal of the suspension from the vial into a syringe, it is recommended to administer the 
suspension immediately. Do not exceed 2 hours between withdrawing the contents of the vial into a 
syringe (Step 8) and administration to the study participant.   
 


 
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The prepared CAB LA suspension in a syringe must be stored at controlled room temperature between 
20°C to 25°C from the time it is withdrawn into a syringe to the time it is administered. 
 
Any entered vials or expired filled syringes should be disposed of in accordance with institutional or 
pharmacy policy. 
 
 


 
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Appendix VI-B: Preparation of RPV LA 
 
1 
Preparation of RPV LA 900mg/3mL (using one 900mg/3 mL vial or two 600 mg/2 mL vials) 
 
1. Remove one 3-mL RPV LA vial or two 2-mL RPV vials (as available) from the refrigerator and 
allow the vial(s) to sit for 15 minutes to come to room temperature (keep vial in the carton while 
coming to room temperature). RPV LA may sit at room temperature for a maximum of 24 hours 
at 25°C. During this period, excursions are allowed up to 30°C for a maximum of 2 hours.  
2. Remove the vial(s) from the carton. Shake the vial(s) moderately for a minimum of 10 seconds to 
ensure a homogeneous suspension. NOTE: Do not vortex the vial(s). 
3. Invert the vial(s) and inspect to ensure complete re-suspension. If sediments are observed, repeat 
Steps 2-3. After re-suspending, it is recommended to use the suspension immediately. 
4. Using aseptic technique under a pharmacy biological safety cabinet, flip off the plastic cap from 
the vial(s). Wipe the top of the vial(s) with a 70% isopropyl alcohol pad or similar and allow the 
alcohol to dry. 
5. Remove one 5-mL syringe and one aspiration needle from the blister pouch (see suggested 
supplies). Remove 2 needles if using two 2-mL vials. Attach one needle to the Luer connection of 
the syringe. 
6. If using two 2-mL RPV vials: 
• 
Pull the syringe plunger rod slowly to allow approximately 1 mL of air into the syringe.  
• 
Push the needle through the stopper of the first vial and inject 1 mL of air into the vial. 
• 
Withdraw approximately 1.5 mL of suspension from the vial into the syringe. 
• 
Remove the needle from the syringe and attach a new aspiration needle. Repeat the steps 
above to withdraw 1.5 mL of suspension from the second vial, for a total of 3 mL from 
two vials. Because the suspension can contain some air after having shaken the vial, take 
out enough suspension in order to be able to de-aerate the syringe properly (Step 9). 
Record for each individual vial the time withdrawn into the syringe.  
7. If using one 3-mL RPV vial: 
• 
Pull back on the syringe plunger to allow approximately 1 mL of air into the syringe. 
• 
Push the needle through the stopper of the vial and inject 1 mL of air into the vial. 
Withdraw the entire contents of the vial into the syringe. Because the suspension can 
contain some air after having shaken the vial, take out enough suspension in order to be 
able to de-aerate the syringe properly (Step 9). Record the time withdrawn into the 
syringe 
 
8. Remove the needle that was used to withdraw the suspension and discard it appropriately. Attach 
the needle for intramuscular administration to the Luer-Lok connection of the syringe or attach a 
syringe cap (per site’s SOP). Consult with clinic staff regarding the recommended needle for IM 
administration (see suggested supplies). 
9. De-aerate the syringe by first tapping with a finger against the syringe and then by moving the 
plunger rod carefully forward with the needle in upright position until first drop appear. Remove 
the excess suspension in order to administer the correct volume (3 mL).   
10. Label the syringe appropriately. 


 
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After withdrawal of the suspension from the vial into a syringe, it is recommended to administer the 
suspension immediately. If required, the prepared syringe containing RPV LA may remain at room 
temperature for a maximum period of 2 hours between dispensing (Step 6 or Step 7) and 
administering and must be protected from light (e.g., syringe covered or enclosed within an amber bag) 
until ready to administer.  
 
Any entered vials or expired filled syringes should be disposed of in accordance with institutional or 
pharmacy policy. 
 
2 
Preparation of RPV LA 600mg/2mL (using one 600mg/2 mL vial) 
 
1. Remove one 2-mL RPV LA vial from the refrigerator. Document the time at which the vial was 
removed from the refrigerator.  Allow the vial to sit for 15 minutes to come to room temperature 
(keep vial in the carton while coming to room temperature). RPV LA may sit at room temperature 
for a maximum of 24 hours at 25°C. During this period, excursions are allowed up to 30°C for a 
maximum of 2 hours.  
2. Remove the vial from the carton. Shake the vial moderately for a minimum of 10 seconds to 
ensure a homogeneous suspension. NOTE: Do not vortex the vial. 
3. Invert the vial and inspect the vial to ensure complete re-suspension. If sediments are observed, 
repeat Steps 2-3. After re-suspending, it is recommended to use the suspension immediately. 
4. Using aseptic technique under a pharmacy biological safety cabinet, flip off the plastic cap from 
the vial. Wipe the top of the vial with a 70% isopropyl alcohol pad or similar and allow the 
alcohol to dry. 
5. Remove one 3-mL syringe and one aspiration needle from the blister pouch (see suggested 
supplies). Attach the aspiration needle to the Luer connection of the syringe. 
6. Pull the syringe plunger rod to allow approximately 1 mL of air into the syringe. 
7. Push the needle through the stopper of the vial and inject 1 mL of air into the vial. 
8. Withdraw the entire contents from the vial. Since the suspension can contain some air after 
shaking, take out all suspension in order to be able to de-aerate the syringe properly. Record the 
time withdrawn from the vial.  
9. Remove the needle that was used to withdraw the suspension and discard it appropriately. Attach 
the needle for intramuscular administration to the Luer-Lok connection of the syringe or attach a 
syringe cap (per site’s SOP). Consult with clinic staff regarding the recommended needle for IM 
administration (see suggested supplies). 
10. De-aerate the syringe by first tapping with a finger against the syringe and then by moving the 
plunger rod carefully forward with the needle in upright position until the first drop appears. 
Remove the excess suspension in order to administer the correct volume (2 mL).   
11. Label the syringe appropriately.  
 
After withdrawal of the suspension from the vial into a syringe, it is recommended to administer the 
suspension immediately. If required, the prepared syringe containing RPV LA may remain at room 
temperature for a maximum period of 2 hours between dispensing (Step 8) and administering and 


 
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must be protected from light (e.g., syringe covered or enclosed within an amber bag) until ready to 
administer.  
Any entered vials or expired filled syringes should be disposed of in accordance with institutional or 
pharmacy policy. 
 
 


 
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Appendix VII:  Guidance for Study Implementation at Sites Experiencing Operational 
Disruptions Due to COVID-19 
 
To safeguard the health and well-being of study participants and study staff in the context of circulating 
SARS-CoV-2 and the associated coronavirus disease 2019 (COVID-19), the guidance provided in this 
appendix may be implemented at sites experiencing disruptions due to COVID-19. 
 
The extent to which site operations may be disrupted by COVID-19 may vary across sites and over time. 
All sites should follow applicable government, health authority, and institutional policies with 
respect to conduct of study visits and procedures, with utmost importance placed on the health and 
well-being of study participants and study staff. All sites must also comply with any directives 
received from the study sponsor, the IMPAACT Network, and/or the IMPAACT 2017 Protocol Team. 
Should a determination be made in the future that the guidance provided in this appendix is no longer 
applicable, sites will be formally notified and instructed to inform their IRBs/ECs and other applicable 
regulatory entities. 
 
Study Products and Background cART Regimens 
• 
For Cohort 1 participants and all LSFU participants: Sites should provide adherence counseling and 
support at each study visit regarding the importance of correctly and consistently taking background 
cART regimens. 
• 
For Cohort 1 Step 1 and Cohort 2 Step 3 participants: Oral study product may be dispensed at the off-
site Week 2 or Week 4a visits in accordance with protocol Section 6.1.3.   
• 
For Cohort 1 Step 2 and Cohort 2 Step 4 participants: Injectable study products (CAB LA, RPV LA) 
must be administered on-site. Sites should carefully assess their ability to utilize alternative 
approaches (as provided below) for monitoring participant safety, in the event of disruptions or 
limitations to conducting on-site visits for non-injection follow-up visits. Sites should only consider 
administering injectable study products if there is adequate assurance that participant safety 
monitoring can be conducted through one of the alternative approaches provided below. In addition, 
injectable study products should only be administered if collection, processing, and storage of PK 
specimens, consistent with the Laboratory Processing Chart (LPC), remains possible for the injection 
visit and for the subsequent non-injection visits.  
- At sites where these conditions can be met, administration of injectable study products may 
continue; the procedures listed in protocol Section 6.9 must be performed before administration. 
- At sites where these conditions cannot be met, Cohort 1 Step 2 participants with study product 
injections remaining should be permanently discontinued from injectable study product and 
followed per the long-term safety and washout PK follow-up (LSFU) visit schedule. The 
IMPAACT 2017 CMC should be consulted for guidance on short-term oral bridging options for 
Cohort 2 Step 4 participants. 
 
Prioritization of Study Visit Procedures 
• 
Sites with limited capacity to conduct non-injection follow-up study visits in-person at the study 
clinic may conduct study visits — in full or in part — off-site or remotely (e.g., by telephone or other 
IRB-approved method).  
- See protocol Section 6.1.3 for detailed guidance on conducting off-site (in-person) non-injection 
follow-up visits.  
- Prior to conducting remote study visits, site staff should communicate with 
participants/parents/guardians as applicable to determine in advance how and when such visits 
will take place, with adequate protections for safety, privacy, and confidentiality. Remote visit 
procedures should be conducted by site staff who are adequately qualified and trained to conduct 
the procedures, as determined by the site Investigator of Record (IoR), with attention paid to data 


 
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chain of custody. These staff should also be adequately qualified and trained to immediately 
assess and/or manage any adverse events or social impacts that may occur during the visits. If 
adverse events requiring further evaluation or management are identified during a remote visit, 
staff conducting the visit should arrange for appropriate clinical management, in consultation 
with the IoR or designee as needed. 
• 
Sites with limited capacity to conduct study visits (whether on-site, off-site or remotely) should 
prioritize the following procedures: 
- Adherence counseling and support for the background cART regimen; this may be done 
remotely. 
- Clinical procedures; local institutional guidance may be followed for prioritization of clinical 
procedures, guided by participant safety. Medical and medication histories may be obtained 
remotely.   
- Laboratory procedures (see protocol Section 6.16.1 for specimen prioritization).  
- Contraceptive counseling; this may be done remotely.  
- Acceptability/tolerability questionnaires; these may be administered remotely or skipped/missed. 
• 
For visits at which PK specimen collection is expected per protocol, before any PK specimen is 
collected, sites should verify that they are able to process and store PK samples, as described in the 
LPC.  If this cannot be verified, the samples should not be collected. As noted above, sites that are not 
able to collect, process, and store PK specimens consistent with the LPC should not administer 
injectable study products. 
- For sites with limited capacity to ship PK or genotypic and phenotypic resistance samples to the 
designated testing laboratory, the ability to store the samples locally must be verified prior to 
sample collection.  
• 
If laboratory tests (other than PK testing) cannot be performed consistent with a site’s Protocol 
Analyte List (non-US sites) or at a CAP/CLIA-certified laboratory, the tests may be performed in 
alternate laboratories using alternate assays (alternate laboratories must adhere to local regulations for 
clinical laboratory testing), in consultation with the CMC.  
 
Documentation 
• 
Site-specific COVID-19 contingency plans, and the implementation thereof, should be documented in 
essential document files for IMPAACT 2017.  
• 
Documentation should be entered in participant study charts in real-time (or close to real-time) should 
any of the following occur: 
- Missed visits  
- Off-site visits (document the location of the visit) 
- Incomplete or partial visits (document which procedures were performed, and which were not) 
- Remote contacts performed in lieu of in-person visits (document method used to complete the 
contact and which procedures were performed) 
- Any other participant contacts  
- Use of alternate laboratories or alternate laboratory assays 
• 
 In consultation with the Division of AIDS, the IMPAACT Network has developed and disseminated 
guidance for documenting and/or reporting protocol deviations that may occur due to limited site 
capacity to conduct study visits or procedures due to COVID-19. Please contact the IMPAACT 
Operations Center Clinical Trials Specialists with any questions related to documentation and 
reporting requirements.  

Prot_000.pdf: 
 
 
IMPAACT 2017 
 
Phase I/II Study of the Safety, Acceptability, Tolerability, and 
Pharmacokinetics of Oral and Long-Acting Injectable Cabotegravir 
and Long-Acting Injectable Rilpivirine in Virologically Suppressed 
HIV-Infected Children and Adolescents 
 
“MOCHA” 
More Options for Children and Adolescents 
 
 
A Study of the International Maternal Pediatric Adolescent  
AIDS Clinical Trials Network 
 
Sponsored by: 
National Institute of Allergy and Infectious Diseases 
Eunice Kennedy Shriver 
National Institute of Child Health and Human Development 
National Institute of Mental Health 
 
 
Pharmaceutical Support Provided by: 
ViiV Healthcare 
 
 
DAIDS ID #30070 
IND #138,754 Held By DAIDS 
 
 
 
Protocol Co-Chairs: 
Carolyn Bolton Moore, MSc, MBBCh 
 
Aditya H. Gaur, MD 
 
NIAID Medical Officer:  
Ellen Townley, MSN, FNP 
 
NICHD Medical Officer: 
Jack Moye, MD 
 
Clinical Research Managers: 
Katherine Calabrese, MPH  
Sarah Buisson, MSW, MPH 
Michael Whitton, BA 
 
 
 
 
FINAL Version 4.0 
 
27 May 2022


 
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IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics 
of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable 
Rilpivirine in Virologically Suppressed HIV-Infected Children and Adolescents 
 
TABLE OF CONTENTS 
 
Protocol Signature Page ......................................................................................................... 6 
ABBREVIATIONS AND ACRONYMS ....................................................................................... 7 
PROTOCOL TEAM ROSTER ...................................................................................................11 
STUDY SITE ROSTER .............................................................................................................15 
SCHEMA ..................................................................................................................................21 
1 
INTRODUCTION ...........................................................................................................27 
1.1 
Background ....................................................................................................................... 27 
1.2 
Prior Research ................................................................................................................... 28 
1.3 
Study Rationale ................................................................................................................. 41 
1.4 
Risk/Benefit Assessment .................................................................................................. 52 
1.5 
Hypotheses ........................................................................................................................ 54 
2 
OBJECTIVES ................................................................................................................54 
2.1 
Primary Objective: Cohort 1 (continuing a background cART regimen) ......................... 54 
2.2 
Primary Objective: Cohort 2 (discontinuing a background cART regimen) .................... 54 
2.3 
Secondary Objectives: Cohort 1 ....................................................................................... 54 
2.4 
Secondary Objectives: Cohort 2 ....................................................................................... 55 
2.5 
Other Objectives ............................................................................................................... 55 
3 
STUDY DESIGN ...........................................................................................................56 
3.1 
Cohort 1 ............................................................................................................................ 57 
3.2 
Cohort 2 ............................................................................................................................ 59 
3.3 
Long-term Safety and Washout PK Follow-up (LSFU) ................................................... 60 
4 
STUDY POPULATION ..................................................................................................61 
4.1 
Inclusion Criteria: Cohort 1 Step 1, Cohort 2A Step 3, and Cohort 2B Step 5 ................. 61 
4.2 
Exclusion Criteria: Cohort 1 Step 1, Cohort 2A Step 3, and Cohort 2B Step 5 ............... 64 
4.3 
Inclusion/Exclusion Criteria, Step 2 (Cohort 1 Progression Criteria, Step 1 to Step 2) ... 66 
4.4 
Inclusion/Exclusion Criteria, Step 4 (Cohort 2A Progression Criteria, Step 3 to Step 4) 67 
4.5 
Inclusion/Exclusion Criteria: Parents/Caregivers ............................................................. 68 
4.6 
Co-Enrollment Considerations.......................................................................................... 68 
4.7 
Recruitment, Screening, and Enrollment Process ............................................................. 69 
4.8 
Participant Retention ......................................................................................................... 70 
5 
STUDY PRODUCT ........................................................................................................70 
5.1 
Study Product Regimen and Administration .................................................................... 71 
5.2 
Study Product Formulation ............................................................................................... 74 
5.3 
Study Product Supply ....................................................................................................... 74 
5.4 
Study Product Accountability ........................................................................................... 75 
5.5 
Final Disposition of Study Product ................................................................................... 75 
5.6 
Concomitant Medications ................................................................................................. 75 
5.7 
Prohibited Medications ..................................................................................................... 75 
5.8 
Precautionary Medications................................................................................................ 75 
6 
STUDY VISITS AND PROCEDURES ...........................................................................76 
6.1 
Study Visit Windows, Split and Interim Visits, and Off-site Visits ................................. 77 
6.2 
Cohort 1 Step 1, Cohort 2A Step 3, and Cohort 2B Step 5 Screening Visit ..................... 79 
6.3 
Cohort 1 ............................................................................................................................ 80 


 
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6.4 
Cohort 2 ............................................................................................................................ 89 
6.5 
Long-Term Safety and Washout PK Follow-Up (LSFU) Visits ..................................... 104 
6.6 
Confirmation of Virologic Failure Visit ......................................................................... 108 
6.7 
Study Exit ....................................................................................................................... 109 
6.8 
Post-Study Contacts ........................................................................................................ 110 
6.9 
Procedures for Continued Oral and Injectable Study Product Administration ............... 110 
6.10 
Medical and Medications History ................................................................................... 111 
6.11 
Physical Examinations .................................................................................................... 113 
6.12 
Performing an Electrocardiogram (ECG/EKG) .............................................................. 114 
6.13 
Pregnancy Testing and Contraceptive Counseling ......................................................... 114 
6.14 
Study Product Adherence Assessment and Adherence Counseling (Study Product, cART 
Regimen, Study Visits) ................................................................................................... 116 
6.15 
Acceptability and Tolerability Assessments ................................................................... 117 
6.16 
Additional Considerations for Laboratory Procedures ................................................... 117 
7 
SAFETY ASSESSMENT, MONITORING, AND REPORTING .................................... 119 
7.1 
Safety-Related Roles and Responsibilities ..................................................................... 119 
7.2 
Safety-Related Data Collection....................................................................................... 120 
7.3 
Expedited Adverse Event (EAE) Reporting ................................................................... 121 
8 
PARTICIPANT MANAGEMENT .................................................................................. 123 
8.1 
Management of Adverse Events ..................................................................................... 123 
8.2 
Management of QTc Prolongation .................................................................................. 132 
8.3 
Management of Contraception and Pregnancy ............................................................... 132 
8.4 
Monitoring and Management of HIV Viral Load ........................................................... 133 
8.5 
Substitution or Dose Modification of cART for Cohort 1 Participants .......................... 134 
8.6 
Deferring Study Product and Criteria for Temporary Hold of Study Product ................ 134 
8.7 
Criteria for Premature Permanent Discontinuation of Study Product ............................. 135 
8.8 
Participant Withdrawal or Termination from the Study ................................................. 136 
9 
STATISTICAL CONSIDERATIONS ............................................................................ 136 
9.1 
General Design Issues ..................................................................................................... 136 
9.2 
Outcome Measures ......................................................................................................... 137 
9.3 
Randomization and Stratification ................................................................................... 140 
9.4 
Sample Size and Accrual ................................................................................................ 140 
9.5 
Monitoring ...................................................................................................................... 142 
9.6 
Analyses .......................................................................................................................... 150 
10 
CLINICAL PHARMACOLOGY PLAN ......................................................................... 155 
10.1 
Clinical Pharmacology Objectives .................................................................................. 155 
10.2 
Primary and Secondary Data: Cohorts 1 and 2 ............................................................... 157 
10.3 
Endpoints and Outcome Measures .................................................................................. 158 
10.4 
Study Design, Data Analysis, and Modeling .................................................................. 159 
10.5 
Expected Outcome .......................................................................................................... 161 
11 
QUALITATIVE PHONE INTERVIEWS (U.S. Sites Only)............................................ 162 
11.1 
Sample Size and Selection Process ................................................................................. 162 
11.2 
Qualitative Phone Interview Procedural Window .......................................................... 163 
11.3 
Consenting Considerations and Scheduling Qualitative Phone Interviews .................... 163 
11.4 
Conducting Qualitative Phone Interviews ...................................................................... 163 
11.5 
Disclosure of Harm ......................................................................................................... 164 
11.6 
Qualitative Phone Interview Data Analyses ................................................................... 164 
12 
DATA HANDLING AND RECORD KEEPING ............................................................. 165 
12.1 
Data Management Responsibilities ................................................................................. 165 
12.2 
Essential and Source Documents and Access to Source Data ........................................ 166 
12.3 
Quality Control and Quality Assurance .......................................................................... 167 


 
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13 
CLINICAL SITE MONITORING ................................................................................... 167 
14 
HUMAN SUBJECTS PROTECTIONS......................................................................... 167 
14.1 
Institutional Review Board/Ethics Committee Review and Approval ........................... 167 
14.2 
Vulnerable Participants ................................................................................................... 168 
14.3 
Informed Consent ........................................................................................................... 168 
14.4 
Potential Benefits ............................................................................................................ 170 
14.5 
Potential Risks ................................................................................................................ 170 
14.6 
Reimbursement/Compensation ....................................................................................... 171 
14.7 
Privacy and Confidentiality ............................................................................................ 172 
14.8 
Communicable Disease Reporting .................................................................................. 172 
14.9 
Management of Incidental Findings ............................................................................... 172 
14.10 Management of New Information Pertinent to Study Participation................................ 173 
14.11 Post-Trial Access to Study Product ................................................................................ 173 
15 
ADMINISTRATIVE PROCEDURES ............................................................................ 173 
15.1 
Regulatory Oversight ...................................................................................................... 173 
15.2 
Protocol Registration ...................................................................................................... 173 
15.3 
Study Implementation ..................................................................................................... 174 
15.4 
Protocol Deviation Reporting ......................................................................................... 174 
15.5 
ClinicalTrials.gov ........................................................................................................... 174 
16 
PUBLICATIONS ......................................................................................................... 175 
17 
REFERENCES ............................................................................................................ 175 
Appendix I: Schedule of Evaluations .................................................................................. 178 
Appendix I-A: Schedule of Evaluations for Cohort 1 Adolescents (Cohort 1C and Cohort 1R) ............. 178 
Appendix I-B: Schedule of Evaluations for Cohort 2A Adolescents........................................................ 180 
Appendix I-C: Schedule of Evaluations for Cohort 2B Adolescents ........................................................ 182 
Appendix I-D: Schedule of Evaluations for Long-Term Safety and Washout PK Follow-Up (LSFU) 
Adolescents .................................................................................................................................. 184 
Appendix II: Sample Informed Consent Forms ................................................................... 185 
Appendix II-A:  Sample Informed Consent Form for Participation in Cohort 1 ......................... 185 
Appendix II-B:  Sample Informed Consent Form for Participation in Cohort 2A ...................... 205 
Appendix II-C:  Sample Informed Consent Form for Participation in Cohort 2B ....................... 226 
Appendix II-D:  Sample Informed Consent Form for Specimen Storage and Future Use .......... 245 
Appendix III: Sample Informed Assent Forms .................................................................... 249 
Appendix III-A: Sample Informed Assent Form for Participation in Cohort 1 ........................... 249 
Appendix III-B:  Sample Informed Assent Form for Participation in Cohort 2 .......................... 255 
Appendix III-C: Sample Informed Assent Form for Specimen Storage and Future Use for 
Participants...................................................................................................................... 261 
Appendix IV: Parent/Caregiver Participation in Qualitative Phone Interviews ................. 264 
Appendix IV-A: Parent/Caregiver Qualitative Phone Interviews ................................................ 264 
Appendix IV-B: Parent/Caregiver Phone Interview Sample Informed Consent Form ................ 270 
Appendix IV-C: Parent/Caregiver Phone Interview Sample Informed Consent Verbal Script ... 273 
Appendix V:  Injectable Study Product Preparation ........................................................... 276 
Appendix V-A: Preparation of CAB LA ..................................................................................... 276 
Appendix V-B: Preparation of RPV LA ...................................................................................... 279 
Appendix VI:  Guidance for Study Implementation at Sites Experiencing Operational 
Disruptions Due to COVID-19 ................................................................................... 282 
 
 LIST OF FIGURES 
 
Figure 1. Overview of Study Design for Cohort 1 Participants .................................................................. 25 
Figure 2. Overview of Study Design for Cohort 2 Participants .................................................................. 26 


 
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Figure 3. Observed preliminary IMPAACT 2017 Cohort 1C CAB concentrations in adolescents compared 
to model predicted concentrations based on POP PK analyses from adult studies ..................................... 43 
Figure 4. Observed IMPAACT 2017 Cohort 1R preliminary data and predicted RPV plasma 
concentrations in adolescents after PO RPV 25 mg once daily (left panel) and IM RPV LA 900-600-600 
mg (right panel)........................................................................................................................................... 44 
Figure 5. Observed trough RPV plasma concentrations in Cohort 1R adolescents (blue dots) and adults 
(boxplots, ATLAS/FLAIR) after PO RPV 25 mg once daily (Week 0; last day of PO lead-in), and IM 
RPV LA 900-600-600 mg (Weeks 4, 8 and 12; concentrations 4 weeks after injection) ........................... 44 
 
LIST OF TABLES 
 
Table 1: Adverse Drug Reactions Observed in Adult Patients Treated with RPV in Combination with 
CAB (16) ....................................................................................................................................................... 41 
Table 2. Predicted Steady State CAB Exposures following Oral CAB 30mg and 60mg QD in Adolescents 
compared to Observed Adult Values .......................................................................................................... 50 
Table 3. Predicted Steady State CAB Parameters following CAB LA IM Q8W regimen compared with 
Observed and Estimated data in Adults ...................................................................................................... 51 
Table 4.  Predicted RPV Trough Concentrations following RPV LA IM Q8W in Adolescents, compared 
with Observed Data in Adults ..................................................................................................................... 52 
Table 5. Cohort 1: Study Product Regimen and Administration ................................................................ 71 
Table 6. Cohort 2A: Study Product Regimen and Administration ............................................................. 72 
Table 7. Cohort 2B: Study Product Regimen and Administration .............................................................. 72 
Table 8. Documentation Requirements for Medical and Medication Histories ........................................ 111 
Table 9. Visits Requiring Complete Physical Examination ...................................................................... 113 
Table 10. Percent of Participants Experiencing ≥ Grade 3 Adverse Events (or ≥ Grade 3 Adverse Events 
Attributed to the Study Medications) with Exact 95% Confidence Intervals ........................................... 142 
Table 11. Probability of Failing Dose Guidelines Under Potential Rates of True Toxicity ..................... 147 
Table 12. Probability of Failing Dose Guidelines Under Potential Rates of True Toxicity ..................... 149 
Table 13. Percent of Participants with HIV-1 RNA<50 c/mL per Snapshot algorithm with Exact 95% 
Confidence Intervals ................................................................................................................................. 153 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics 
of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable 
Rilpivirine in Virologically Suppressed HIV-Infected Children and Adolescents 
 
DAIDS Study ID #30070 
 
 
Version 4.0 
Protocol Signature Page 
 
 
 
I will conduct this study in accordance with the provisions of this protocol amendment and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) Health 
and Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonisation Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
__ 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 
 
 


 
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IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics 
of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable 
Rilpivirine in Virologically Suppressed HIV-Infected Children and Adolescents 
 
ABBREVIATIONS AND ACRONYMS  
 
3TC 
Lamivudine 
ABC 
Abacavir 
ADR 
Adverse drug reaction 
AE 
Adverse Event  
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine Transaminase 
ARV 
Antiretroviral 
ART 
Antiretroviral Therapy 
AST 
Aspartate Aminotransferase 
ATV 
Atazanavir 
AUC 
Area under the plasma concentration-time curve 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
C28D 
Concentration at 28 days 
CAB 
Cabotegravir 
CAB LA 
Long-Acting Injectable Cabotegravir 
cART 
Combination Antiretroviral Therapy 
CAR 
Continued Antiretroviral Regimen 
CBC 
Complete Blood Count 
CD4 
Cluster of differentiation 4 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CHOP 
Children’s Hospital of Philadelphia 
CI 
Confidence intervals 
CK 
Creatine Kinase 
CL/F 
Apparent total body clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum concentration 
CM 
Clarification Memorandum 
CMC 
Clinical Management Committee 
COVID-19 
Coronavirus disease 2019 
CPK 
Creatine phosphokinase 
CrCl 
Creatinine clearance 
CRMS 
NIAID Clinical Research Management System 
CRPMC 
NIAID Clinical Research Products Management Center 
CT 
Cohort 
C 
Trough concentration 
CNDx 
Concentration at a specified time (x) after administration of a specific dose number (ND) 
CV% 
Coefficient of variation 
CVF 
Confirmed Virologic Failure 
DAIDS 
Division of AIDS  
DAIDS RSC 
DAIDS Regulatory Support Center 


 
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DAIDS PRO 
DAIDS Protocol Registration Office 
DAERS 
DAIDS Adverse Experience Reporting System 
DILI 
Drug-induced liver injury 
DMC 
Data Management Center 
DMPK  
Drug Metabolism and Pharmacokinetics 
DTG 
Dolutegravir 
EAE 
Expedited Adverse Event 
EC 
Ethics Committee 
ECG/EKG 
Electrocardiogram 
 
eCRF  
Electronic Case Report Form 
EFV 
Efavirenz 
EIA  
Enzyme immunoassay 
ETV 
Etravirine 
EU 
European Union 
FDA 
Food and Drug Administration 
FSTRF 
Frontier Science and Technology Research Foundation 
FTC 
Emtricitabine 
GCLP 
Good Clinical Laboratory Practice 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practice 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C virus 
HDPE 
High density polyethylene 
HIV 
Human Immunodeficiency Virus 
HPLC/MS/MS High-performance liquid chromatography and tandem mass spectrometry 
HSP 
Human Subject Protection 
HVTN 
HIV Vaccine Trials Network 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
IC90 
90% inhibitory concentration 
ICH 
International Council on Harmonisation 
IM 
Intramuscular 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
IND 
Investigational New Drug 
INSTI 
Integrase Strand Transfer Inhibitor 
IoR 
Investigator of Record  
IRB  
Institutional review board 
ISR 
Injection site reaction 
ITT-E 
Intention to treat-efficacy 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
z 
Terminal slope 
LA 
Long-acting 
LDMS 
Laboratory Data Management System 
LoA 
Letter of Amendment 
LPC 
Laboratory processing chart 
LSFU 
Long-term Safety and Washout PK Follow-Up 
MC 
Monte Carlo simulations 
MOCHA 
More Options for Children and Adolescents 
MOP 
Manual of Procedures 


 
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NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NNRTI 
Non-nucleoside Reverse Transcriptase Inhibitor 
NOAEL 
No-observed-adverse-effect-level 
NRTI  
Nucleoside Reverse Transcriptase Inhibitors 
NTD 
Neural Tube Defect  
OHRP 
US Office for Human Research Protection 
OLI 
Oral lead-in 
PCR 
Polymerase Chain Reaction 
PDVF 
Protocol defined virologic failure 
pH 
proton concentration 
PI 
Protease Inhibitor 
PID 
Participant Identification Number 
PK 
Pharmacokinetics 
PO 
By mouth 
POP PK 
Population PK 
PoR 
Pharmacist of Record 
PPN 
Pre- and postnatal 
Q4W 
Study drug administration every 4 weeks 
Q8W 
Study drug administration every 8 weeks 
q.d. 
One a day 
QTc 
Corrected Q-T interval 
QTcB 
Corrected QT interval according to Bazett 
QTcF 
Corrected QT interval according to Fridericia 
RNA 
Ribonucleic Acid 
RPV 
Rilpivirine 
RPV LA 
Long-acting injectable rilpivirine 
RSC 
DAIDS Regulatory Support Center 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SD 
Standard deviation 
SDMC               Statistical and Data Management Center 
SES 
Subject Enrollment System 
SID 
Study Identification Number 
SMC 
Study Monitoring Committee 
SMR 
Sexual Maturity Rating 
SoC 
Standard of Care 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected, Unexpected Serious Adverse Reactions 
TAF 
Tenofovir alafenamide 
TDF 
Tenofovir disoproxil fumarate 
Tmax 
Time of maximum concentration 
TQT 
Thorough QT 
ULN 
Upper Limit of Normal 
US 
United States of America 
V/F 
 
Apparent volume of distribution 
VL 
 
Viral load 
VQA 
 
Virology Quality Assurance Program 


 
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WHO  
World Health Organization 
 


 
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IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics 
of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable 
Rilpivirine in Virologically Suppressed HIV-Infected Children and Adolescents 
 
PROTOCOL TEAM ROSTER 
 
Protocol Co-Chairs 
Carolyn Bolton Moore, MSc, MBBCh  
Centre for Infectious Disease Research in 
Zambia/University of Alabama Birmingham 
Plot # 34620, Off Alick Nkhata Road 
Mass Media, Lusaka, 10101, Zambia 
Phone: +260973876922 
Email: Carolyn.bolton@cidrz.org 
 
Aditya H. Gaur, MD 
Department of Infectious Diseases 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Phone: 901-595-2862 
Email: aditya.gaur@stjude.org 
 
Clinical Research Managers 
Katherine Calabrese, MPH 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: 919-544-7040 x11306 
Email: kcalabrese@fhi360.org 
 
Sarah Buisson, MSW, MPH 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: 919-544-7040 x11585 
Email: sbuisson@fhi360.org 
 
Michael Whitton, BA  
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: 919-544-7040  
Email: mwhitton@fhi360.org 
 
NIAID Medical Officer 
Ellen Townley, MSN, FNP  
Maternal Adolescent Pediatric Branch DAIDS, 
NIAID, NIH  
Room 8B39, 5601 Fishers Lane  
Rockville, MD 20852-9831  
Phone: 240-292-4784  
Email: ellen.townley@nih.gov 
 
NICHD Medical Officer 
John (Jack) H Moye, Jr, MD 
Eunice Kennedy Shriver National Institute of 
Child Health and Human Development 
(NICHD) 
Building 6710B, Room.2130, 
Rockledge Drive 
Bethesda, MD 20817-7002 USA 
Phone: 301-594-8624 
Email: john.moye@nih.gov 
 
Protocol Pharmacist 
Cindy Parker, PharmD 
Pharmaceutical Affairs Branch 
NIH/NIAID/DAIDS/OCSO 
5601 Fishers Lane, 9D37 
Rockville, MD 20852 
Phone: 301-761-7199 
Email: cindy.parker@nih.gov 
 
Protocol Pharmacologists 
Edmund V. Capparelli, PharmD 
School of Medicine and Skaggs School of 
Pharmacy and Pharmaceutical Sciences 
University of California San Diego 
9500 Gilman Drive MC 0657 
La Jolla, CA 92093-0657 
Phone: 858-246-0009 
Email: ecapparelli@ucsd.edu 
 
Brookie M. Best, PharmD, MAS 
Skaggs School of Pharmacy and Pharmaceutical 
Sciences 
University of California San Diego 


 
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9500 Gilman Drive MC 0657 
La Jolla, CA 92093-0657 
Phone: 858-822-5550 
Email: brookie@ucsd.edu  
 
Mark Marzinke, PhD, DABCC 
Johns Hopkins University School of Medicine 
1800 Orleans Street, Sheikh Zayed Tower, 
Room B1-1020G 
Baltimore, MD 21287 
Office: (443) 287-7516 
CPAL Office: (410) 550-9702 
Email:  mmarzin1@jhmi.edu 
 
Protocol Statisticians 
Kristin Baltrusaitis, PhD  
Harvard T. H. Chan School of Public Health 
Center for Biostatistics in AIDS Research 
(CBAR) FXB Building 
651 Huntington Avenue 
Boston, MA 02115  
Phone: 617-432-7496 
Email: kbaltrus@sdac.harvard.edu 
 
Shawn Ward, MS 
Statistical and Data Management Center 
(SDMC) 
Frontier Science Foundation (FSTRF) 
1371 Beacon Street, Suite 203,   
Brookline, MA 02446  
Phone: 617-632-2000 ext 4045  
Email: sward@sdac.harvard.edu 
 
Ryan Milligan, MB 
Statistical and Data Management Center 
(SDMC) 
Frontier Science Foundation (FSTRF) 
1371 Beacon Street, Suite 203,   
Brookline, MA 02446  
Phone: 617-632-2000 ext 4048  
Email: rmilliga@sdac.harvard.edu 
 
Protocol Investigators 
Jennifer Chapman, MPH 
Qualitative Project Manager 
Children's Hospital of Philadelphia  
Roberts Building, 11232 
2716 South Street, 
Philadelphia, PA 19146 
Phone: 267-426-1247 
Email: ChapmanJ1@email.chop.edu 
 
Elizabeth Lowenthal, MD 
Departments of Pediatrics and Epidemiology 
University of Pennsylvania Perelman School of 
Medicine 
Children’s Hospital of Philadelphia 
Phone: 267-426‐2306  
Email: lowenthale@email.chop.edu 
 
Sharon Nachman, MD 
SUNY Stony Brook 
Stony Brook, NY 11794-8111 
Phone: 631-444-7692 
Email: 
Sharon.nachman@stonybrookmedicine.edu 
 
Allison Agwu, MD, ScM 
Johns Hopkins School of Medicine 
200 North Wolfe Street, Rm 3145 
Baltimore, MD  21287 
Phone: 410-614-3917 
Email: ageorg10@jhmi.edu 
 
Pharmaceutical Representatives 
Cindy McCoig, MD 
ViiV Healthcare 
Severo Ochoa, 2 
28760 Tres Cantos (Madrid), Spain 
Phone:  +34 608 831 611 
Email: cynthia.c.mccoig@viivhealthcare.com 
 
Conn M. Harrington 
ViiV Healthcare 
5 Moore Drive 
Research Triangle Park, NC 27709 
Phone: +1 919 272 4513 
Email: conn.m.harrington@viivhealthcare.com 
 
Jenny Huang 
GlaxoSmithKline 
7333 Mississauga Road 
Mississauga, Canada, L5N 6L4 
Phone: +1 647-787-2286 
Email: jenny.o.huang@gsk.com  
 
Susan Ford, PharmD 
ViiV Healthcare 
5 Moore Drive 
Research Triangle Park, NC 27709 
Phone: 919-483-0392 
Email: susan.l.ford@gsk.com 


 
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Herta Crauwels, PhD 
Janssen Research and Development 
Turnhoutseweg 30 
2340 Beerse, Belgium 
Phone:  +32 (0)14 64 1054 
Email: hcrauwel@its.jnj.com 
 
Kati Vandermeulen M.Sc. 
Janssen Research and Development 
Turnhoutseweg 30 
2340 Beerse, Belgium 
Phone: +32 14641233 
Email: kvanderm@its.jnj.com 
 
Rodica M. Van Solingen-Ristea, MD 
Janssen Research & Development 
Bldg. K102, Rm. 244 
Turnhoutseweg 30 
Beerse 2340, Belgium 
Phone: +32 478 63 2199 
Email: rvsolin1@its.jnj.com 
 
Protocol Data Managers 
Barbara Heckman, BS 
Frontier Science and Technology Research 
Foundation, Inc 
4033 Maple Road 
Buffalo, NY 14226-1056 
Phone: 716-834-0900 x7231 
E-mail: bheckman@frontierscience.org 
 
Jared L. Kneebone, PhD 
Frontier Science and Technology Research 
Foundation, Inc 
4033 Maple Road  
Buffalo, NY 14226-1056 
Phone: 716-834-0900 x7263 
E-mail: kneebone@frontierscience.org 
 
Kelsey Simon, MPH 
Frontier Science and Technology Research 
Foundation, Inc 
4033 Maple Road  
Buffalo, NY 14226-1056 
Phone: 716-834-0900 x7299 
Email: ksimon@frontierscience.org 
 
Protocol Laboratory Data Managers 
Kyle Whitson, MA 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7273 
E-mail: whitson@frontierscience.org 
 
Laboratory Center Representatives 
Sara Zabih 
ACTG Laboratory Center 
IMPAACT Laboratory Center 
University of California Los Angeles 
675 Charles E. Young Dr. South 
MRL #4774  
Los Angeles, CA 90095 
Phone: (310)-794-9084 
Email: szabih@milabcentral.org  
 
Emma Duffy 
ACTG Laboratory Center 
IMPAACT Laboratory Center 
University of California Los Angeles 
10990 Wilshire Blvd, Suite 260 
Los Angeles, CA 90024 
Phone:  617-407-8713 
Email: eduffy@milabcentral.org 
 
Orlinda Maforo 
ACTG Laboratory Center 
IMPAACT Laboratory Center 
University of California Los Angeles  
675 Charles E. Young Dr. South 
MRL # 4-774 
Los Angeles, CA 90095 
Phone:  240-643-2630 
Email:  omaforo@milabcentral.org  
 
Protocol Laboratory Technologists 
Chiraphorn Kaewkosaba, MSc 
Chiang Mai University HIV Treatment  
(CMU HIV Treatment) CRS 
110 Intavaroros Road, Sriphum, Muang 
Chiang Mai 50200 THAILAND 
Phone: 66 5393 6148 Ext. 243 
Email: chiraphorn@rihes.org 
 
Christine Inguglia  
Ann & Robert H. Lurie Children’s Hospital of 
Chicago 
467 W Deming, Rm 3012, Box 82, Chicago, 
Illinois 60614 


 
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Phone:  312-227-4395 
Email: CInguglia@luriechildrens.org 
 
Westat Clinical Research Associates 
Scott Watson, BS, RN  
Westat, Inc.  
1441 W. Montgomery Ave  
Rockville, MD 20850  
Phone: 415-494-5575 
Email: ScottWatson@westat.com 
 
Community Program Manager 
Cheryl D. Blanchette, BS  
IMPAACT Operations Center  
FHI 360 359 Blackwell St., Suite 200  
Durham, NC 22701 USA  
Phone: 919-544-7040 x11359  
Email: ccokley@fhi360.org 
 
Community Advisory Board Member 
Joel Pagan-Lizardi, MD 
University of Puerto Rico 
Medical Sciences Campus- School of Medicine  
Proyecto ACTU Biomedical Building II-1st 
Floor-Room 125 
San Juan, Puerto Rico 00936-6528 
Phone: 787-759-9595 
Email: jplizardi@hotmail.com  
 
 


 
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STUDY SITE ROSTER 
 
Site 4001, Ann & Robert H. Lurie Children's 
Hospital of Chicago 
Ellen Chadwick, MD 
IoR  
Lurie Children's Hospital 
225 East Chicago Ave, Box 20 
Chicago IL 60611-2605 
Phone: 312-227-4080 
Email: egchadwick@luriechildrens.org 
 
Emanuela (Lela) Lartey, RN  
Study Coordinator  
Lurie Children's Hospital  
225 East Chicago Ave, Box 155  
Chicago IL 60611-2605  
Phone: 312-227-8266  
Email: Elartey@luriechildrens.org  
 
Site 4601, University of California, UC San 
Diego 
Stephen Spector, MD 
IoR 
9500 Gilman Drive 
Stein Clinical Research Building 
Room 430, Mail Code 0672 
La Jolla, CA 92093 
Phone: 858-534-7170 
Email: saspector@ucsd.edu 
 
Megan Loughran, BA 
Study Coordinator 
4076 3rd Avenue 
Suite 301 
San Diego, CA 92103 
Phone: 858-534-9218 
Email: meloughran@ucsd.edu 
 
Site 5013, Jacobi Medical Center 
Andrew Wiznia, MD 
IoR 
Jacobi Medical Center 
1400 Pelham Parkway South 
Building # 1, Suite 1W5 
Bronx, NY 10461 
Phone: 718-918-4664 or 914-450-6462 
Email: andrew.wiznia@einsteinmed.org or 
Andrew.Wiznia@nychhc.org 
 
Marlene Burey, MSN, PNP 
Study Coordinator 
Jacobi Medical Center 
1400 Pelham Parkway South 
Building # 1, Suite 1W5 
Bronx, NY 10461 
Phone: 718-918-4783 or 718- 918-4518 
Email: Marlene.Burey@nychhc.org 
 
Site 5030, Emory University School of Medicine  
Andres Camacho-Gonzalez MD, MSc. 
IoR 
Emory University School of Medicine 
Children’s Healthcare of Atlanta 
2015 Uppergate Drive Office 550 
Atlanta, GA, 30322 
Phone: 404-727-5642 
Email: acamac2@emory.edu 
 
LaTeshia Seaton, MS, APRN 
Study Coordinator 
Grady-Family and Youth Clinic at Ponce 
341 Ponce de Leon Avenue, Room 201 
Atlanta, GA 30308 
Phone: 404-616-5936 
Email:  lseaton@emory.edu 
  
Site 5040, SUNY Stony Brook  
Sharon Nachman, MD  
IoR        
Stony Brook Children’s Hospital 
Stony Brook, NY 11794-8111 
Phone: 631-444-7692 
Email: 
Sharon.Nachman@stonybrookmedicine.edu 
 
Cristina Witzke, MPH 
Study Coordinator 
Stony Brook Children’s Hospital 
Stony Brook, NY 11794-8224 
Phone: 631-444-1313 
Email: 
Cristina.Witzke@stonybrookmedicine.edu 
 
Site 5048, The University of Southern 
California- LA 
Allison Bearden, MD 
IoR 
USC Keck School of Medicine 
1640 Marengo St. Suite #300 MC 9264 


 
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Los Angeles, Ca 90033-9033 
Phone: 213-509-9811 
Email: allison.bearden@usc.edu 
 
Yvonne T. Morales, LVN 
Study Coordinator 
USC Keck School of Medicine 
1640 Marengo St. Suite #300 MC 9264 
Los Angeles, Ca 90033-9033 
Phone: 323-865-1561 
Email: ytr@usc.edu  
 
Site 5051, University of Florida- Jacksonville 
Mobeen H. Rathore, MD, CPE, FAAP, FPIDS, 
FIDSA, FACPE, FSHEA 
IoR 
University of Florida Center for HIV/AIDS, 
Research, Education & Service (UFCARES) 
655 West 8th Street, Clinical Center 3rd Floor 
|Jacksonville, FL  32209 
Phone: 904-798-4179 
Email: Mobeen.Rathore@jax.ufl.edu 
 
Saniyyah Mahmoudi. MSN, ARNP, AGPCNP 
Study Coordinator  
University of Florida Center for HIV/AIDS, 
Research, Education & Service (UFCARES) 
655 West 8th Street, Clinical Center 3rd Floor| 
Jacksonville, FL  32209 
Phone: 904-244-5331 or 904-244-4881 
Email: saniyyah.mahmoudi@jax.ufl.edu  
 
Site 5052, University of Colorado- Denver 
Christiana Smith-Anderson, MD, MSc 
IoR 
University of Colorado School of Medicine 
Department of Pediatrics, Section of Infectious 
Diseases 
13123 East 16th Ave B055 
Aurora, CO  80045 
Phone: 720-777-8990 
Email: christiana.smith@childrenscolorado.org 
 
Emily Barr CPNP, CNM, MSN 
Study Coordinator  
13123 East 16th Avenue B055 
Aurora, Colorado 80045 
Phone: 720-777-8233 
Email: emily.Barr@childrenscolorado.org 
 
Site 5055, South Florida CDTC Ft. Lauderdale 
Lisa-Gaye Robinson, MD, MPH  
IoR 
Children’s Diagnostic & Treatment Center 
1401 S Federal Highway 
Fort Lauderdale, Florida 33316 
Phone: 954-728-1136 
Email: lerobinson@browardhealth.org 
 
Amy Inman  
Director, Research  
Children’s Diagnostic & Treatment Center  
1401 South Federal Highway  
Fort Lauderdale, FL 33316  
Telephone:  954-728-1050  
Email: ainman@browardhealth.org  
 
Paulino Four Castro 
Study Coordinator 
Children’s Diagnostic & Treatment Center  
1401 South Federal Highway  
Fort Lauderdale, FL 33316  
Telephone:  954-712-5052  
Email: pfourcastro@browardhealth.org 
 
Site 5083, Rush University Cook County 
Hospital  
Mariam Aziz, MD 
IoR 
600 S Paulina, ste 140 
Chicago IL 60612 
Phone: 312-942-4265 
Email: mariam_aziz@rush.edu 
  
Maureen McNichols, RN, MSN 
Study Coordinator 
2020 W Harrison, Rm 2130 
Chicago IL 60612 
Phone: 312-572-4541 
Email: maureen_mcnichols@rush.edu 
 
Site 5092, Johns Hopkins University  
Allison Agwu, MD, ScM 
IoR 
Johns Hopkins School of Medicine 
200 North Wolfe Street, Rm 3145 
Baltimore, MD  21287 
Phone: 410-614-3917 
Email: ageorg10@jhmi.edu 
 
Aleisha Collinson-Streng, RN, ACRN 


 
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Study Coordinator 
Johns Hopkins University 
200 N Wolfe St., Suite 3096 
Baltimore, MD 21287 
Phone: 443-287-8888 
Email: Acolli14@jhmi.edu 
 
Site 5112, David Geffen School of Medicine at 
UCLA 
Jaime G. Deville, MD 
IoR 
UCLA Department of Pediatrics, Infectious 
Diseases 
10833 Le Conte Avenue 
MDCC 22-442 
Los Angeles, CA 90095-1752 
Phone: 310-825-9660 
Email: jdeville@mednet.ucla.edu  
 
Michele Carter, RN 
Study Coordinator 
UCLA Department of Pediatrics, Infectious 
Diseases 
10833 Le Conte Avenue 
MDCC 22-442 
Los Angeles, CA 90095-1752 
Phone: 310-206-2165 
Email: mfcarter@mednet.ucla.edu  
 
Site 5114, Bronx-Lebanon Hospital Center 
Murli U. Purswani, MBChB, FAAP 
IoR 
Suites 1E and 1G, 1685 Morris Avenue, 
Bronx, NY 10457 
Phone: 718-960-1010 
Email: mpurswan@bronxleb.org 
  
Martha Cavallo, MS, CPNP 
Study Coordinator 
1685 Morris Ave Suite 1 G 
Bronx, NY 10457 
Phone: 718-960-1016  
Email: mcavallo@bronxleb.org 
 
Site 5115, Siriraj Hospital CRS 
Kulkanya Chokephaibulkit, MD. 
IoR 
Pediatric Infectious Diseases Unit,  
Department of Pediatrics,  
Fl. 8th, Chao-fah Building, 
Siriraj Hospital, 
2 Wanglang Road, Bangkok-noi,  
Bangkok 10700, Thailand 
Phone: +66-2-418-0544 
Email: Kulkanya.cho@mahidol.ac.th 
 
Puangphet Songsirithat, Pharm D  
Study Coordinator  
Pediatric Infectious Diseases Unit,   
Department of Pediatrics,   
Fl. 3rd, Chao-fah Building,  
Siriraj Hospital,  
2 Wanglang Road, Bangkok-noi,   
Bangkok 10700, Thailand  
Phone: +66-2-866-0225; +66-2-419-5695  
Phone: 66-2-419-5695  
Email: puangphet.song@gmail.com  
 
Site 5116, Chiangrai Prachanukroh Hospital 
CRS 
Pradthana Ounchanum, MD 
IoR 
1039 Sathanpayaban Road 
Chiang Rai, 57000, Thailand 
Phone: +66 (0) 53520 359 
Email: doctorbaiplu@gmail.com 
 
Tim Cressey, PhD 
Study Coordinator 
195 Kaew Nawarat Road (3-4 Fl.) 
Wat Ked, Muang 
Chiang Mai 50000 Thailand 
Phone: +66 (0) 5324 0910 
Email: tim.cressey@phpt.org 
 
Site 5126, MU-JHU Research Collaboration 
CRS 
Maxensia Owor, MBChB, MMed, MPH 
IoR 
Makerere University- Johns Hopkins University 
Research Collaboration 
Upper Mulago Hill Road, P.O. Box 23491, 
Kampala, Uganda 
Phone: +256 787952048 
Email: maxowor@mujhu.org 
 
Hajira Kataike, MBChB 
Study Coordinator 
Makerere University -Johns Hopkins University 
Research Collaboration 
Upper Mulago Hill Road, P.O.BOX 23491, 
Kampala, Uganda 


 
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Phone: +256 774885488 
Email: hkataike@mujhu.org 
 
Site 5127, Pediatric Perinatal HIV Clinical 
Trials Unit 
Charles Mitchell, MD  
IoR  
University of Miami Miller School of Medicine  
BCRI Room 286  
1580 NW Tenth Avenue  
Miami, Florida 33136  
Phone: 305-243-2755  
Email: cmitchel@med.miami.edu   
 
Grace A. Alvarez A. FMD, MPH 
Study Coordinator 
University of Miami School of Medicine 
Pediatric Infectious Diseases and Immunology 
Batchelor's Children's Research Institute 
1580 N.W. 10th Ave., Suite 286 
Miami, FL 33136 
Phone:  305-243-4447 
Email:  galvarez2@miami.edu 
 
Site 5128, Texas Children's Hospital 
Mary E. Paul MD, 
IoR 
Texas Children’s Hospital 
1102 Bates Ave., Feigin Center 6th Floor 
Retrovirology ＆ Global Health  
Houston, TX 77030 
Phone: 832-824-1038 
Email: mepaul@texaschildrens.org 
 
Mariam Pontifes, CCRP  
Study Coordinator  
Texas Children’s Hospital  
1102 Bates, Suite FC330  
Houston, TX 77030  
Phone: 832-822-1268  
Email: mepontif@texaschildrens.org 
 
Site 6501, St. Jude Children’s Research Hospital 
Aditya H. Gaur, MD 
IoR 
Department of Infectious Diseases 
262 Danny Thomas Place 
Memphis, TN 38105 
Phone: 901-595-2862 
Email: aditya.gaur@stjude.org 
 
Adrienne English, RN 
Study Coordinator 
Department of Infectious Diseases 
262 Danny Thomas Place, MS 600 
Memphis, TN 38105 
Phone: 901-595-3078 
Email: adrienne.english@stjude.org  
 
Site 8051, Wits RHI Shandukani Research 
Centre CRS 
Faeezah Patel, MBBCh 
IoR 
Shandukani Research, Wits RHI, 2nd floor, 
Hillbrow Health Precinct  
Corner Esselen and Klein Street, Hillbrow  
Johannesburg, Gauteng, 2001, South Africa 
Phone: +2783 532 1814 
Email: fpatel@wrhi.ac.za 
 
Sibongile Phathokuhle Mncube  
Study Coordinator  
Shandukani Research, Wits RHI, 2nd floor, 
Hillbrow Health Precinct  
Corner Esselen and Klein Street, Hillbrow  
Johannesburg, Gauteng, 2001, South Africa 
Phone: 27-11-358-5500 
Email: smncube@wrhi.ac.za 
 
Site 8052, Soweto IMPAACT CRS 
Avy Violary, MD, FCPaed 
Co-IoR 
Perinatal HIV Research Unit Chris Hani 
Baragwanath Academic Hospital  
PO Box 114,  
Diepkloof Soweto Johannesburg,  
South Africa 
Phone: +27 11 989 9707 
Email: violari@mweb.co.za 
 
Sisinyana Ruth Mathiba, MBCHB 
Co-IoR 
Perinatal HIV Research Unit Chris Hani 
Baragwanath Academic Hospital  
PO Box 114,  
Diepkloof Soweto Johannesburg,  
South Africa 
Phone: +27 11 989 9761 
Email: mathibas@phru.co.za 
 
Nastassja Ramsagar, BSc 


 
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Study Coordinator 
Perinatal HIV Research Unit Chris Hani 
Baragwanath Academic Hospital  
PO Box 114,  
Diepkloof Soweto Johannesburg,  
South Africa  
Phone: +27 11 989 9858 
Email: choonilaln@phru.co.za 
 
Site 8950, FAMCRU CRS 
Samantha Fry, MD, MMED 
IoR 
Department of Paediatrics and Child Health          
FAMCRU, Stellenbosch University 
 Ward J8, Tygerberg Hospital 
Francie van Zijl Ave, Parow Valley 
South Africa, 7505 
Phone: +27-21-9384153 
Email: fry@sun.ac.za 
 
Jeanne de Jager, MSc 
Study Coordinator 
Department of Paediatrics and Child Health          
FAMCRU, Stellenbosch University 
Ward J8, Tygerberg Hospital 
Francie van Zijl Ave, Parow ValleySouth 
Africa, 7505 
Phone: +27-21-9384290 
Email: jeannes@sun.ac.za 
 
Site 12701, Gaborone CRS 
Gaerolwe R. Masheto, MD 
IoR 
Botswana Harvard AIDS Institute Partnership 
Plot 1836, North Ring Road, 
Princess Marina Hospital Grounds,  
Gaborone, Botswana 
Phone: +267 3975999; +267 72371278 
Email: gmasheto@bhp.org.bw 
 
Ponego L, Ponatshego, MD 
Study Coordinator 
Plot 2403, Hospital Way 
Gaborone, Botswana 
Phone: +267 3930335; +267 75600305 
Email: pponatshego@bhp.org.bw 
 
Site 12702, Molepolole CRS  
Gaerolwe R. Masheto, MD 
IoR 
Botswana Harvard AIDS Institute Partnership 
Plot 1836, North Ring Road, 
Princess Marina Hospital Grounds,  
Gaborone, Botswana 
Phone: +267 3975999; +267 72371278 
Email: gmasheto@bhp.org.bw 
 
Ponego L, Ponatshego, MD 
Study Coordinator 
Plot 2403, Hospital Way 
Gaborone, Botswana 
Phone: +267 3930335; +267 75600305 
Email: pponatshego@bhp.org.bw 
 
Site 30300, Umlazi CRS 
Sherika Hanley, MBChB, MMedFamMed, 
FCFP 
Co-IoR 
Prince Mshiyeni Memorial Hospital,  
1358 Mangosuthu Highway,  
Philasande Clinic, 4066 
Umlazi, 4060, South Africa 
Phone: +27 31 2602731; +2772 516 0566 
Email: hanley@ukzn.ac.za 
 
Dhayendre Moodley, MMedSc, PhD 
Co-IoR 
Prince Mshiyeni Memorial Hospital,  
1358 Mangosuthu Highway,  
Philasande Clinic, 4066 
Umlazi, 4060, South Africa 
Phone: +27 31 2601935 
Email: moodleyd1@ukzn.ac.za 
 
Vani Govender, ND Biotechnology, BSc Honors 
Medical Biochemistry, B-tech Business 
administration. 
Study Coordinator 
Prince Mshiyeni Memorial Hospital,  
1358 Mangosuthu Highway,  
Philasande Clinic, 4066 
Umlazi, 4060, South Africa 
Phone: +27 31 2601998 
Email: Vani.Govender@caprisa.org 
 
Site 31784, Chiang Mai University HIV 
Treatment CRS 
Linda Aurpibul, MD, MPH   
IoR 
Research Institute for Health Sciences 
Chiang Mai University 
110 Intavaroros Road, Muang 


 
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Chiang Mai 50200, Thailand 
Phone: +66 53936148 ext 445 
Email: lindaa@rihes.org   
 
Chintana Khamrong, M.Sc. 
Study Coordinator 
Research Institute for Health Sciences 
Chiang Mai University 
110 Intavaroros Road, Muang 
Chiang Mai 50200, Thailand 
Phone: +66 53936148 ext 446 
Email: chintanak@rihes.org   
 
Site 31798, Baylor-Uganda CRS 
Violet Korutaro, MBChB MScPH 
IoR 
Baylor College of Medicine Children’s 
Foundation-Uganda 
Block 5 Mulago Hospital. BOX 72052  
Kampala, Uganda 
Phone: +256 417-119200/100    
Email: vkorutaro@baylor-uganda.org  
 
Lilian Birungi, BSN, DPPM, MPH  
Study Coordinator  
Baylor College of Medicine Children’s 
Foundation-Uganda  
Block 5 Mulago Hospital. BOX 72052   
Kampala, Uganda  
Phone: +256 417-119200/100  
Email: lbirungi@baylor-uganda.org  
 
Site 33001, University of South Florida (USF) 
College of Medicine ATN CRS 
Carina Rodriguez, MD 
IoR 
Pediatrics Division of Infectious Diseases 
17 Davis Blvd., Suite 200 
Tampa, FL 33606 
Phone: 813-259-8800 
Email: crodrig1@health.usf.edu 
 
Denise Casey, RN, BSN 
Study Coordinator 
17 Davis Blvd., Suite 200 
Tampa, FL 33606 
Phone: 813-259-8750 
Email: dcasey1@health.usf.edu 
 
Site 33019, Wayne State University ATN CRS 
Elizabeth Secord, MD 
IoR 
3901 Beaubien 
Detroit, MI, 48201 
Phone: 313-745-4450 
Email: esecord@med.wayne.edu 
 
Charnell Cromer, RN, MSN 
Study Coordinator 
Department of Pediatrics 
4201 St. Antoine 
Detroit, MI 48201 
Phone: 313-966-0622 
Email: ccromer@med.wayne.edu 
 
Ayanna Walters RN, BSN  
Study Coordinator  
Wayne Pediatrics  
400 Mack Avenue  
Detroit, MI 48201  
Phone: 313-448-9600  
Email: aywalter@med.wayne.edu  
 
 
 
 
 
 


 
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IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics 
of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable 
Rilpivirine in Virologically Suppressed HIV‐Infected Children and Adolescents 
 
SCHEMA 
 
Purpose: 
To confirm the dose and evaluate the safety, tolerability, acceptability, and 
pharmacokinetics (PK) of oral cabotegravir (CAB), long-acting injectable cabotegravir 
(CAB LA), and long-acting injectable rilpivirine (RPV LA) in virologically 
suppressed children and adolescents living with HIV aged 12 to <18 years.  
  
Design: 
Phase I/II, multi‐center, open‐label, non‐comparative study 
 
Study Population: Children and adolescents, 12 to <18 years of age living with HIV-1, who are 
virologically suppressed on stable cART consisting of 2 or more drugs from 2 or 
more classes of antiretroviral drugs, and selected parents/caregivers.  
 
Sample Size: 
Up to 155 adolescents in total 
 
Cohort 1:  Up to 55 adolescents to achieve approximately 30 to 35 dose-evaluable 
receiving the oral followed by the LA dose of CAB (Cohort 1C) or RPV (Cohort 1R), 
in addition to cART, which, passing safety and PK guidelines, are recommended as 
dosing for Cohort 2. Cohort 1C and Cohort 1R assignment is based on the 
adolescent’s pre-study cART regimen. 
 
• Cohort 1C:  Up to 30 adolescents to achieve approximately 15 to 20 dose-
evaluable for CAB. The dose-evaluable population will include at least 4 
adolescents assigned female at birth, at least 4 adolescents assigned male at birth, 
at least 5 adolescents weighing 35 kg to less than 50 kg at study entry, and at least 
5 adolescents weighing at least 50 kg at study entry.  
 
• Cohort 1R:  Up to 25 adolescents to achieve approximately 15 dose-evaluable for 
RPV. The dose-evaluable population will include at least 4 adolescents assigned 
female at birth, at least 4 adolescents assigned male at birth, at least 5 adolescents 
weighing 35 kg to less than 50 kg at study entry, and at least 5 adolescents 
weighing at least 50 kg at study entry. 
 
Cohort 2:  Up to 155 adolescents enrolled across Cohort 2A and Cohort 2B to 
achieve the following: 
• At least 100 participants exposed to the final recommended dose for Cohort 2 
(including adolescents enrolled to Cohort 2 who previously participated in Cohort 
1), which includes 
• Approximately 70 evaluable participants receiving the final recommended doses 
for Cohort 2 who had not previously participated in Cohort 1. 
 
Up to 60 parents or caregivers of adolescent participants, as selected by the protocol 
team, to complete a single qualitative phone interview (U.S. sites only). 
 


 
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Note: For definition of “dose-evaluable”, please refer to Section 9.5.1.3 of the 
protocol. For definition of “evaluable”, please refer to Section 9.1 (General Design 
Issues) of the protocol. 
 
Study Product: 
Cohort 1: 
• Cohort 1C:  30 mg CAB once daily orally for at least four weeks (up to a 
maximum of 6 weeks) in addition to cART (Step 1 oral phase), followed by two 
single intramuscular injections of CAB LA four weeks apart (600 mg injections) 
in addition to cART (Step 2 injection phase). 
 
• Cohort 1R:  25 mg RPV once daily orally for at least four weeks (up to a 
maximum of 6 weeks) in addition to cART (Step 1 oral phase), followed by two 
single intramuscular injections of RPV LA four weeks apart (900 mg injections) 
in addition to cART (Step 2 injection phase). 
 
Dose adjustments are not anticipated but may occur as described in protocol Sections 
9 and 10. 
 
Cohort 2: 
• Cohort 2A (oral lead-in followed by injections): 30 mg CAB + 25 mg RPV once 
daily orally for at least four weeks, and up to a maximum of 6 weeks, during Step 
3 oral phase, followed by intramuscular injections of CAB LA + RPV LA: first 
and second injections four weeks apart (CAB LA 600 mg injection + RPV LA 900 
mg injection), with subsequent injections every eight weeks through and including 
Week 96 (CAB LA 600 mg injections + RPV LA 900 mg injections) during Step 
4 injection phase. 
 
• Cohort 2B (start with injections): Intramuscular injections of CAB LA + RPV LA: 
first and second injections four weeks apart (CAB LA 600 mg injection + RPV 
LA 900 mg injection), with subsequent injections every eight weeks through and 
including Week 92 (CAB LA 600 mg injections + RPV LA 900 mg injections) 
during Step 5 injection phase. 
 
Duration of  
Follow-Up: 
Adolescents in Cohort 1 will be followed for up to 64 weeks. Adolescents will be 
followed for at least four weeks in Step 1 (oral phase) and at least 12 weeks in Step 2 
(injection phase). All Step 2 adolescents will be followed (on cART, off study 
product) for up to an additional 48 weeks as part of long-term safety and washout PK 
follow-up (LSFU) after their last study product injection. Cohort 1 participants enroll 
into Cohort 2, if eligible, prior to completing long-term safety and washout PK 
follow-up. 
 
Adolescents in Cohort 2 will be followed for up to 144 weeks. Cohort 2A adolescents 
will be followed for at least four weeks in Step 3 (oral phase) and 92 weeks in Step 4 
(injection phase). Cohort 2B (start with injections) adolescents will be followed for 
92 weeks in Step 5. After completing 92 weeks of follow-up in the injection phase, 
Cohort 2 adolescents may continue access to injectable study products through a 
mechanism external to the protocol and will exit the study. Cohort 2 adolescents who 
prematurely permanently discontinue injectable study product use or upon 
completion of their study product dosing regimen do not wish to receive CAB LA + 


 
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RPV LA external to the protocol, will be followed (on cART, off study product) for 
an additional 48 weeks as part of long-term safety and washout PK follow-up after 
their last study product injection.   
 
Enrolled parents/caregivers will complete a single qualitative phone interview (U.S. 
sites only). 
 
Study Duration: 
Approximately 7 years total. Accrual into Cohort 1 is expected to require 
approximately two years. Following reviews of data from Cohort 1, accrual into 
Cohort 2 is expected to require approximately 18 months. Adolescents in Cohort 2 
will be followed for up to three years. 
 
Primary Objectives: Cohort 1 (continuing a background cART regimen) 
• 
To confirm the doses for oral CAB followed by injectable CAB LA in adolescents living with HIV 
who are virologically suppressed by evaluating: 
o Safety and multiple dose PK of oral CAB through Week 4; 
o Safety and multiple dose PK of CAB LA through Week 16. 
 
• 
To confirm doses for injectable RPV LA in adolescents living with HIV who are virologically 
suppressed by evaluating safety and multiple dose PK of RPV LA through Week 16. 
 
Primary Objective: Cohort 2 (discontinuing a background cART regimen) 
• 
To assess the safety of CAB + RPV in adolescents living with HIV who are virologically suppressed 
through: 
o Week 24 (Cohort 2A: oral followed by injectable) ; 
o Week 20 (Cohort 2B: injectable only). 
 
Secondary Objectives: Cohort 1 
• 
To monitor maintenance of viral suppression through Week 16 adolescents living with HIV who are 
virologically suppressed. 
 
• 
To evaluate the tolerability and acceptability of CAB LA through Week 16 adolescents living with 
HIV who are virologically suppressed. 
 
• 
To evaluate the tolerability and acceptability of RPV LA through Week 16 in adolescents living with 
HIV who are virologically suppressed. 
 
Secondary Objectives: Cohort 2 
• 
To assess safety of CAB LA + RPV LA in adolescents living with HIV who are virologically 
suppressed through: 
o Week 48 (Cohort 2A: oral followed by injectable);  
o Week 44 (Cohort 2B: injectable only). 
 
• 
To evaluate repeat-dose pharmacokinetics of CAB LA + RPV LA in adolescents living with HIV 
who are virologically suppressed through: 
o Week 24 and through Week 48 (Cohort 2A: oral followed by injectable); 
o Week 20 and through Week 44 (Cohort 2B: injectable only). 
 


 
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• 
To assess antiviral activity of CAB LA + RPV LA in adolescents living with HIV who are 
virologically suppressed through: 
o Week 24 and through Week 48 (Cohort 2A: oral followed by injectable); 
o Week 20 and through Week 44 (Cohort 2B: injectable only). 
 
Other Objectives 
• 
To evaluate the tolerability and acceptability of CAB LA + RPV LA in adolescents living with HIV 
who are virologically suppressed through:  
o Week 24, through Week 48, and through Week 96 (Cohort 2A: oral followed by injectable); 
o Week 20, through Week 44, and through Week 92 (Cohort 2B: injectable only). 
 
• 
To evaluate the safety, antiviral and immunologic activity, and characterize PK of CAB LA + RPV 
LA in adolescents living with HIV who are virologically suppressed through:  
o Week 96 (Cohort 2A: oral followed by injectable); 
o Week 92 (Cohort 2B: injectable only). 
 
• 
To evaluate adolescent participant’s experience of CAB LA and/or RPV LA, and parent/caregiver’s 
experience and perceptions of adolescent acceptability and tolerability of CAB LA and/or RPV LA 
(Cohort 1 and Cohort 2). 
 
• 
To evaluate the tolerability and acceptability, and characterize long-term safety and washout PK 
through 48 weeks following permanent discontinuation of CAB LA or RPV LA (Cohort 1). 
 
• 
To evaluate the tolerability and acceptability, and characterize long-term safety and washout PK 
through 48 weeks following permanent discontinuation of CAB LA + RPV LA (Cohort 2). 
 
• 
To describe HIV-1 genotypic and phenotypic resistance patterns in participants experiencing 
confirmed virologic failure (Cohort 1 and Cohort 2). 
 
 


 
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IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV‐Infected 
Children and Adolescents 
 
Figure 1. Overview of Study Design for Cohort 1 Participants 
  


 
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Figure 2. Overview of Study Design for Cohort 2 Participants  
 


 
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1 
INTRODUCTION  
 
1.1 
Background  
 
Contemporary antiretroviral therapy (ART) for management of HIV includes many potent, safe 
dosing options, some of which are available for adolescents and adults as one-pill, once-a-day, 
combination ART regimens. The long term success of HIV treatment remains dependent upon 
sustaining adherence to daily ART, which can be challenging (1, 2). In pediatrics, this is often 
further nuanced by factors specific to adolescents and their caregivers (3). Successful progression 
through the continuum of HIV care is poorer among adolescents than adults in the United States 
of America (US), with as many as 43% failing to reach and sustain HIV viral suppression (4). 
Unstructured treatment interruptions are a major issue for youth living with perinatally acquired 
HIV-1, with medication fatigue being the most common cited reason for such interruptions (5). 
While the current ART standard of care includes a backbone of two nucleoside reverse 
transcriptase inhibitors (NRTIs) plus another antiretroviral (ARV), alternative approaches are 
being examined that simplify treatment, reduce lifelong drug exposure and drug burden, preserve 
future treatment options, and minimize or avoid ART toxicities, particularly of NRTIs. Regimens 
being explored are "NRTI-reducing" or “NRTI-sparing”, including two-drug ART (from two 
independent classes) as initial treatment or a switch strategy (in virologically suppressed 
individuals) (6).  
 
Long‐acting (LA) injectable antiretrovirals are promising new therapies both for HIV treatment 
(7) and HIV prevention (8) that may change the treatment paradigm, although present unique 
implementation challenges. These monthly/2-monthly intramuscular (IM) injections, and other 
long-acting ART drug delivery platforms, could provide options to the current daily oral ART 
standard of care. These regimens could optimize treatment adherence and ultimately maximize 
the benefits of ART. This approach is similar to modern contraceptive product development, 
which has greatly expanded client choices and includes a diversity of drug delivery options, such 
as oral tablets, intramuscular injections, long-acting implants and skin patches.  
 
Cabotegravir (CAB) is a potent integrase strand transfer inhibitor (INSTI) with attributes 
allowing formulation and delivery as a LA parenteral product. Rilpivirine (RPV), also formulated 
as a LA product, is a diarylpyrimidine derivative and a potent non-nucleoside reverse 
transcriptase inhibitor (NNRTI) with in vitro activity against wild type HIV-1 and select NNRTI-
resistant mutants. Long-acting CAB LA and RPV LA have been shown in clinical trials in adults 
living with HIV to be safe, well tolerated and efficacious as a dual injectable ART in treatment-
naïve settings (step down, maintenance therapy after an oral three drug ARV induction therapy 
(9, 10) (Phase 3 Clinical trial ongoing; FLAIR, 201584, ClinicalTrials.gov Identifier: 
NCT02938520). A Phase 3 clinical trial of CAB LA plus RPV LA as a dual therapy approach in 
treatment experienced, virologically suppressed individuals (ATLAS 201585) showed that the 
regimen of monthly injections of CAB LA + RPV LA was noninferior to continued 3-drug oral 
ART at Week 48 and is currently ongoing, [ClinicalTrials.gov Identifier: NCT02951052] (11). 
Another study, ATLAS-2M [ClinicalTrials.gov Identifier: NCT03299049], demonstrated the non-
inferior antiviral activity and acceptable safety profile of CAB LA + RPV LA administered every 
8 weeks (Q8W) compared to CAB LA + RPV LA administered every 4 weeks (Q4W) over a 48-
week treatment period in virologically suppressed adults (12). These studies support both Q4W 
and Q8W duration regimens as treatment choices. A two-drug combination therapy with CAB LA 
plus RPV LA may therefore offer a comparable tolerability and resistance profile, as well as 
improved adherence and treatment satisfaction in virologically suppressed participants (9).  
 


 
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Building on the experience to date with CAB LA and RPV LA in adults living with HIV, 
IMPAACT 2017 Cohort 1 will assess the safety and PK of sequentially dispensed oral CAB 
followed by CAB LA (Cohort 1C), as well as oral RPV followed by RPV LA (Cohort 1R) in 
virologically suppressed adolescents living with HIV who continue their oral cART regimen. 
IMPAACT 2017 Cohort 2 will then establish if virologically suppressed adolescents living with 
HIV remain suppressed upon switching to a two-drug intramuscular (IM) regimen of CAB LA 
plus RPV LA. The age studied will be adolescents aged 12 to <18 years and ≥35kg.  
 
1.2 
Prior Research 
 
1.2.1 
Cabotegravir 
 
Cabotegravir (GSK1265744) is an HIV INSTI that has attributes favorable for both HIV 
treatment and prevention indications. CAB is available as both oral and injectable long-acting 
formulations.  
 
Summary of Cabotegravir Drug Metabolism and Pharmacokinetics (DMPK) 
 
CAB is rapidly absorbed following oral administration of the micronized tablet formulation, with 
median Tmax observed 2 to 3 hours post dose in the fasted state. Co-administration of single dose 
CAB 5 mg and 30 mg tablets with a moderate fat meal demonstrated minimal impact (<15% 
increase in CAB AUC(0-∞) and no impact on Cmax. In clinical studies to date, CAB tablets were 
taken without regard to the timing of or type of food consumed. CAB half-life of 35 to 42 h has 
been noted following oral administration. (13)  
 
 
 
CAB LA is a 200 mg/mL nanosuspension that has been administered as an IM injection and a SC 
injection of single doses of 100 to 800 mg and repeat doses from 200 to 800 mg. CAB LA 
exhibits absorption-limited (flip-flop) kinetics, and CAB has been detected in plasma up to 52 
weeks or longer after administration of repeat IM injections of CAB LA. Due to limited 
sampling, the observed apparent Tmax is generally observed at approximately one week post IM 
injection in Phase 2 studies. Apparent terminal phase t½ following CAB LA reflects absorption 
and ranges from approximately 18 to 50 days. Steady state appears to be achieved by 20 to 40 
weeks of the first IM injection of CAB LA Q4W or Q8W regimens. Variability in CAB Cmax 
following CAB LA is moderate to high with CV% ranging from 30 to >100%, due to variability 
in absorption rate. However, AUC (0-∞), which reflects the extent of absorption rather than the 
rate of absorption, exhibits lower variability with CV% ranging from 12 to 53%. In addition, 
variability decreases upon repeat administration. (13) 
 
Following administration in humans, CAB is primarily eliminated through metabolism, and renal 
elimination of unchanged CAB represents less than 1% of the total dose administered. In vitro 
and in vivo data indicate that CAB is primarily metabolized by UGT1A1 with some involvement 
from UGT1A9. CYP-mediated CAB metabolism is expected to be minimal as evidenced by the 
lack of effect observed when co-administered with etravirine (ETV), a known CYP3A4 inducer, 
in human participants. Cabotegravir is the predominant circulating compound in plasma, 
representing > 90% of plasma total radiocarbon. Fifty-eight percent of the total oral dose is 
excreted as unchanged CAB in the feces and 26.8% of the total oral dose is excreted in the urine, 
primarily as a glucuronide metabolite (75% of urine radioactivity, 14% of total dose). (13) 
 


 
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CAB LA has been administered intramuscularly to healthy adults and adults living with HIV at 
doses of 100mg to 800mg. In participants living with HIV, CAB LA has maintained virologic 
suppression on maintenance doses of 400mg IM Q4W and 600mg IM Q8W injections in 
conjunction with RPV LA (200056, 201584, 201585 and 207966). A population PK model 
including all relevant clinical PK data including IM data in 1647 adults (26% female) indicated 
that gender and BMI were statistically significant covariates (but clinically insignificant) 
affecting the absorption rate constant following IM administration, such that absorption was 
slower in females than males and in participants of larger BMI (up to 60kg/m2). (13) The slower 
absorption in females and high BMI participants resulted in lower peaks and higher troughs and 
was not associated with clinical outcome differences. Potential participants with high BMI have 
been excluded from Cohort 1 to minimize variability in characterization of PK parameters but 
high BMI will not be an exclusion for Cohort 2. 
 
CAB has no reported significant effect on cardiac repolarization. (13) 
 
Summary of cabotegravir safety data:  
 
 
The integrated analysis of safety data across the Phase III clinical studies when considered in 
combination with Phase I and Phase II data supports an acceptable safety profile of CAB + RPV. 
Safety conclusions from the clinical development program demonstrate the following: 
 
• 
The most frequently reported adverse events (AEs) in the Phase III program were injection 
site reactions (ISRs), mainly ISR pain. ISRs were generally mild or moderate with no Grade 4 
or Grade 5 or serious ISRs.  22 (4%) participants had Grade 3 ISRs, suggesting that ISRs 
generally did not interfere with daily activities.  Most ISRs resolved within 7 days.  The 
percentage of participants reporting ISRs at each visit decreased over time.  Few ISRs led to 
withdrawal. 
• 
Participant acceptance scores for anxiety pre- and post-injection decreased over time during 
the Phase III studies in the CAB + RPV treatment regimen. 
• 
The most common non-ISR AEs (10%) in the Phase III program for CAB + RPV and 
continued antiretroviral regimen (CAR) were nasopharyngitis, upper respiratory tract 
infection, and headache.  The majority of events reported had an intensity of Grade 1 or 
Grade 2.  47 (8%) participants in the CAB + RPV group and 35 (6%) participants in the CAR 
group experienced AEs that were Grade 3 to Grade 5.  No Grade 5 events were reported in 
the Phase III studies for participants receiving CAB + RPV. 
• 
Non-ISR AEs that occurred more frequently with CAB + RPV were hemorrhoids, pyrexia, 
dizziness, fatigue, and headache.  Except for headache, the incidence of these AEs in the 
CAB + RPV group was <10%. 
• 
A higher incidence of non-ISR, drug-related AEs in the CAB + RPV group was noted.  Most 
drug-related AEs were Grade 1, although a few Grade 3 to 4 AEs occurred.  The most 
frequent drug-related Grade 3 to 4 AEs were pyrexia (4%), fatigue (3%), and asthenia (2%). 
Different frequencies of non-ISR, drug-related AEs between treatment groups may be 
expected for an open-label switch study where the participants in the comparator CAR group 
had been on a stable and tolerable ART regimen.   


 
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• 
In the pooled analysis from the Phase III Maintenance Phases, 1 participant in the CAR group 
died due to a serious adverse event (SAE) of methamphetamine overdose.  This case was not 
considered to be related to study drug by the investigator and was the only Grade 5 SAE. 
• 
The rate of SAEs was low overall and was comparable between the CAB + RPV and CAR 
treatment groups.  The most frequently reported SAEs were hepatitis A, colitis, and 
anogenital warts. 
• 
31 (5%) participants in the CAB + RPV group and 26 (4%) participants in the CAR group 
had drug-related, non-ISR SAEs. 
• 
The rate of discontinuation was low overall for the Phase III studies.  Discontinuations from 
the study were more frequent in the CAB + RPV group.  Reasons for discontinuations were 
primarily ISRs and acute viral hepatitis.  22 (4%) participants in the CAB + RPV group and 9 
(2%) participants in the CAR group had AEs leading to withdrawal/permanent 
discontinuation of study drug during the Maintenance Phase.  17 (3%) participants in the 
CAB + RPV group and 9 (2%) participants in the CAR group had non-ISR AEs leading to 
discontinuation.  All individual AEs leading to withdrawal had an incidence of <1%. 
• 
Results from the Phase III studies indicate that CAB + RPV appears to have no clinically 
relevant effect on safety related to QT prolongation, seizures, rhabdomyolysis, pancreatitis, or 
impact on creatinine. 
• 
Incidence of neuropsychiatric events was low overall for suicidal ideation/behavior, 
depression, and anxiety.  Events occurred with similar frequency between treatment groups. 
• 
A higher incidence for mood disorders was observed in the CAB + RPV group compared 
with the CAR group.  
• 
The incidence of sleep disorders events (including drug-related events), particularly 
insomnia, was higher in the CAB + RPV group compared with that of the CAR group during 
the Phase III studies. 
• 
Modest weight gain occurred in both CAB + RPV and CAR treatment groups, although 
median weight gain was greater in the CAB + RPV group.  BMI increased in both CAB + 
RPV and CAR treatment groups, with a greater median change in the CAB + RPV group.  
The clinical significance of this weight gain is not clear.  There were some shifts in BMI for 
the CAB + RPV group that trended toward unfavorable. 
• 
Overall, the frequency and categories of drug related adverse events reported with daily oral 
CAB 30 mg have been similar to those reported with CAB LA and are infrequently treatment 
limiting. 
• 
The majority (74.7% CAB + RPV, 80.2% CAR%) of the maximum post-baseline emergent 
clinical chemistry toxicities were Grade 1 or Grade 2 in intensity.  With the exception of 
creatine kinase and lipase, there were similar frequencies of Grade 3/4 clinical chemistry 
abnormalities between the treatment groups.  No clinically relevant differences were 
observed overall in Grade 3 and Grade 4 post-baseline emergent toxicities between the CAB 
+ RPV and CAR groups. 


 
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• 
Results from the Phase III clinical program do not suggest any effect of age, sex, or race on 
the safety profile of CAB + RPV.  
• 
Patients living with HIV with evidence of hepatitis B virus (HBV) coinfection were excluded 
from the CAB + RPV clinical program as CAB + RPV do not have activity against HBV.  No 
conclusions can be made about the safety of CAB + RPV in Hepatitis B co-infected patients.   
• 
In the Phase III studies, 41/591 participants on CAB + RPV and 40/591 participants on CAR 
were determined to be co-infected with hepatitis C virus (HCV) at Baseline, as shown by 
HCV serology testing alone.  The participants without advanced chronic HCV were not at 
increased risk of developing hepatotoxicity or increased transaminases compared with 
participants living with HIV.  None of the participants in Studies 201584 and 201585 who 
became acutely infected with HCV on study resumed CAB + RPV after temporarily 
discontinuing dosing while the acute HCV infection either spontaneously resolved or 
stabilized. 
• 
No dose adjustment in CAB (oral or LA) or RPV (oral or LA) is required for patients with 
mild or moderate hepatic impairment.  No data are available in severe hepatic impairment. 
• 
No dose adjustment of oral CAB or CAB LA or oral RPV or RPV LA is required for patients 
with mild to moderate renal impairment.  No dose adjustment of oral CAB or CAB LA is 
required for severe renal impairment.  No data are available in severe renal impairment or 
end-stage renal disease for RPV. 
• 
Medication errors and device malfunctions were infrequent occurrences, and no adverse 
events were directly attributable to these errors and no evidence for lack of efficacy has been 
detected as the result of an error.  Overall, no discernable trends or systematic errors were 
identified, apart from an initial lack of familiarity by the health care provided.   
• 
In the Phase IIIb study ATLAS-2M Q8W dosing of CAB+RPV LA was noninferior to Q4W 
dosing and well tolerated. CAB+RPV LA Q8W was noninferior to Q4W dosing in both the 
primary (proportion with plasma HIV-1 ribonucleic acid (RNA) ≥50 c/mL 1.7% vs 1.0%) and 
secondary analysis (proportion with HIV-1 RNA <50 c/mL 94.3% vs 93.5%) at Week 48. 
ISRs were mostly mild or moderate (98% overall) with a median duration of 3 days. (12) 
Results from the CAB + RPV development program support the use of the regimen in virally 
suppressed patients living with HIV.  In clinical studies, a higher incidence of AEs leading to 
withdrawal and Grade 3/4 AEs was reported in the CAB + RPV group.  Overall, CAB + RPV 
appeared to be tolerated as well as comparator regimens.  Although ISRs occurred frequently, few 
were treatment limiting.   
 
Summary of side effects observed and/or monitored for in patients on cabotegravir include:  
 
Long-acting properties of cabotegravir injection  
Residual concentrations of CAB remain in the systemic circulation of participants who stop HIV 
treatment (e.g. for tolerability issues or treatment failure) for prolonged periods (up to 12 months 
or more) (13). Participants discontinuing an LA regimen may be at risk for developing viral 
resistance to CAB many weeks after discontinuing injectable therapy; therefore, adoption of an 
alternative, fully suppressive antiretroviral regimen is essential.  
 


 
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Hepatobiliary disorders 
Four participants with possible or probable drug-induced liver injury (DILI) related to CAB have 
been identified in the Phase 2b HIV treatment studies. Three of these participants met liver 
stopping criteria 4-8 weeks after initiation of oral treatment with CAB (60 mg n=2, 30 mg n=1). 
The fourth participant met liver stopping criteria after having received approximately 44 weeks of 
treatment with oral CAB 30 mg. In all cases participants remained asymptomatic, did not develop 
hepatic dysfunction and liver aminotransferase elevations returned to normal or approached pre-
treatment levels following withdrawal of all antiretroviral treatment. A role of CAB in these cases 
could not be ruled out. One of the four participants, with ongoing active chronic hepatitis C 
infection, developed a concomitant increase in total and direct bilirubin. This participant had 
underlying liver fibrosis. The three remaining participants had evidence of hepatosteatosis on 
liver imaging - which may have been pre-existing (13). In addition, a single case of suspected 
DILI was identified in a CAB/rifabutin drug interaction study (205712).  A 55-year-old male 
developed Grade 3 elevations in liver aminotransferases three weeks after co-administration of 
oral CAB and rifabutin ended. Liver workup was unremarkable except for a fatty liver on 
ultrasound examination, the participant was asymptomatic throughout, and the findings were 
consistent with a mixed hepatocellular and cholestatic type hepatitis.  The elevated liver 
aminotransferases fully resolved after approximately 23 weeks. One further case of possible DILI 
occurred in the Phase III study (207966) and involved a 20-30-year-old female who was 
randomized at Baseline to the Q4W group. The participant had previously received standard of 
care (SoC) with lopinavir + ritonavir + abacavir + lamivudine as part of Study 201585. She had 
an asymptomatic increase in alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST).  ALT was 206 U/L [>4x upper limit of normal (ULN)], AST was 137 U/L [>3x ULN] 
with no elevation in bilirubin at Week 4a, after receiving 28 days of oral CAB + RPV. 
Investigations were negative for viral hepatitis, syphilis, and an autoimmune screen. The oral 
lead-in (OLI) was extended while the participant was investigated for alternative causes. During 
this time ALT and AST remained elevated and the participant was eventually withdrawn from the 
study after receiving a total of 11 weeks of oral CAB + RPV. The participant commenced 
Abacavir (ABC)/Lamivudine (3TC)/Dolutegravir (DTG) and the ALT/AST returned to normal 
after 12 weeks. 
 
Elevated transaminases (AST/ALT) were observed in some participants receiving CAB + RPV 
during the pivotal Phase 3 trials, however, the primary reason for these elevations was the 
occurrence of acute viral hepatitis (Hepatitis A, B, C).  
 
No suspected cases of DILI have emerged to date in participants receiving CAB LA. 
 
Studies to date have incorporated close monitoring of liver chemistries and have adopted liver 
stopping criteria. Participants with known and documented Hepatitis B or Hepatitis C infection, 
with clinically relevant hepatic disease, or ALT Grade 3 or higher are excluded from IMPAACT 
2017, per Section 4. Additionally, studies to date involving exposure to the long-acting injection 
have incorporated an oral lead-in period as a precautionary measure to reduce the risk of severe 
hypersensitivity (see below) or liver injury developing during exposure to the LA formulation.  
 
Injection site reactions: ISRs are very common, but generally mild or moderate, most frequently 
comprising pain at the injection site, with localized erythema, pruritis, warmth, swelling, nodule 
formation, induration or bruising occurring less commonly. Severe ISRs were reported in 4% of 
participants. Abscess and cellulitis at the injection site have been reported uncommonly (<1% of 
participants). Median duration of the reactions overall was 3 days. To date, most reactions have 
been self-limited. (13) 
 


 
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Hypersensitivity reactions 
Hypersensitivity reactions have not been reported with cabotegravir but have been reported in 
association with other integrase inhibitors including the closely related compound, dolutegravir. 
These reactions were characterized by rash, constitutional findings and sometimes organ, 
including liver, dysfunction. However, no such reactions have been observed to date in 
association with CAB. An oral lead-in is being implemented within clinical studies to reduce the 
risk of a hypersensitivity reaction occurring following the initiation of LA therapy.(13) 
 
Use in pregnancy:  
Data in pregnancy are limited. Non-clinical data from rat pre- and postnatal (PPN) studies have 
indicated reduced survival and viability rates amongst rat pups during the first 4 days of life at the 
maximum tested dose of 1000 mg/kg/day (maternal exposure). No-observed-adverse-effect-level 
(NOAEL) was established at the mid dose 5 mg/kg/day, which remains >20 fold predicted Cmax 
and AUC exposures for anticipated clinical CAB LA exposures. The clinical significance of these 
findings is unknown. (13) 
 
Suicidal Ideation and Behavior Monitoring: 
CAB exposure has not been associated with an increased risk of suicidal ideation or psychiatric 
disorders. However, patients living with HIV or those in some categories with a high-incidence of 
HIV acquisition may occasionally experience symptoms of depression and/or suicidal ideation or 
behavior. In addition, there have been some reports of depression, suicidal ideation and behavior 
(particularly in participants with a pre-existing history of depression or psychiatric illness) in 
some patients being treated with INSTIs. Dolutegravir (DTG) (a closely related integrase 
inhibitor) has been associated with reports of suicidal ideation or behavior (particularly in patients 
with a pre-existing history of depression or psychiatric illness). (13) 
 
Seizures:  
Overall, there is not convincing evidence that CAB exposure may be causally associated with 
seizure or with reduction of seizure threshold, due to the low frequency of reports, the 
confounders present in the cases received to date and lack of any pre-clinical signal or identified 
plausible mechanism. Three cases of seizures have been documented in the CAB program 
cumulatively through 01 October 2016. Two of the cases occurred in HIV uninfected participants 
with a prior history of seizure and one case involved a participant in study 200056 with 
circumstantial and anecdotal evidence of illicit drug use. (13) 
 
Dolutegravir and Pregnancy 
 
Dolutegravir (DTG) is an INSTI in the same class of pharmaceuticals as CAB. Thus far, limited 
safety or efficacy data for DTG in pregnancy in humans have been published or presented. In 
May 2018, World Health Organization (WHO) and several other regulatory agencies released 
advisories regarding the safety of DTG in early pregnancy. (14) 
 
This was based on information received from the Botswana NICHD-funded Tsepamo Birth 
Outcomes Surveillance Study, the largest body of data related to birth outcomes following the use 
of DTG in pregnancy. This study was designed to evaluate adverse birth outcomes by maternal 
HIV status and ART regimen, and to determine whether there is an increased risk of neural tube 
defects (NTDs) among infants exposed to efavirenz (EFV) from conception. Botswana’s HIV 
program moved to universal ART with dolutegravir/tenofovir disoproxil fumarate/emtricitabine 
(DTG/TDF/FTC) in first line for patients starting ART (including pregnant women) in May of 
2016 (women already on other regimens were not switched to DTG). The previous first-line 
regimen was EFV/TDF/FTC. Almost all women on DTG-based and EFV-based ART took these 


 
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drugs in combination with TDF/FTC. More than 95% of women in Botswana deliver in a 
hospital, and obstetric records were available for >99% of women. The Tsepamo surveillance 
study was originally conducted at 8 of the largest public maternity wards across Botswana 
(representing ~45% of the total births in the country). This was later increased to 18 sites. 
Research assistants abstracted exposure data from the maternity card for all consecutive in-
hospital deliveries (both women living with and without HIV). Each newborn, whether stillborn 
or live-born, undergoes a systematic infant surface examination that is completed by trained nurse 
midwives. Reports and photographs (where available) of major abnormalities are reviewed by an 
experienced medical geneticist who is blinded to exposure information.  In the birth outcome 
surveillance study in Botswana there were 5 cases of neural tube defects reported (as of March 
2019) in 1,683 deliveries (0.3%) to mothers taking dolutegravir-containing regimens from the 
time of conception, compared with 15 cases in 14,792 deliveries (0.1%) to mothers taking non-
dolutegravir-containing regimens from the time of conception (Prevalence Difference 0.20%; 
95% CI 0.01-0.59). In the same study, one out of 3,840 deliveries (0.03%) to mothers who started 
dolutegravir during pregnancy had a neural tube defect, compared with three out of 5,952 
deliveries (0.05%) to mothers who started non-dolutegravir-containing regimens during 
pregnancy. More recent data from this study suggest an even lower incidence of neural tube 
defects amongst women taking dolutegravir-containing regimens from the time of conception. 
 
A causal relationship of these events to the use of dolutegravir has not been established. 
The incidence of neural tube defects in the general population ranges from 0.5-1 case per 
1,000 live births. As neural tube defects occur within the first 4 weeks of fetal development (at 
which time the neural tubes are sealed) this potential risk would concern women exposed to 
dolutegravir at the time of conception and in early pregnancy. More than 1,000 outcomes from 
second and third trimester exposure in pregnant women indicate no evidence of increased risk of 
adverse birth outcomes. 
 
Cabotegravir is not dolutegravir. While these medications share a common molecular backbone, 
and have a similar mechanism of activity, they are different chemical compounds. It is not known 
if the potential safety signal identified with DTG will be confirmed in other studies and/or 
settings where DTG is being used. There is insufficient data to confirm or refute any potential 
INSTI class effect. 
 
CAB was evaluated in a complete package of reproductive toxicology studies, including 
embryofetal development studies, and no safety findings suggestive of teratogenesis or neural 
tube defects were identified as of the information included in the 17 December 2019 version of 
the Investigator’s Brochure. Given limited clinical experience with use of CAB in pregnancy, as a 
precautionary measure, women of reproductive potential are required to adopt highly reliable 
means of contraception during participation and throughout long term follow up phases of studies 
following exposure to CAB LA as well as have a negative pregnancy test prior to study entry. 
 
1.2.2 
Rilpivirine 
 
Rilpivirine (TMC278, RPV) is a NNRTI with in vitro activity against wild type and NNRTI 
resistant HIV-1. Rilpivirine 25-mg once daily (oral tablet) is approved for the treatment of HIV-1 
in ART-naïve patients 12 years of age and older in multiple countries including the US, the 
European Union (EU), Canada, and Japan as EDURANT®(15). In most countries, including the 
US and EU, this indication is further restricted to patients with a plasma viral load (VL) ≤100,000 
HIV-1 RNA copies/mL. RPV (dose 25 mg) as part of a once-daily single-tablet oral regimen is 
also approved for adults and adolescents in several countries as Complera®/Eviplera® 


 
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(FTC/RPV/TDF) or Odefsey® (FTC/RPV/tenofovir alafenamide [TAF]) and as part of a single-
tablet dual regimen for adults, JULUCA® (DTG/RPV).  
 
A parenteral long-acting formulation of RPV (RPV LA) for intramuscular (IM) injection is 
indicated, in the US and the European Union (EU), in combination with the integrase 
inhibitor cabotegravir long-acting (CAB LA), as a complete regimen for monthly or 
every 2 months dosing for the treatment of HIV-1 infection in virologically suppressed 
adults (single agent REKAMBYS®, component of co-pack CABENUVA®). Phase III/IIIb 
studies in combination with a parenteral long-acting formulation of CAB (CAB LA) are ongoing. 
Of note both the oral and injectable formulation of RPV needs to be protected from direct 
exposure to light and are dispensed accordingly.  
 
The exposure to RPV as the tablet formulation was approximately 40 -to-50% lower when taken 
under fasting conditions or with only a nutritional drink as compared to intake with a standard or 
high fat breakfast. Therefore, oral RPV must always be taken with a meal. (16) 
 
The exposure to RPV can be affected by modulators of CYP3A4-enzyme activity and by drugs 
that increase the gastric anti-logarithmic proton concentration (pH), the latter being only 
applicable to oral RPV. Proton pump inhibitors (e.g. omeprazole) should not be co administered 
with oral RPV as this will decrease the exposure to RPV due to the increase in gastric pH. H2-
receptor antagonists, however, can be used if administered either at least 12 hours before or at 
least 4 hours after intake of RPV, and antacids can be used if administered either at least 2 hours 
before or at least 4 hours after intake of RPV. Drugs that induce CYP3A4 activity (e.g. rifampin, 
carbamazepine) can reduce the RPV exposure (either as oral or LA formulation) and should not 
be co-administered. Drugs that inhibit CYP3A4 activity (e.g. ketoconazole, boosted protease 
inhibitors [PIs]) can increase the exposure to RPV (either as oral or LA formulation) but do not 
require dose adjustments. (16) 
 
The approval of oral RPV 25 mg once daily for adolescents was based on the results of study 
TMC278-TiDP38-C213. The 48-week results of the adolescent cohort (N=36) in this study 
demonstrated that treatment with RPV 25 mg once daily, in combination with an investigator-
selected background regimen, is efficacious, generally safe and well tolerated in adolescents of 
≥12 to <18 years of age (17). The 25 mg once daily dose in adolescents resulted in similar RPV 
exposure as observed in adults. Also, no apparent relationships were observed between the RPV 
pharmacokinetics and efficacy or safety parameters in adolescents at Week 48. In the adult trials 
with the RPV doses of 25 mg once daily, no clear effect of body weight on the RPV exposure was 
seen. Similarly, data in adolescents between 12 and 18 years of age weighing approximately 33 to 
93 kg also showed no effect of body weight on the RPV exposure. (17) The Week 240 long-term 
data in the adolescents who continued treatment in the post-Week 48 treatment extension period 
also demonstrated efficacy and no new safety findings were identified; there were no relevant 
differences from the safety profile in adults living with HIV-1(16). 
 
Oral RPV 25mg has been co-administered with oral CAB in one Phase 1 study in healthy 
participants and two Phase 2 studies of participants living with HIV. Study LAI116181 
(ClinicalTrials.gov Identifier: NCT01467531) showed that there was no relevant drug interaction 
between CAB and RPV. (16) 
 
Population pharmacokinetic analysis of RPV in patients living with HIV indicate that race has no 
clinically relevant effect on the exposure to RPV. No clinically relevant differences in the 
pharmacokinetics of RPV have been observed between men and women. (16)  


 
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The pharmacokinetics of RPV have not been studied in patients with renal insufficiency. Renal 
elimination of RPV is negligible. Therefore, the impact of renal impairment on RPV elimination 
is expected to be minimal. As RPV is highly bound to plasma proteins, it is unlikely that it will be 
significantly removed by hemodialysis or peritoneal dialysis. No dose adjustment of RPV is 
required in patients with renal impairment. (16) 
 
RPV is primarily metabolized and eliminated by the liver. In a study comparing 8 participants 
with mild hepatic impairment (Child Pugh score A) to 8 matched controls, and 8 participants with 
moderate hepatic impairment (Child Pugh score B) to 8 matched controls, the multiple dose 
exposure of RPV was 47% higher in participants with mild hepatic impairment and 5% higher in 
participants with moderate hepatic impairment. No dose adjustment is required in participants 
with mild or moderate hepatic impairment. RPV has not been studied in participants with severe 
hepatic impairment (Child Pugh score C). (16) 
 
The effect of RPV at the recommended dose of 25 mg q.d. (marketed dose) on the QT interval 
corrected for heart rate according to Fridericia (QTcF) interval was evaluated in a randomized, 
placebo and active (moxifloxacin 400 mg q.d.) controlled crossover study thorough QT (TQT) in 
60 healthy adults, with 13 measurements over 24 hours at steady state. RPV at the recommended 
dose of 25 mg q.d. is not associated with a clinically relevant effect on QTc. Higher doses of RPV 
(75 and 300 mg q.d., 3 and 12 times higher than the recommended dose, respectively) examined 
in a previous TQT study, were associated with mean maximum QTcF prolongations > 10 ms, 
which were dose and plasma concentration dependent. Plasma concentrations after administration 
of RPV LA are substantially lower than those obtained with 75 mg q.d. and 300 mg q.d. and 
comparable to or lower than the plasma concentrations achieved with RPV 25 mg q.d. given 
orally. Therefore, no clinically relevant increase in QTcF is expected with the plasma 
concentrations achieved with RPV LA. In the RPV LA studies performed in healthy participants, 
no increases in QTc have been seen. (16) 
 
Data on pregnancy and lactation remain limited; the prescribing information recommends that 
RPV should be used during pregnancy only if the potential benefit justifies the potential risk and 
that the mothers should be instructed not to breastfeed if they are receiving RPV. (15) RPV in 
combination with a background regimen was evaluated in the RPV treatment arm of study 
TMC114HIV3015, in 19 pregnant women during the second and third trimesters, and postpartum. 
RPV was well tolerated during pregnancy and postpartum. There were no new safety findings 
compared with the known safety profile of RPV in adults living with HIV-1. (16) 
 
RPV LA (formulation G001) has been administered IM to healthy adults and adults living with 
HIV at doses of 300 mg to 1200 mg. Up to July 2019, in total, 318 healthy volunteers participated 
in studies with the long acting (LA) injectable form of RPV of whom 283 received RPV LA. 
RPV pharmacokinetic parameters following successive monthly intramuscular administration of 
1200/600/600 mg RPV LA in the gluteal muscle in healthy adult participants showed a half-life 
of 91 days +/- 41 days (t/1/2; mean +/- SD) (16). In a Phase IIb study in participants living with 
HIV (n=230), RPV LA maintained suppression of viral load following monthly (Q4W) IM 
injections of 600 mg or bi-monthly (Q8W) injections of 900 mg, in conjunction with CAB LA 
monthly or bi-monthly (study 200056 or LATTE-2 [ClinicalTrials.gov Identifier: 
NCT02120352]). (9) Currently, a dosing regimen of an RPV LA 900 mg IM loading dose 
followed by Q4W IM injections of 600 mg, in conjunction with CAB LA Q4W, is being 
evaluated in two Phase 3 studies in adults (ATLAS [ClinicalTrials.gov Identifier: NCT02951052] 
and FLAIR [ClinicalTrials.gov Identifier: NCT02938520]). and a dosing regimen of RPV LA 900 
mg IM every 2 months is, in conjunction with CAB LA 600 mg, is being evaluated in Phase III 


 
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study ATLAS-2M. The results of these clinical studies in participants living with HIV are 
discussed in Section 1.2.3 below.  
 
Summary of side effects observed and/or monitored for in participants on rilpivirine 
include: 
 
Virologic Failure and Development of Resistance: 
In the pooled analysis from the phase III trials of oral RPV with 2 NRTIs through 96 weeks, 
participants treated with oral RPV with a baseline viral load >100,000 HIV-1 RNA copies/mL 
had a greater risk of virologic failure compared to participants with a baseline viral load ≤100,000 
HIV-1 RNA copies/mL. The greater risk of virologic failure for participants in the oral RPV arm 
was observed in the first 48 weeks of these trials while low rates of virologic failure, similar 
between the treatment arms, were observed from week 48 to week 96. Participants with a baseline 
viral load >100,000 HIV-1 RNA copies/mL who experienced virologic failure exhibited a higher 
rate of treatment emergent resistance to the NNRTI class. More participants who failed 
virologically on oral RPV than who failed virologically on EFV developed 3TC/FTC associated 
resistance. The use of RPV in combination with CAB is described in Section 1.2.3. No new 
findings were identified in adolescent participants ≥12 to <18 years of age in trial C213. (16) 
 
Interactions with medicinal products 
Caution should be given to prescribing RPV with medicinal products that may reduce the 
exposure of rilpivirine. 
 
Fat Redistribution 
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement 
(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and ‘cushingoid 
appearance’ have been observed in patients receiving ART. The mechanism and long-term 
consequences of these events are currently unknown. A causal relationship has not been 
established. (16) 
 
Injection Site Reactions 
Intramuscular or SC injections are procedures which, even with physiological saline, occasionally 
induce transient reactions at the site of injection, called ISRs. By preferred term, local pain and 
erythema are the most common expected AEs of this type. 
 
Post-injection reactions 
In clinical trials in adults, there have been occurrences of serious and non-serious post-injection 
reactions which were reported within minutes after the injection of RPV LA. Some of these 
events may have been associated with accidental partial intravenous (IV) administration of RPV 
during the intramuscular injection procedure, as suggested by pharmacokinetic (PK) assessments 
showing unexpectedly high plasma RPV concentrations post-dose. Symptoms ranged from mild 
to severe, with some participants receiving supportive care. These events have included 
symptoms such as dyspnea, bronchospasm, agitation, abdominal cramping, rash/urticaria, 
dizziness, flushing, sweating, oral numbness and, changes in blood pressure, and pain (e.g. back 
and chest). Symptoms typically began to resolve within a few minutes after the injection. These 
participants made a full recovery after the event resolved. 
 
These events are infrequent and occurred in less than 0.5% of participants receiving repeat doses 
of RPV LA in clinical trials in adults. Of the symptomatic patients who had confirmed RPV PK 
elevations consistent with accidental partial IV administration, no patients had loss of virological 
control within weeks after the event.  


 
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Systemic reactions following RPV LA injections are rare. (16) 
 
Further details about oral rilpivirine can be obtained from the FDA approved full prescribing 
information. (15) 
 
1.2.3 
Clinical trial experience using cabotegravir plus rilpivirine as a dual antiretroviral therapy 
regimen 
 
Three Phase III/IIIb studies, Study 201584 (FLAIR), Study 201585 (ATLAS) and study 207966 
(ATLAS-2M), and two Phase IIb studies [Study LAI116482 [LATTE] (18) and Study 200056 
[LATTE-2] (9)] have been conducted with oral CAB and/or IM CAB LA and oral RPV and/or 
IM RPV LA. 
 
Study 201584 (FLAIR) 
The data from Study 201584 indicate that CAB + RPV is effective in maintaining the suppression 
of plasma HIV-1 RNA (<50 c/mL) and non-inferior to CAR at Week 48. The study employed a 
Q4W injection dosing regimen for CAB and RPV following a once daily oral led for 4 weeks. 
 
Of the participants that completed the Induction Phase, a total of 566 participants were 
randomized (1:1) and treated with CAB+ RPV (n=283) or continue CAR (n=283).  Similar 
proportions of participants in each treatment group withdrew from the study (CAB + RPV: 9%; 
CAR: 8%).  The most frequent primary reason for withdrawal was adverse events (CAB + RPV: 
3%; CAR: 1%). 
 
Overall, in the intent to treat -efficacy (ITT-E) population, 2.1% of participants in the CAB + 
RPV group and 2.5% of participants in the CAR group met the ‘virologic failure’ primary 
efficacy endpoint of plasma HIV-1 RNA 50 c/mL at Week 48 (Snapshot algorithm).  Based on a 
6% non-inferiority margin, the efficacy analysis demonstrated that CAB + RPV is non-inferior to 
CAR at Week 48 because the upper bound of the 95% CI for the adjusted treatment difference [-
0.4 (-2.8, 2.1)] is less than 6%.  The results for the per protocol population were consistent with 
those from the ITT-E (primary) population.  Treatment differences across stratification factors 
(Baseline HIV-1 RNA and sex at birth) and across additional subgroup analyses (age, race, 
Baseline CD4+ count, and Baseline Centers for Disease Control and Prevention [CDC] stage of 
disease) are consistent with the finding of non-inferiority observed in the overall population 
analysis of the primary endpoint (HIV-1 RNA 50 c/mL at Week 48).   
 
The FLAIR 96-week results reaffirm the 48-week results, showing long-acting cabotegravir and 
rilpivirine continued to be non-inferior compared with continuing a standard care regimen in 
adults with HIV-1 for the maintenance of viral suppression. These results support the durability 
of long-acting cabotegravir and rilpivirine, over an almost 2-year-long period, as a therapeutic 
option for virally suppressed adults with HIV-1. (19) 
 
After 24 weeks of follow-up, switching to long-acting treatment with or without an oral lead-in 
phase had similar safety, tolerability, and efficacy, supporting future evaluation of the simpler 
direct-to-injection approach. The week 124 results for participants randomly assigned originally 
to the long-acting therapy show long-acting cabotegravir plus rilpivirine remains a durable 
maintenance therapy with a favorable safety profile. (20) 
 
Study 201585 (ATLAS) 


 
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The data from Study 201585 indicate that CAB + RPV is effective in maintaining the suppression 
of plasma HIV-1 RNA (<50 c/mL) and non-inferior to CAR at Week 48. The study employed a 
Q4W injection dosing regimen for CAB and RPV following a once daily oral led for 4 weeks.  
 
A total of 616 participants were randomized (1:1) and treated with CAB+ RPV (n=308 or 
continue CAR (n=308).  Similar proportions of participants in each treatment group withdrew 
from the study (CAB+ RPV: 8%; CAR: 6%).  The most frequent primary reason for withdrawal 
was adverse events (CAB+ RPV: 4%; CAR: 2%).   
 
Overall, in the ITT-E population, 1.6% of participants in the CAB + RPV group and 1.0% of 
participants in the CAR group met the ‘virologic failure’ primary efficacy endpoint of plasma 
HIV-1 RNA 50 c/mL at Week 48 (Snapshot algorithm). Based on a 6% non-inferiority margin, 
the efficacy analysis demonstrated that CAB + RPV is non-inferior to CAR at Week 48 because 
the upper bound of the 95% CI for the adjusted treatment difference 0.7 (-1.2, 2.5) is less than 
6%. The results for the per protocol population were consistent with those from the ITT-E 
(primary) population.  Treatment differences across stratification factors (baseline third agent 
treatment class and sex at birth) and across additional subgroup analyses (age, race, country, 
baseline viral load, baseline CD4+ count, and baseline CDC stage of disease) are consistent with 
the finding of non-inferiority observed in the overall population analysis of the primary endpoint 
(HIV-1 RNA 50 c/mL at Week 48).   
 
Study 207966 (ATLAS-2M) 
In ATLAS-2M, a total of 1,049 participants were randomized (1:1) and treated with CAB + RPV 
Q8W (n=524) or CAB + RPV Q4W (n=525). Similar proportions of subjects in each treatment 
group withdrew from the study (CAB + RPV Q8W: 7%); CAB + RPV Q4W: 8%. In the ITT-E 
population, 1.7% of subjects in the CAB + RPV Q8W group and 1.0% of subjects in the CAB + 
RPV Q4W group met the primary efficacy endpoint of plasma HIV-1 RNA > 50 c/mL at Week 
48. A multivariable logistic regression analysis demonstrated that the strongest association of 
Snapshot HIV-1 RNA ≥ 50 c/mL was BMI. Overall, injections for Q8W CAB LA + RPV LA 
were well tolerated with few withdrawals due to injection intolerability (1% in Q8W group and 
2% in Q4W group). The most common AEs in both treatment groups were mild/moderate ISRs.  
 
The frequency of subjects reporting at least 1 SAE was similar in the 2 treatment groups (Q8W: 
5%; Q4W: 4%). There was 1 fatal (Grade 5) AE; 1 subject in the Q8W group died due to sepsis 
as a result of a complication of acute pancreatitis. Acute pancreatitis was considered related to 
study drug by the investigator. Overall, the data from ATLAS 2M indicate that every 2-month 
(Q8 Week) dosing with CAB + RPV is effective in the suppression of plasma HIV-1 RNA (<50 
c/mL) and non-inferior to monthly (Q4 Week) CAB+ RPV at Week 48. 
 
Long-acting cabotegravir and rilpivirine dosed every 8 weeks had non-inferior efficacy compared 
with that of every 4 weeks through the 96-week analysis, with both regimens maintaining high 
levels of virological suppression. These results show the durable safety, efficacy, and 
acceptability of dosing long-acting cabotegravir and rilpivirine monthly and every 2 months as 
maintenance therapy for people living with HIV-1. (21) 
 
Study 200056 (LATTE-2) 
In Study 200056, at Week 160, 83% of participants receiving CAB + RPV monthly IM dosing 
(Q4W) and 90% of participants receiving CAB + RPV bimonthly dosing (Q8W) maintained 
virologic suppression (HIV-1 RNA <50 c/mL by the Snapshot algorithm).  The difference in 
virologic success was primarily due to non-virologic reasons.  Of the 44 participants in the oral 
treatment group who opted to switch to CAB + RPV (Q4W or Q8W) at Week 100 (beginning of 


 
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the Extension phase), 100% (Q4W) and 97% (Q8W) maintained virologic suppression (HIV-1 
RNA <50 c/mL) at Week 160.  In the Maintenance and Extension periods of this study there have 
been 3 protocol-defined virologic failure (PDVFs), 2 in the Q8W arm and 1 in the oral CAB arm.  
No PDVFs were observed in the Q4W arm throughout the study and no additional PDVFs have 
been observed since Week 48. 
 
Study LAI116482 (LATTE) 
In Study LAI116482, at Week 96, 79% (CAB 10 mg group), 85% (CAB 30 mg group), 93% 
(CAB 60 mg group) and 83% (EFV 600 mg group) of participants maintained virologic 
suppression (HIV-1 RNA <50 c/mL).  After the last participant completed the Week 96 visit the 
study was unblinded and all participants, including those in the EFV group, were transitioned to 
the Sponsor selected regimen of CAB 30 mg + RPV 25 mg.  The transition took place between 
Weeks 108 and 120.  There were 9 PDVFs on the CAB arms with 3 occurring between Week 96 
and Week 144. 
 
Adverse Drug reactions  
The safety assessment (and Adverse Drug Reactions [ADR] identification) was performed for the 
CAB + RPV regimen as these agents were administered together in the clinical studies for RPV 
LA. The assessment was based on the analysis of pooled 48-week data from 1,182 virologically 
suppressed participants living with HIV-1 in 2 international, multicenter, open-label pivotal Phase 
III studies, 201584 (FLAIR) and 201585 (ATLAS). Additional safety information from earlier 
clinical studies in the CAB and RPV programs have been considered in assessing the overall 
safety profile of RPV LA. 
 
The ADR frequencies are based primarily on the pooled data of the Phase III registrational 
program. 
 
The ADRs are listed by System Organ Class (SOC) and frequency. Frequencies are defined as 
very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). 
 


 
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Table 1: Adverse Drug Reactions Observed in Adult Patients Treated with RPV in 
Combination with CAB (16)  
 
ISRs were the most frequent AEs associated with the IM use of CAB + RPV. Out of 14,682 
injections, 3,663 ISRs were reported. The percentage of participants reporting ISRs decreased 
over time (Week 4, 70% and Week 48, 16%). A total of 1% of participants discontinued 
treatment with CAB LA and RPV LA injections, because of ISRs. In Phase III studies 201584 
(FLAIR) and 201585 (ATLAS) at the Week 48 analysis, 84% of participants had at least one 
local ISR at some point over the analysis period, consisting primarily of localized pain/discomfort 
(79% of participants), see Table 1 above for overall ISR incidence. Other manifestations of ISRs 
reported in more than 1% of participants over the duration of the analysis period included nodules 
(14%), induration (12%), swelling (8%), erythema (4%), pruritus (4%), bruising (3%), warmth 
(2%), and hematoma (2%). Abscess and cellulitis at the injection site were each reported in <1% 
of patients. The severity of reactions was generally mild (Grade 1, 75% of participants) or 
moderate (Grade 2, 36% of participants). 4% of participants experienced severe (Grade 3) ISRs, 
and no participants experienced Grade 4 ISRs. The median duration of overall ISR events was 3 
days. 
 
1.3 
Study Rationale 
 


 
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The IMPAACT 2017 is a Phase I/II study being conducted to assess the safety, acceptability, 
tolerability, and pharmacokinetics of oral and long-acting injectable cabotegravir and long-acting 
injectable rilpivirine in virologically suppressed children and adolescents living with HIV-1. The 
age group studied will be adolescents aged 12 to <18 years and ≥35 kg.  
 
1.3.1 
Protocol Version History 
 
Protocol Version 1.0 was finalized on March 2, 2018 but never implemented. Protocol Version 
2.0 was finalized on August 16, 2018. The main purpose of the amendment was to implement 
protocol modifications recommended by the Division of AIDS (DAIDS) relating to information 
about the study products that became available after protocol Version 1.0 was finalized, as well as 
increasing the flexibility in the timing of opening of Cohort 2 to participants who have not 
previously enrolled to Cohort 1. The amendment also incorporated other modifications, 
clarifications and administrative edits to improve consistency across protocol sections. See the 
Summary of Changes to IMPAACT 2017 from Protocol Version 1.0 to Version 2.0 for additional 
details regarding the modifications and rationale, which is available upon request to the Protocol 
Team.   
 
Interim analysis #1 was conducted under protocol Version 2.0 and using the evaluable participant 
definitions presented in protocol Version 2.0. Participants enrolled to IMPAACT 2017 protocol 
Version 2.0 received the Q4W dosing regimen presented in that version. The protocol was 
amended to Version 3.0 to incorporate a dosing regimen modification of Q8W. See the Summary 
of Changes to IMPAACT 2017 from Protocol Version 2.0 to Version 3.0 for additional details 
regarding the modifications and rationale, which is available upon request to the Protocol Team.  
 
Protocol Version 4.0 modifies the study design of Cohort 2 to allow the oral lead-in phase to be 
an optional component of Cohort 2 study participation for participants enrolled under that 
protocol version. To accommodate this, Cohort 2 has been modified to include two groups: 
Cohort 2A (oral lead-in followed by injections) and Cohort 2B (injections only). Study 
participants enrolled to Cohort 2 under protocol Version 3 and still on-study will be re-consented 
to Cohort 2A. See the Summary of Changes to IMPAACT 2017 from Protocol Version 3.0 to 
Version 4.0 for additional details regarding the modifications and rationale, which is available 
upon request to the Protocol Team. 
 
1.3.2 
Preliminary Review of Study Data 
 
Review of PK Data  
Preliminary PK data were reviewed by the Study Monitoring Committee (SMC) on January 17, 
2020 and were found to achieve PK targets.  
 
At the time of the January 2020 SMC review, a total of 16 participants had PK collected and 
analyzed, 7 in Cohort 1C (CAB) and 9 in Cohort 1R (RPV). The Cohort 1C median PK 
parameters were within the desired median PK target ranges, at Week 2 taken orally (PO) (n=7) 
and Week 16 IM (n=4), - PO AUC 167.4 (131.1-326.8) mcg*h/mL and IM trough 3.1 (1.2-6.2) 
mcg/mL.  Similarly, the median Cohort 1R PK parameter was within the desired median PK 
target range at Week 16 IM troughs (n=6) - observed median (target range): 43.8 (40.7-126) 
ng/mL.   
 
Adult CAB and RPV LA Population (POP) PK models were developed utilizing exposure data 
from adult clinical studies with efficacious dosing regimens having an acceptable safety profile 
with Q4W and Q8W injections. Simulations were conducted with these models, also taking into 


 
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account any potential age and weight related impact on PK, to recommend appropriate doses in 
adolescents that achieve comparable exposures to those seen in adults, initially for a Q4W dosing 
regimen in line with available clinical data in adults at that time. The preliminary adolescent PK 
data from the SMC review were compared against a priori model predictions and are in 
agreement with the predicted exposure range and within thresholds as displayed in Figure 3,  
 
 
Figure 4, and Figure 5 for CAB and RPV respectively.  
 
Figure 3. Observed preliminary IMPAACT 2017 Cohort 1C CAB concentrations in 
adolescents compared to model predicted concentrations based on POP PK analyses 
from adult studies 
 
Note: The plots represent the CAB systemic exposure: solid line and shaded band reflect the population 
pharmacokinetic model predictions (median and 90% interval); the dots represent the observed individual 
subject data. The dashed lines represent the maximum observed geometric mean exposure from the TQT 
study at (22.5 mcg/mL) at supratherapeutic doses following 150 mg q12h x 3 and the target threshold 
concentrations at trough (0.65 mcg/mL).  
 
 
 
 
 
 
 
 
 
 
 
 


 
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Figure 4. Observed IMPAACT 2017 Cohort 1R preliminary data and predicted RPV 
plasma concentrations in adolescents after PO RPV 25 mg once daily (left panel) 
and IM RPV LA 900-600-600 mg (right panel) 
Note: Black line and blue shaded area: median and 90% prediction interval for adolescents; black dots: 
observed data in Cohort 1R adolescents. 
Figure 5. Observed trough RPV plasma concentrations in Cohort 1R adolescents (blue 
dots) and adults (boxplots, ATLAS/FLAIR) after PO RPV 25 mg once daily (Week 0; last 
day of PO lead-in), and IM RPV LA 900-600-600 mg (Weeks 4, 8 and 12; concentrations 4 
weeks after injection)  
 


 
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Interim Analysis #1 took place on June 19, 2020. Based upon study data from the first seven 
evaluable participants in each Cohort 1C and Cohort 1R, the IMPAACT 2017 CMC concluded 
that dosing regimens for CAB PO and LA and for RPV LA achieved the PK targets as per 
protocol Version 2.0. Additionally, the LSFU PK results indicate both CAB and RPV 
concentrations maintain pharmacologically relevant concentrations, above the IC90, for several 
weeks after their final IM injection. 
 
A preliminary analysis of safety and PK data found that CAB LA and RPV LA when given 
individually, in conjunction with background ART, achieve PK targets in the enrolled adolescents 
living with HIV (22). The Cohort 1C median CAB (oral and IM) PK parameters were within the 
desired median PK target ranges: Cohort 1C Week 2 Oral median (range) CAB AUC0-τ: 160 
(94.3-325) mcg*h/mL (target median 46-277 mcg*h/mL), Week 16 IM median (range) CAB 
trough: 3.11 (1.22-6.19) mcg/mL (target median 0.71-6.7 mcg/mL). Similarly, the Cohort 1R 
median RPV PK parameter was within the desired median PK target range: Week 16 IM median 
(range) RPV trough: 52.9 (31.9-148) ng/mL (target for median 25-100 ng/mL).  
 
Review of Safety Data  
Safety data were reviewed by the SMC in March 2020, and no safety issues or concerns were 
identified.  All available safety data for the eight enrolled participants in Cohort 1C and the 15 
enrolled participants in Cohort 1R were presented.  At the time of the review, based on the 
available data, the following were deemed evaluable (with PK and Week 16 safety data): seven 
evaluable participants in Cohort 1C, and nine evaluable participants in Cohort 1R. 
 
The safety data used in the March 2020 review showed that out of the seven evaluable 
participants in Cohort 1C, only one participant had a Grade 3 study product-related AE (insomnia 
on day 41 of study that resolved) but remained in the study. Of the first eight evaluable 
participants in Cohort 1R, only one participant had a Grade 3 study product-related AE (urticaria 
assessed to be an acute allergic reaction related to study product) which resulted in permanent 
discontinuation of study treatment. There were no safety concerns for the other participants in 
both cohorts.  
 
Interim Analysis #1 confirmed that the doses implemented for both Cohort 1C and Cohort 1R 
passed the safety guidelines in Section 9.5.1.3 of protocol Version 2.0 for the first seven 
evaluable participants in each group. The CMC concluded that protocol criteria to open Cohort 2 
to Cohort 1 graduates had been met, and the SMC agreed with this conclusion. 
 
A preliminary safety and PK analysis was conducted based on the first 23 participants enrolled to 
the study: eight participants enrolled to Cohort 1C, and 15 participants enrolled to Cohort 1R 
(22).  The analysis included all available safety data for these enrolled participants and no new or 
unexpected safety issues or safety concerns were identified. Based on this preliminary safety and 
PK analysis, as well as extrapolated data from the adult CAB and RPV studies, CAB LA + RPV 
LA is approved for treating virologically suppressed adolescents living with HIV who are 12 
years of age or older and weighing over 35kgs by the US Food and Drug Administration (FDA) 
(23). 
 
Interim Analysis #2 was conducted in April 2022 and the doses implemented for both Cohort 1C 
and Cohort 1R passed the safety guidelines per Section 9.5.1.3 of protocol Version 3.0. The CMC 


 
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concluded that the analysis supported opening Cohort 2 accrual to participants who were not 
previously enrolled in Cohort 1, and the SMC agreed with this conclusion. 
 
1.3.3 
Rationale for use of oral lead-in prior to injectable dosing 
 
The CAB LA and RPV LA formulations have a pharmacokinetic decay rate, resulting from 
gradual release from the IM injection site, that exposes the injected individual to detectable levels 
of cabotegravir and rilpivirine for up to 52 weeks or longer after an injection. A 4-6-week lead-in 
period of daily oral CAB and RPV prior to injectable administration, with serial safety 
assessments, will allow identification of any acute toxicity prior to administration of a non-
dialyzable, non-removable depot injection. A similar oral lead-in period has been employed in 
previous trials in adults using these LA formulations.   
 
The oral lead-in period is also designed to provide uninterrupted study product coverage while 
awaiting the Week 4 safety laboratory test results, which will determine eligibility for receiving 
the LA formulations. The safety assessment is done towards the end of the 4-week oral lead-in 
and, for clarity, has been named the visit 4a. Safety lab results from the 4a study visit will be 
reviewed and, if appropriate, the next visit will be scheduled as soon as possible to administer the 
first study injection; this next visit has been named visit 4b. This nomenclature has been adopted 
to promote consistency across the CAB/RPV studies and allow for clearer interpretation and 
comparisons. Given a participant population with a history of durable viral load suppression at 
and prior to study entry, a viral load assessment at the 2-week visit, and questionable clinical 
meaningfulness of a single HIV viral load blip, a repeat HIV viral load assessment is not part of 
the laboratory assessments done at visit 4a to approve giving the first study injection at visit 4b. A 
HIV viral load sample is collected at visit 4b to time with the first injection(s). 
 
1.3.4 
Rationale for Cohort 1 and the related components of the study design 
 
Oral RPV is approved for use as an antiretroviral medication in adolescents 12 years of age and 
older. In Cohort 1, CAB and RPV will first be studied separately to confirm adult-matched 
exposure/PK and gather initial safety information for oral and injectable CAB (Cohort 1C) as 
well as injectable RPV following lead-in with oral RPV (Cohort 1R). Cohort 1 eligibility criteria 
require study participants to have demonstrated virologic suppression on a stable cART, and this 
cART regimen is continued throughout the Cohort 1 study period to ensure continued virologic 
suppression. Enrollment into Cohort 1C versus Cohort 1R is determined by what cART regimen 
the participants have been receiving in order to avoid drug interactions (e.g., between RPV and 
boosted protease inhibitors or boosted integrase inhibitors) as well as duplication of study agent 
with another ARV from the same drug class. Hence, participants whose background cART 
contains a NNRTI or boosted PI will be enrolled in Cohort 1C and those on a non-boosted INSTI-
based cART will be enrolled in Cohort 1R.  
 
Based on the data presented above, the study target sample size for interim analysis #1 has been 
revised from N=8 to N=7 dose-evaluable participants for Cohort 1C and Cohort 1R.  Interim 
analysis #1 of safety and PK data will be performed (as described in Sections 9 and 10) following 
the first seven evaluable Cohort 1C and the first seven evaluable Cohort 1R participants 
completing their Cohort 1, Step 2 Week 16 study visit.   
 
Safety, not PK, will primarily drive Cohort 1 enrollment and flow. As long as no safety concerns 
are noted, Cohort 1 enrollment will continue uninterrupted while a continuous assessment of PK 
is made (including interim analyses for participants in Cohort 1C and Cohort 1R). See Section 10 
for the details regarding the interim PK analysis. 


 
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1.3.5 
Rationale for Cohort 2 (2A and 2B) and the related components of the study design 
 
The PK and safety data from the initial group (demonstrating satisfactory agreement of observed 
PK with adult exposures and POP PK model predictions, and the absence of any overt safety 
signals) in Cohort 1 will support the opening of Cohort 2 for Cohort 1 participants, where 
virologically suppressed adolescents living with HIV-1 (including Cohort 1 participants meeting 
study eligibility criteria) will stop their oral cART and switch to CAB plus RPV. See Section 9 
for the details regarding opening Cohort 2 to former Cohort 1 participants. Building on the 
successful experience from the trials in adult participants living with HIV-1 in LATTE-2, 
ATLAS, FLAIR and ATLAS-2M, based on the most recent clinical information in adults, 
supporting 2-monthly dosing, the Q8W injectable regimen has now also been chosen for further 
evaluation in adolescents, under MOCHA. (21) 
 
Cohort 2 will begin to enroll, starting with the participants who passed Cohort 1, once the dosing 
of the oral/IM CAB and oral/IM RPV been established, based on data of the first 7 dose-
evaluable participants from Cohorts 1C and 1R, as described above. Once approximately 15-20 
participants in Cohort 1C and approximately 15 participants in Cohort 1R who could contribute to 
the dose-finding algorithm are enrolled with 80% of participants in each arm passing the Week 8 
visit, another interim analysis of the safety and PK data will be conducted and Cohort 2 will open 
to accrual for study-naïve participants if approved by SMC. 
 
The Cohort 2 component of the study design is consistent with, and responsive to, HIV pediatric 
regulatory guidance from the EU and US, which allow extrapolation of adult efficacy data. To 
incorporate an optional oral lead-in aspect to the study, as further described below, Cohort 2 will 
include Cohort 2A (oral lead-in followed by injections) and Cohort 2B (injections only). As 
Cohort 2A participants will receive the oral study product and therefore have a longer study 
follow-up period with an additional 4-6 weeks in the oral lead-in phase. Both Cohort 2A and 
Cohort 2B participants will have the same number of injections over 92 weeks in the injection 
phase. Therefore, the specified primary and secondary endpoints for Cohort 2B reflect the study 
visit weeks and shorter duration of overall study follow-up for this group of participants. The 
week 24 safety assessment time point will serve as the primary endpoint for Cohort 2A and week 
20 will serve as the primary endpoint for Cohort 2B. For Cohort 2A, safety, acceptability, PK and 
antiviral efficacy will continue to be assessed through week 96 with related study endpoints at 
weeks 24, 48 and 96. For Cohort 2B, safety, acceptability, PK and antiviral efficacy will continue 
to be assessed through week 92 with related study endpoints at weeks 20, 44 and 92. These data 
will provide important information on the short term and long term, through 96 weeks, use of this 
2-monthly, two-drug injectable ART in adolescents.  
 
Optional Oral Lead-In  
 
Throughout the course of the clinical development program for CAB and RPV LA 
including the large P3 trials of FLAIR, ATLAS and ATLAS 2M, an oral lead-in phase of 
cabotegravir (30 mg) along with rilpivirine (25mg), administered daily for 30 days, was 
an integral component of these trials and allowed for a safety assessment before study 
participants were allowed to advance to the LA phase of these studies. As a result, all 
study participants underwent a one-month period of oral dosing with CAB/RPV followed 
by an evaluation of safety labs, and if labs were within normal limits, participants were 
allowed to transition into LA dosing. 
 
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FLAIR and ATLAS (ViiV’s two registrational clinical trials) was recently undertaken. After 24 
weeks of follow-up, switching to long-acting treatment with or without an oral lead-in phase had 
similar safety, tolerability, and efficacy, supporting future evaluation of the simpler direct-to-
injection approach. As a result of the accumulated safety data which has been generated, the 
safety of oral CAB and RPV during these four weeks of oral lead-in was not significantly 
different than at any other time during the FLAIR/ATLAS studies. (20)  
 
The IMPAACT 2017 study will therefore also allow an optional oral lead in for participants 
entering Cohort 2 – Cohort 2A will be designated for participants choosing the oral lead-in 
whereas Cohort 2B will be designated for participants choosing to skip the oral lead-in and begin 
directly with the long-acting injections. This decision to dose with or without an oral-lead-in will 
be determined by the study participant following informed consent discussions with the 
investigator. 
 
1.3.6 
Rationale for Change in IM Dosing Regimen (from Q4W to Q8W) 
 
CAB and RPV have demonstrated their efficacy when dosed in a Q8W (ATLAS 2M) regimen in 
addition to earlier Q4W data. Investigating the Q8W regimen in adolescents living with HIV 
facilitates its use in adolescents and the benefits that a decreased administration regime provides 
including ease of compliance. Adult PK data indicates that Q8W concentrations can be 
extrapolated from Q4W data with one descriptive POP PK model accurately predicting both 
regimens. The current adolescent data indicates that Q4W provided CAB and RPV concentrations 
similar to or higher than those observed in adults and so it is expected that Q8W will perform 
similarly providing efficacious concentrations and trough concentrations. 
 
The agreement of the preliminary observed PK data with the expected criteria and model 
simulations indicated that the respective POP PK models for CAB and RPV are capable of 
accurately predicting PK in adolescents with no unexpected PK issue. Additionally, adolescent 
PK is generally expected to vary only slightly from adult PK for most drugs and it is 
commonplace to use adult dose regimes for adolescents.  Of 92 products assessed by the Food 
and Drug Administration (FDA), 95% had equivalent dosing for adults and adolescent patients 
(24). When given the same CAB and RPV dosage as adults, slightly higher mean exposures are 
expected in adolescents due to their lower body weights. These differences are however not likely 
to be clinically relevant given the broad range of exposures observed in adults.  
 
The observed concentrations following PO and IM administration are well predicted by the POP 
PK models with nearly all the individual participant values within the 90% prediction intervals 
throughout the PK sampling interval.  This dosing provides exposures comparable to those 
previously seen in adults and it is highly unlikely that collection of additional PK data with the 
current dosing regimen would impact conclusions about exposure adequacy for CAB or RPV. 
The similarity of CAB and RPV PK between adolescents and adults is independent of dosing 
regimen. Subsequently, in conjunction with the clinical experience in the adult population with 
Q8W dosing, similar modeling and simulation has been utilized to recommend a Q8W dosing 
regimen for adolescents for evaluation in IMPAACT 2017.  
 
1.3.7 
Rationale for Long-Term Safety and Washout PK Follow-up (LSFU) 
 
As earlier mentioned, the CAB LA and RPV LA formulations have a pharmacokinetic decay rate 
which exposes the injected individual to detectable levels of CAB and RPV for up to 52 or more 
weeks after an injection. Given this prolonged decay rate, clinical protocols to date using these 
LA agents have included a long-term follow-up to assess safety and potential viral rebound and 


 
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development of resistance in the setting of declining study product levels following the last 
intramuscular injection of either or both CAB LA and RPV LA. Any participant discontinuing the 
intramuscular injections, will then be followed per the 48-week follow-up visit schedule.  
 
1.3.8 
Rationale for Acceptability and Tolerability Assessments including Qualitative Phone 
Interviews: Participants and Parent/caregiver 
 
Following enfuvirtide, an HIV fusion inhibitor, that was the first of a novel class of antiretroviral 
drugs proposed as twice-a-day subcutaneous injections as part of cART for the treatment of HIV-
1, the intramuscular LA formulations will be the first injectable antiretroviral agents to be studied 
in adolescents. Acceptability and tolerability will be critical to understand from both the 
standpoint of the participants and their caregivers, who facilitate their access to healthcare. 
Soliciting feedback on the LA formulations from diverse groups of participants and their 
caregivers will help inform ways to further optimize the delivery of these agents and their 
acceptability in future clinical trials as well as their offering as part of standard of care when these 
agents are approved. To accomplish this important study aim, assessments will be administered 
by site staff to participants via questions covering topics on participant perceptions of the study 
product injections, reasons for switching from daily oral cART to long-acting study products, 
satisfaction with treatment, and quality of life at multiple time points throughout the study. In 
addition, a single in-depth qualitative phone interview will be conducted with selected 
participants, and, separately, with selected parents or caregivers, to identify acceptability 
concerns unique to the participant population. The written assessments are similar to ones that 
have been utilized for adult studies of LA agents but have been adapted to be age appropriate. 
These assessments will allow comparisons of adolescent feedback to that from adults. Some 
assessments such as the feedback from the caregivers will be unique to pediatric and adolescent 
populations and IMPAACT 2017 will provide the first opportunity to get this information.  
 
1.3.9 
Rationale for Proposed Doses of Study Agents 
 
1.3.9.1 Oral CAB 
 
Oral CAB has been administered to adults living with HIV at doses of 5 mg to 60 mg once daily. 
Oral CAB 10 mg, 30 mg, and 60 mg once daily were administered safely to participants living 
with HIV for 2 years or longer (LAI116482, LATTE). Oral CAB 30 mg was the dose used in the 
lead-in phases in the successful efficacy trials investigating the Q4W and Q8W regimens [the 
ATLAS study, FLAIR and ATLAS-2M.  A geometric mean Cmax of 22.5 g/mL [median (range) 
21.9 (16.9-39.2) g/mL] has been observed for CAB in healthy adults at supratherapeutic doses 
following 150 mg q12h x 3 in the TQT study without any impact on the QT interval 
(LAI117009).  
 
A CAB POP PK model was built based on CAB plasma concentrations collected from 1,647 
healthy adult (28%) and (72%) adult participants living with HIV (age 18 to 74 years) in 16 
studies at 7 dose levels (10 mg to 60 mg for the oral tablet; 100 mg to 800 mg for CAB LA). The 
CAB POP PK model was employed to recommend doses in adolescents after accounting for 
relevant factors related to this population e.g. body weight. The predicted exposures with the 30 
mg daily dose are summarized by weight group in Table 2. For adolescents weighing 
35 to <50kg, oral CAB 30mg once daily is predicted to achieve median exposures that are ~60-
70% higher than that observed at 30mg in adults in LATTE and comparable to exposures 
observed at 60 mg in adults in LATTE, which has been administered safely in adult participants 
living with HIV. These slightly higher exposures predicted in adolescents are largely due to their 


 
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relatively lower body weight and are not of clinical concern based on observed efficacy and 
safety data from adult clinical studies. The Cmax CAB exposures at the proposed dose regimen are 
expected to be below the 22.5 g/mL – the geometric mean Cmax exposure at 150 mg q12h x 3 f. 
 
Table 2. Predicted Steady State CAB Exposures following Oral CAB 30mg and 60mg QD 
in Adolescents compared to Observed Adult Values 
Plasma CAB 
Parameter 
Observed Adult Data 
(LAI116482, LATTE) 
Median 
(range) 
Adolescent Weight Group 
35 to <50kg 
50kg 
30mg QD 
(54-105kg) 
60mg QD 
(69-106kg) 
Predicted 
Median 
[5th, 95th %] 
Predicted 
Median 
[5th, 95th %] 
Cmax 
(g/mL) 
8.5 
(4.9-10.8) 
13.1  
(7.3-18.5) 
13.3 
[8.4, 21.3] 
9.7  
[5.8, 15.8] 
C 
(g/mL) 
4.4 
(2.5-7.7) 
6.4 
(2.4-11.3) 
7.3  
[4.0, 13.1] 
5.6  
[3.0, 10.0] 
AUC(0-) 
(g•h/mL) 
144   
(79-208) 
209  
(103-334) 
237 
[142, 393] 
175 
[102, 299] 
 
1.3.9.2 Injectable Cabotegravir 
 
CAB LA has been administered intramuscularly to healthy and adults living with HIV at doses of 
100mg to 800mg. In participants living with HIV, CAB LA has maintained virologic suppression 
on maintenance doses of 400mg and 600 mg IM given Q4W and Q8W respectively with RPV LA 
(LATTE-2), demonstrating noninferiority of the Q4W regimens in the Phase 3 Studies ATLAS 
and FLAIR. In Phase IIIb Study 207966 (ATLAS-2M) CAB LA demonstrated noninferiority of 
the Q8W regimen to the Q4W regimen). 
 
The previously developed POP PK model was updated with data from both a Q8W and Q4W 
CAB IM injection dosing scheme. Model performance was evaluated and deemed adequate with 
appropriate qualification and validation. Clinical trial simulations for adolescents were 
subsequently conducted with the updated CAB POP PK model to recommend a Q8W dosing 
regimen. The proposed dosing is the same as that in adults and listed in Section 5. 30 mg CAB 
once daily orally for at least four weeks in addition to cART (Step 1 oral phase), followed by a 
single intramuscular injection of CAB LA 600 mg as first injection and a second CAB LA 600 
mg injection 4 weeks later, in addition to continuing cART (Step 2 injection phase) is 
recommended for the remainder of Cohort 1C. Cohort 2 will employ the following dosing for 
CAB – 30 mg CAB once daily orally for at least four weeks (Step 3 oral Phase), followed by a 
single intramuscular injection of CAB LA 600 mg as first injection, a second CAB LA 600 mg 
injection 4 weeks later and followed by CAB LA 600mg every 8 weeks thereafter during Step 4 
injection phase. 
 
The expected CAB concentration time profile from the Q8W injections suggest that minimal 
CAB accumulation is expected with the Q8W injections, as also observed in adults with the CAB 
Q8W regimen. The shorter first dose interval (4 weeks in between 2 first injections) will lead to 
predicted steady-state concentrations almost immediately after the first injection with trough 
concentrations expected to be well above the minimum target threshold of 0.65 ug/mL. The 
predicted trough exposures (C) are listed in Table 3 below.  Exposures in adolescents are 
expected to be slightly higher largely due to their relatively lower body weight. These differences 
are not of clinical concern based on observed efficacy and safety data from adult clinical studies. 


 
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In summary, the Q8W regimen has been demonstrated to be effective and have an acceptable 
safety profile in pivotal trials in adults and, as such, is suitable for investigating in adolescent 
participants living with HIV. Pharmacokinetics and safety data following CAB PO and LA will 
be reviewed for participants in Cohort 1C of the study. 
 
Table 3. Predicted Steady State CAB Parameters following CAB LA IM Q8W regimen 
compared with Observed and Estimated data in Adults  
 
 
Predicted C (g/mL)b 
Post First Injection 
Post Second Injectionc 
Adolescent Body weight 
35 to <50kg 
2.49 [0.98, 4.72] 
2.34 [0.84, 3.98] 
50kg 
1.76 [0.69, 3.49] 
1.76 [0.77, 3.05] 
Observed adult data 
1.50 [0.65, 2.90] a 
1.61 [0.80, 2.99]d 
a. 
Geometric mean [5th and 95th percentile] - Week 8 pre-dose concentrations were obtained following a 
CAB 600 mg IM dose. 
b. 
Median [90% prediction Interval] 
c. 
C after second injection is 8 weeks post injection 
d. 
Geometric mean [5th and 95th percentile] - C at Week 48 with Q8W dosing regimen 
 
 
1.3.9.3 Oral Rilpivirine (RPV) 
 
RPV 25-mg once daily (oral tablet) is approved for the treatment of HIV-1 in ART-naïve patients 
12 years of age and older in multiple countries including the US, the EU, Canada, and Japan as 
EDURANT®, and as part of ODEFSEY® (emtricitabine/rilpivirine/tenofovir alafenamide). This 
approved dose of oral rilpivirine will be used one component of the oral lead-in in Cohort 1R and 
Cohort 2. 
 
1.3.9.4 Injectable Rilpivirine 
 
RPV LA (formulation G001) has been administered intramuscularly (IM) to healthy adults and 
adults living with HIV at doses of 300 mg to 1200 mg. In participants living with HIV, RPV LA 
maintained virologic suppression on maintenance IM doses of 600 mg monthly (Q4W), in 
conjunction with CAB LA monthly (ATLAS, FLAIR) or RPV 900 mg 2-monthly (Q8W) in 
conjunction with CAB LA bi-monthly (LATTE-2, ATLAS-2M).  
 
A POP PK model for RPV LA after IM administration was developed based on data in healthy 
participants and those living with HIV. Factors including BMI, bodyweight, gender, and race 
were not identified as significant covariates for the POP PK model of RPV LA. Only age was 
identified to be a statistically significant covariate for absorption rate. This, however, was not 
considered clinically relevant, as it has no discernable effect on the RPV AUC and C (C28D) for 
RPV LA, and only a limited effect on the RPV Cmax after IM administration. 
 
In order to assess what could occur in case bodyweight would become more important for the 
absorption of RPV LA in adolescents, a conservative approach using an allometric scaling term 
for absorption rate from the injection site was used (Table 4). The impact of making the 
absorption rate a function of bodyweight however had minimal effects on the RPV Cmax or C 
(C28D) values. Even with the added scaling factor, in adolescent participants weighing 
35 to <50kg or 50kg, a RPV LA regimen of 600mg IM Q4W (after loading dose of 900 mg IM) 
or 900 mg IM Q8W (with first 2 injections separated by 4 weeks) is predicted to achieve median 
steady state trough concentrations that are similar to those in adults with the same RPV LA 


 
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regimen and to those with oral RPV 25mg once daily (Table 4). The first participants in Cohort 
1R (Step 2) received an initial injection of RPV LA 900 mg, followed by two RPV LA 600 mg 
monthly doses thereafter, in line with the available adult data at that time. In the remainder of 
Cohort 1R, two injections of RPV LA 900mg will be given 4 weeks apart, in line with currently 
available data for the Q8W regimen from Study 207966 in adults.  
 
The proposed dosing is the same as that in adults and listed in Section 5. 25 mg RPV once daily 
orally for at least four weeks in addition to continuing cART (Step 1 oral phase), followed by a 
single intramuscular injection of RPV LA 900 mg as first injection and a second RPV LA 900 mg 
injection 4 weeks later in addition to continuing cART (Step 2 injection phase) is recommended 
for Cohort 1R. Cohort 2 will employ the following dosing for RPV (in combination with CAB) – 
25 mg RPV once daily orally for at least four weeks (Step 3 oral Phase) followed by a single 
intramuscular injections of RPV LA 900 mg as first injection and a second RPV LA 900 mg 
injection 4 weeks later followed by RPV LA 900mg every 8 weeks thereafter during Step 4 
injection phase. 
 
Table 4.  Predicted RPV Trough Concentrations following RPV LA IM Q8W in 
Adolescents, compared with Observed Data in Adults  
 
 
Predicted (Adolescents)a,c or Observed (Adults)b C (ng/mL) 
 
 
Week 8 
(4 Weeks After 
First Injection) 
Week 16 
(4 Weeks After 
Second Injection) 
Week 24 
(8 Weeks After 
Third Injection) 
Week 48 
(8 Weeks After 
Sixth Injection) 
Adolescents 
35 to <50kg 
41.0 (19.3-81.9) 
32.5 (16.3-62.1) 
40.4 (20.0-75.9) 
57.0 (28.7-107) 
50kg 
41.8 (19.7-85.3) 
32.7 (16.0-64.8) 
40.3 (20.1-75.1) 
56.9 (28.0-106) 
Adults 
 
49.1 (20.9-116) 
45.2 (23.0-92.4) 
50.1 (23.3-90.4) 
64.7 (33.0-120) 
a. 
Median (90% prediction Interval) 
b. 
Median (5th, 95th percentile) 
c. 
Simulations for 1000 adolescents aged 12-<18y and weighing 35-<50kg or ≥50kg, with allometric scaling.  
 
1.4 
Risk/Benefit Assessment 
 
1.4.1 
Cohort 1 
 
Cohort 1 participants will remain on the same cART regimen on which they have a previous 
history of sustained HIV virologic suppression throughout Cohort 1 participation. Additionally, 
assignment to Cohort 1C or Cohort 1R is based on their cART composition such that there are no 
drug interactions with study agents and avoiding redundancy of agents from the same class of 
antiretrovirals. Given all of this, there is no anticipated risk of loss of HIV virologic control 
specifically related to participation in Cohort 1.  
 
Oral rilpivirine is currently approved for use in patients 12 years and older living with HIV and 
the side effect profile has been well described and outlined in the package insert. The safety 
profile of oral cabotegravir, CAB LA and RPV LA is summarized earlier in this section and 
detailed in the related investigator’s brochures. In order to help identify any safety concerns prior 
to administration of a non-dialyzable, non-removable depot injection of the CAB LA and RPV 
LA that have a slow pharmacokinetic decay, a 4-6 week lead-in period of daily oral (short acting) 
CAB or RPV is planned, followed by 2 injections, 4 weeks apart. By enrolling patients with a 


 
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history of sustained virologic suppression on cART and maintaining this cART backbone 
throughout Cohort 1 follow-up, the likelihood of virologic failure and associated development of 
resistance to study agents is highly unlikely.  
 
Injection site reactions reported to date have been relatively common but not significant, 
becoming less frequent over time, and not life threatening nor serious.  Despite occurrence of 
ISRs, there has been high acceptability of the long-acting study agents amongst the adult study 
participants. 
 
Other than a potential for an improved understanding of, and engagement in, HIV care both from 
the standpoint of the patients and their caregiver through participating in a safety, PK and 
acceptability/tolerability study of novel antiretroviral study agents and interacting with study 
staff, there is no immediate benefit to participation in Cohort 1. However, there is the potential of 
early access of Cohort 1 participants to Cohort 2 and its related risk-benefits. Based on the results 
of the interim PK and safety analysis of Cohort 1, graduates of Cohort 1 are likely, as per the 
study design, to have earlier access to enrollment into Cohort 2 and with that an opportunity to 
stop oral cART and switch to an entirely IM LA regimen. 
 
1.4.2 
Cohort 2 
 
In addition to the study agents’ specific side effects, There is a growing body of evidence 
assessing the efficacy and safety of contemporary dual-drug antiretroviral regimens as first-line 
treatment or as a simplification strategy in patients living with HIV. A systematic review and 
meta-analysis on this topic concluded as a switch strategy, dual therapy was equally efficacious to 
standard cART and although the dual therapy tended to have lower rates of adverse events than 
standard cART be it in an initial treatment setting or a switch strategy, it was associated with a 
higher relative risk of selecting virus with drug resistance mutations at virological failure.(6) The 
overall assessment of this anticipated risk of development of resistance in Cohort 2 of IMPAACT 
2017 is judged to be low for several reasons. Results from pivotal efficacy studies in naïve and 
treatment-experienced  adults living with HIV show that the CAB LA plus RPV LA regimen is 
well tolerated, demonstrates durable virologic response and the rate of treatment emergent 
resistance is extremely low through week 96  for ATLAS and FLAIR and week 48 for ATLAS 2-
M. (9, 11, 12, 25) Secondly, the dose of study agents confirmed from Cohort 1 PK in adolescents 
is likely to be the same as that which has currently been shown to be efficacious in adults. Lastly, 
only participants with durable virologic suppression are enrolled in Cohort 2 and, in addition with 
an injectable only regimen for majority of the study period, will get directly observed therapy 
making the likelihood of unobserved poor adherence to medications much less likely.  
 
Injection site reactions reported to date in adults have been very common but not significant, 
becoming less frequently reported over time, and not life threatening nor serious. Despite 
occurrence of ISRs, there has been high acceptability of the long-acting study agents amongst the 
adult study participants.  
 
The potential benefit of participating in Cohort 2 relates to the convenience of not having to take 
daily oral cART and avoiding any oral cART related toxicities, medication fatigue and adherence 
issues. Long-acting two class therapy consisting of CAB LA + RPV LA as an IM regimen has the 
benefit of being a NRTI-sparing regimen for long-term treatment of HIV which will avoid known 
NRTI-associated adverse drug reactions and associated long-term toxicities. Additionally, a two-
drug combination therapy with CAB LA plus RPV LA may offer a better tolerability and 
resistance profile, as well as improved adherence (particularly with Q8W) and treatment 


 
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satisfaction in virologically suppressed participants improving the quality of life for participants 
living with HIV. 
 
Taking into account the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with CAB LA and RPV LA, and the study as a whole, are justified 
by the anticipated benefits that may be afforded to treatment-experienced adolescents living with 
HIV who are virologically suppressed. 
 
1.5 
Hypotheses 
 
Cohort 1: CAB (oral and LA) and RPV LA will be safe and will achieve pharmacokinetic targets 
through Week 16 in adolescents living with HIV who are virologically suppressed at the chosen 
dose to ultimately allow for a final dose to be selected.  
 
Cohort 2: CAB LA and RPV LA, when given as dual therapy to stable, virologically suppressed 
adolescents will maintain viral suppression and will be safe through Week 24 (for Cohort 2A oral 
followed by injectable) and through Week 20 (for Cohort 2B injectable only) in adolescents 
living with HIV who are virologically suppressed at the selected dose. 
 
 
2 
OBJECTIVES 
 
2.1 
Primary Objective: Cohort 1 (continuing a background cART regimen) 
 
The primary objectives of this study are:  
 
2.1.1 
To confirm the doses for oral CAB followed by injectable CAB LA in adolescents living 
with HIV who are virologically suppressed by evaluating: 
2.1.1.1 Safety and multiple dose PK of oral CAB through Week 4;  
2.1.1.2 Safety and multiple dose PK of CAB LA through Week 16. 
 
2.1.2 
To confirm doses for injectable RPV LA in adolescents living with HIV who are 
virologically suppressed. by evaluating safety and multiple dose PK of RPV LA through 
Week 16. 
 
2.2 
Primary Objective: Cohort 2 (discontinuing a background cART regimen) 
 
The primary objective of this study is:  
 
2.2.1 
To assess the safety of CAB + RPV in adolescents living with HIV who are virologically 
suppressed through: 
2.2.1.1 Week 24 (Cohort 2A: oral followed by injectable);  
2.2.1.2 Week 20 (Cohort 2B: injectable only). 
 
2.3 
Secondary Objectives: Cohort 1 
 


 
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The secondary objectives of this study are:  
 
2.3.1 
To monitor maintenance of viral suppression through Week 16 in adolescents living with 
HIV who are virologically suppressed. 
 
2.3.2 
To evaluate the tolerability and acceptability of CAB LA through Week 16 in adolescents 
living with HIV who are virologically suppressed. 
 
2.3.3 
To evaluate the tolerability and acceptability of RPV LA through Week 16 in adolescents 
living with HIV who are virologically suppressed.  
 
2.4 
Secondary Objectives: Cohort 2 
 
The secondary objectives of this study are:  
 
2.4.1 
To assess safety of CAB LA + RPV LA in adolescents living with HIV who are 
virologically suppressed through: 
2.4.1.1 Week 48 (Cohort 2A: oral followed by injectable);  
2.4.1.2 Week 44 (Cohort 2B: injectable only). 
 
2.4.2 
To evaluate repeat-dose pharmacokinetics of CAB LA + RPV LA in adolescents living 
with HIV who are virologically suppressed through: 
2.4.2.1 Week 24 and through Week 48 (Cohort 2A: oral followed by injectable);  
2.4.2.2 Week 20 and through Week 44 (Cohort 2B: injectable only). 
 
2.4.3 
To assess antiviral activity of CAB LA + RPV LA in adolescents living with HIV who 
are virologically suppressed through: 
2.4.3.1 Week 24 and through Week 48 (Cohort 2A: oral followed by injectable);  
2.4.3.2 Week 20 and through Week 44 (Cohort 2B: injectable only). 
 
2.5 
Other Objectives 
 
The other objectives of this study are:  
 
2.5.1 
To evaluate the tolerability and acceptability of CAB LA + RPV LA in adolescents living 
with HIV who are virologically suppressed through: 
2.5.1.1 Week 24, through Week 48, and through Week 96 (Cohort 2A: oral followed by 
injectable); 
2.5.1.2 Week 20, through Week 44, and through Week 92 (Cohort 2B: injectable only). 
 
2.5.2 
To evaluate the safety, antiviral and immunologic activity, and characterize PK of CAB 
LA + RPV LA in adolescents living with HIV who are virologically suppressed through: 


 
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2.5.2.1 Week 96 (Cohort 2A: oral followed by injectable); 
2.5.2.2 Week 92 (Cohort 2B: injectable only). 
 
2.5.3 
To evaluate adolescent participant’s experience of CAB LA and/or RPV LA, and 
parent/caregiver’s experience and perceptions of adolescent acceptability and tolerability 
of CAB LA and/or RPV LA (Cohort 1 and Cohort 2). 
 
2.5.4 
To evaluate the tolerability and acceptability, and characterize long-term safety and 
washout PK through 48 weeks following permanent discontinuation of CAB LA or RPV 
LA (Cohort 1). 
 
2.5.5 
To evaluate the tolerability and acceptability, and characterize long-term safety and 
washout PK through 48 weeks following permanent discontinuation of CAB LA + RPV 
LA (Cohort 2). 
 
2.5.6 
To describe HIV-1 genotypic and phenotypic resistance patterns in participants 
experiencing confirmed virologic failure (Cohort 1 and Cohort 2). 
 
 
3 
STUDY DESIGN 
 
This is a Phase I/II, multi‐center, open‐label, non‐comparative study to confirm the dose and 
evaluate the safety, tolerability, acceptability, and PK of oral CAB, long-acting injectable CAB 
(CAB LA), and long-acting injectable RPV (RPV LA) among up to 155 children and adolescents 
aged 12 to <18 years living with HIV who are virologically suppressed.  
 
Up to 60 parents/caregivers of adolescent participants in the U.S. will also be enrolled to take part 
in in-depth qualitative interviews. Unless otherwise noted, the term ‘participant’ will refer to the 
adolescent participants. 
 
The study will open to accrual in Cohort 1, in which participants, in addition to continuing their 
pre-study cART regimen, will receive either oral CAB or oral RPV (Step 1) followed by either 
CAB LA or RPV LA (Step 2). Cohort 1 participants will be assigned either CAB (Cohort 1C) or 
RPV (Cohort 1R) based on their pre-study cART regimen. A first interim analysis will be 
performed with a sub-set of participants in Cohort 1 to first determine whether to open Cohort 2 
to Cohort 1 participants who meet criteria to enter Cohort 2 and establish the doses for Cohort 2. 
A second interim analysis will then be performed to determine whether to open Cohort 2 to 
additional participants who were not previously enrolled in Cohort 1. A final Cohort 1 analysis 
will be performed to confirm the final doses for Cohort 2.  See Section 3.1 below for further 
details describing these Cohort 1 data analyses.   
 
Cohort 2 participants will discontinue their pre-study cART regimen and receive both study 
products — CAB and RPV — at the doses established in Cohort 1. Cohort 2 participants may 
enroll to either: 
• 
Cohort 2A to receive both oral CAB + oral RPV (Step 3) followed by both CAB LA + RPV 
LA (Step 4), or  
• 
Cohort 2B to receive both CAB LA + RPV LA (Step 5).  
 


 
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Unless otherwise specified, the term ‘Cohort 2’ applies to participants in both Cohort 2A and 
Cohort 2B.   
 
Participants who permanently discontinue injectable study product will continue on-study for an 
additional 48 weeks after their last study product injection, per the long-term safety and washout 
PK follow-up (LSFU) schedule and as detailed in Section 3.3. 
 
Safety and PK evaluations will be performed in each cohort, as well as during LSFU. Antiviral 
activity assessments will be performed in each cohort. Acceptability and tolerability will be 
assessed in each cohort and during LSFU, with all participants completing quantitative 
questionnaires and a sub-set of participants completing in-depth qualitative interviews.  
 
Further information describing the two cohorts is provided in Sections 3.1 and 3.2. Further 
information describing the LSFU visit schedule, for both Cohort 1 and Cohort 2 participants, is 
provided in Section 3.3. Refer to Figure 1, and Figure 2 for an overview of the study design of 
Cohort 1 and Cohort 2 for the adolescent participants; Section 4 for the eligibility criteria relevant 
to each cohort and step; and Section 6 and Appendix I for the study visit and procedure schedules 
for each cohort. Details regarding the in-depth qualitative interviews are provided in Section 11.  
 
Parent/caregiver eligibility criteria are provided in Section 4, with further details regarding the 
parent/caregiver in-depth qualitative interviews in Appendix IV. 
 
3.1 
Cohort 1 
 
Up to 55 participants will be enrolled in Cohort 1 to achieve approximately 30-35 dose-evaluable 
(refer to Section 9.5.1.3 for the definition of dose-evaluable for this cohort). Within this cohort, 
participants will be assigned to either Cohort 1C (approximately 15-20 dose-evaluable), in which 
participants will receive CAB, or Cohort 1R, in which participants will receive RPV 
(approximately 15 dose-evaluable). Assignment to Cohort 1C or 1R will be based on each 
participant’s pre-study cART regimen:   
 
• 
Participants on a PI-based and/or NNRTI-based cART regimen will be assigned to Cohort 1C 
• 
Participants on a non-boosted INSTI-based cART regimen will be assigned to Cohort 1R 
 
All participants in Cohort 1 will remain on their pre-study cART regimen and will additionally 
receive either CAB (Cohort 1C) or RPV (Cohort 1R). 
 
Upon enrollment, Cohort 1 participants will receive oral CAB (Cohort 1C) or oral RPV (Cohort 
1R) for at least 4 weeks (and up to 6 weeks) in Step 1. An intensive PK visit will be conducted at 
the Week 2 visit. Data collected through the Week 4a study visit will be assessed to determine 
eligibility for each participant to enter Step 2 and receive injectable CAB LA or RPV LA, 
respectively. The Cohort 1 Week 4b visit serves as the Step 2 Entry visit. This visit should be 
scheduled to occur as soon as possible after Week 4a laboratory test results are available, to 
minimize the time between the Week 4a visit and initiation of the injectable study products in 
Step 2. Clinical assessments conducted at the Week 4b visit, and prior to administering the first 
injection, will also be used to confirm Step 2 eligibility.  
 


 
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Cohort 1 participants who meet eligibility criteria for Step 2 are generally expected to receive 
their last oral dose of CAB or RPV on the same day as their first injection of CAB LA or RPV 
LA, at the Week 4b Step 2 Entry visit (see Section 6.3.4 for further details). See Section 4.3 for 
eligibility criteria to enter Step 2. Cohort 1 participants who do not meet eligibility criteria for 
Step 2 will discontinue use of oral CAB or RPV and exit the study 28 days after their last oral 
study product dosing.    
 
In Step 2, participants will receive CAB LA (Cohort 1C) or RPV LA (Cohort 1R) while 
continuing their cART regimen. A single intramuscular (IM) injection of CAB LA or RPV LA 
will be administered at the following visits: once at the Week 4b (Step 2 Entry) visit and once at 
the Week 8 visit. Cohort 1 Step 2 participants will be followed for safety and PK assessments 
through their Week 16 visit.  
 
In Step 2, Weeks 5 through 16 visits will be scheduled based on the date of first injection 
administration (Week 4b Step 2 Entry visit). Cohort 1 Step 2 participants will be followed for up 
to an additional 48 weeks, per the LSFU visit schedule, upon premature injectable study product 
discontinuation or upon completion of the Step 2 Week 16 visit. Cohort 1 participants who have 
completed all Step 2 visits may enroll to Cohort 2 (if eligible), prior to completing all LSFU 
visits. Further guidance on scheduling study visits is provided in the IMPAACT 2017 Manual of 
Procedures (MOP). 
 
Interim Analysis #1 (conducted under protocol version 2.0; see protocol Section 1.3) 
Once seven dose-evaluable Cohort 1C participants and seven dose-evaluable Cohort 1R 
participants have completed Step 2 injectable study product dosing and safety and PK evaluations 
through the Cohort 1 Step 2 Week 16 visit, an interim analysis of safety and PK data will be 
performed to: 
 
• 
Determine whether criteria have been met to open Cohort 2 to accrual — limited to Cohort 1 
participants 
• 
Establish the dose of the oral and injectable CAB study products, and the injectable RPV 
study product to be provided in Cohort 2   
 
Interim Analysis #2 
Once approximately 15-20 Cohort 1C participants and approximately 15 Cohort 1R participants 
who could contribute to the dose-finding algorithm have enrolled, and 80% of these participants 
have completed the Step 2 Week 8 visit, an interim analysis of safety and PK evaluations will be 
performed to determine whether criteria have been sufficiently met to fully open Cohort 2 to 
accrual, including accrual of participants who were not previously enrolled in Cohort 1. Once 
Cohort 2 is opened to accrual for new participants who were not previously enrolled in Cohort 1, 
accrual into Cohort 1 will close. 
 
Cohort 1 Final Analysis 
Once Cohort 1 participants have all completed safety and PK evaluations through the Cohort 1 
Step 2 Week 16 visit, the final analysis of all Cohort 1 safety, PK and maintenance of viral 
suppression data will be performed to confirm the dose of the oral and injectable CAB study 
products, and the injectable RPV study product provided in Cohort 2. 
 
Refer to Section 9 for the definition of dose-evaluable, and detailed descriptions of all Cohort 1 
analyses and associated decision-making.  
 


 
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Participant safety will be monitored throughout follow-up, and samples for antiviral activity and 
PK evaluations will be collected at visits as specified in Section 6, with blood volume ranges 
provided in . Acceptability and tolerability will be assessed with all participants completing 
quantitative questionnaires, and a sub-set of participants also completing in-depth qualitative 
interviews.  
 
3.2 
Cohort 2 
 
Up to 155 adolescents may be enrolled across Cohort 2A and Cohort 2B to achieve the following: 
• At least 100 participants exposed to the final recommended dose for Cohort 2 (including 
adolescents enrolled to Cohort 2 who previously participated in Cohort 1), which includes 
• Approximately 70 evaluable participants receiving the final recommended doses for Cohort 2 
who had not previously participated in Cohort 1. 
 
In addition to the participants enrolling directly into Cohort 2, adolescents who participated in 
Cohort 1 Step 2 (up to 55 participants) may continue study participation in Cohort 2, if eligible. 
These participants may screen and enroll into Cohort 2 either prior to completing all scheduled 
LSFU study visits or resume study participation if after having already exited the study. See 
Section 6.2 for additional considerations regarding Cohort 1 Step 2 participants screening and 
enrolling into Cohort 2. 
 
As noted above, Cohort 2 will consist of two groups: Cohort 2A and Cohort 2B. Participants 
enrolled to Cohort 2A will receive both oral CAB + oral RPV (Step 3) followed by both CAB LA 
+ RPV LA (Step 4). Participants enrolled to Cohort 2B will receive both CAB LA +RPV LA 
(Step 5), thus skipping the oral lead-in phase. The decision of which group a Cohort 2 participant 
will enroll to will be determined by the potential study participant and the parent/legal guardian 
(as applicable) in consultation with the IoR, or designee, as part of the informed consent or assent 
process, and confirmed prior to study entry. Participants may not change their Cohort 2A or 
Cohort 2B group selection after enrollment. Upon enrollment into Cohort 2, all participants will 
discontinue their pre-study cART regimen.  
 
Cohort 2A Step 3 (oral lead-in phase) 
For participants enrolling to Cohort 2A Step 3 (oral lead-in), a PK visit will be conducted at the 
Week 2 visit. Data collected through the Week 4a study visit will be assessed to determine 
eligibility for each participant to enter Step 4 and receive injectable CAB LA + RPV LA. The 
Cohort 2A Week 4b visit serves as the Step 4 Entry visit. This visit should be scheduled to occur 
as soon as possible after Week 4a laboratory test results are available, to minimize the time 
between the Week 4a visit and initiation of the injectable study products in Step 4. Clinical 
assessments conducted at the Week 4b visit, and prior to administering the first injection, will 
also be used to confirm Step 4 eligibility. 
 
Cohort 2A participants who meet eligibility criteria for Step 4 are generally expected to receive 
their last oral dose of CAB + RPV on the same day as their first injection of CAB LA + RPV LA, 
at the Week 4b Step 4 Entry visit (see Section 6.4.4 for further details). See Section 4.4 for 
eligibility criteria to enter Step 4. Cohort 2A participants who do not meet eligibility criteria for 
Step 4 will discontinue use of oral CAB + RPV and exit the study 28 days after their last oral 
study product dosing. Cohort 1 Step 2 participants who continue in Cohort 2A Step 3 but are not 
eligible to progress to Cohort 2A Step 4 will be followed per the LSFU visit schedule.    
 
Cohort 2A Step 4 and Cohort 2B Step 5 (injection phase) 


 
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In Cohort 2A Step 4 and in Cohort 2B Step 5, participants will receive injectable CAB LA + RPV 
LA. Refer to Section 5.2 for details regarding the study product administration schedule and 
dosing regimen. Injection study visits will be scheduled based on the date of which the first CAB 
LA + RPV LA injections were administered (Week 4b Step 4 Entry for Cohort 2A, and Step 5 
Entry for Cohort 2B).  
 
Upon premature discontinuation of injectable study products, participants will be followed for 48 
weeks per the LSFU visit schedule. Further guidance on scheduling study visits is provided in 
Section 6.1 and the IMPAACT 2017 MOP. At the final study visit during the Cohort 2 injection 
phase (Week 96 for Cohort 2A, and Week 92 for Cohort 2B), participants who wish to receive 
injectable CAB LA + RPV LA external to the protocol will exit the study. Those who do not wish 
to receive injectable CAB LA + RPV LA external to the protocol will not exit the study and will 
be followed for 48 weeks per the LSFU visit schedule. See Section 14.11 for more information 
regarding post-trial access to study products.  
 
Participant safety will be monitored, and samples for antiviral activity and PK evaluations will be 
collected, at visits as specified in Section 6; blood volume ranges are provided in Appendix I-B 
and Appendix I-C. Acceptability and tolerability of CAB LA and RPV LA will be assessed with 
all participants completing quantitative questionnaires, and a sub-set of participants also 
completing in-depth qualitative interviews.  
 
3.3 
Long-term Safety and Washout PK Follow-up (LSFU) 
 
Participants will enter into the LSFU visit schedule at different timepoints for up to an additional 
48 weeks to assess long-term safety and washout PK of the study products:  
• 
Premature permanent discontinuation of injectable study product  
• 
Completion of the Cohort 1 Step 2 Week 16 visit but not enrolling to Cohort 2 
• 
Completion of Cohort 2A Step 4 Week 96 or Cohort 2B Step 5 Week 92 study visit but do 
not wish to receive injectable CAB LA + RPV LA external to the protocol 
• 
Participants assigned female at birth who discontinue study product use (either oral or 
injectable study product) due to pregnancy during Steps 1-5 
 
LSFU visits will be scheduled approximately 8, 24, 36, and 48 weeks after the last injection, after 
which participants will exit the study.  Cohort 1 Step 2 participants who complete their Week 16 
visit will skip the LSFU Week 8 visit. Cohort 1 Step 2 participants who enroll to Cohort 2 Step 3 
but are then not eligible to progress to Cohort 2 Step 4 will be followed per the LSFU visit 
schedule, also based on the date of their last study product injection (i.e. their Cohort 1 Step 2 
Week 8 visit). Cohort 2 Step 3 participants being followed per the LSFU visit schedule will 
resume (non-study provided) oral cART within 4 weeks of discontinuing oral study product.  
 
As noted above, at the Week 96 or Week 92 visit, Cohort 2 participants who do not wish to 
receive injectable CAB LA + RPV LA external to the protocol will discontinue their study 
product (as they have completed the study product dosing regimen) and will be followed per the 
LSFU visit schedule. All Cohort 2 participants following the LSFU visit schedule will complete 
all LSFU study visits, including the LSFU Week 8 study visit.  Cohort 2 Step 4 and Step 5 
participants will resume (non-study provided) oral cART at 8 weeks (±7 days) of discontinuing 
injectable study products. See Section 8.8 for criteria for premature permanent discontinuation of 
study product. 
 


 
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Participants assigned female at birth who permanently discontinue study product use (either oral 
or injectable study product) due to pregnancy during Steps 1-5 will be followed for an additional 
48 weeks based on their confirmed positive pregnancy test result, per the LSFU visit schedule. 
For participants who become pregnant during LSFU visits, the LSFU visits will continue as 
scheduled and not restart. Further details on participant management of contraception and 
pregnancy are located in Sections 6.13 and 8.3. 
 
Participant safety will be monitored, and samples for antiviral activity and PK will be collected, 
at visits as specified in Section 6; blood volume ranges are provided in Appendix I-D. 
Acceptability and tolerability will be assessed with all participants completing quantitative 
questionnaires, and a sub-set of participants also completing in-depth qualitative interviews.  
 
 
4 
STUDY POPULATION 
 
This study will be conducted among up to 155 adolescents living with HIV who are virologically 
suppressed, and up to 60 parents/caregivers of study participants. Inclusion and exclusion criteria 
for each of the study populations are provided in Sections 4.1– 4.5 below.  
 
Adolescents will be enrolled into either Cohort 1 Step 1, Cohort 2A Step 3, or Cohort 2B Step 5. 
Adolescents who previously participated in Cohort 1 Step 2 and are continuing study 
participation by enrolling into Cohort 2, must meet the same eligibility criteria as other 
participants enrolling directly into Cohort 2, unless otherwise noted.  
 
The study-specific approach to recruitment, screening, and enrollment is described in Section 4.7. 
Considerations related to participant retention and withdrawal/termination from the study are 
provided in Sections 4.8 and 8.8, respectively. 
 
4.1 
Inclusion Criteria: Cohort 1 Step 1, Cohort 2A Step 3, and Cohort 2B Step 5 
 
All the criteria specified below must be met for inclusion of any adolescent participant in Step 1 
of Cohort 1, in Step 3 of Cohort 2A, or in Step 5 of Cohort 2B. Unless otherwise noted, “at entry” 
is used to refer to the day of enrollment into the applicable cohort. 
 
4.1.1 
At enrollment, 12 to < 18 years of age 
 
Note: For Cohort 1 Step 2 participants, age will not be exclusionary for enrollment into 
Cohort 2, if otherwise eligible. 
 
4.1.2 
If not of legal age or otherwise not able to provide independent informed consent as 
determined by site SOPs and consistent with site institutional review board (IRB)/ ethics 
committee (EC) policies and procedures:  Parent or legal guardian is willing and able to 
provide written informed consent for study participation and potential participant is 
willing and able to provide written assent for study participation 
 
If of legal age or otherwise able to provide independent informed consent as determined 
by site SOPs and consistent with site IRB/EC policies and procedures:  Willing and able 
to provide written informed consent for study participation 
 
4.1.3 
At enrollment, body weight ≥ 35 kg (77 lbs.) 
 


 
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Note: For Cohort 1 Step 2 participants, body weight will not be exclusionary for 
enrollment into Cohort 2, if otherwise eligible. 
 
4.1.4 
For Cohort 1, at enrollment, body mass index (BMI) < 31.5 kg/m2 
 
4.1.5 
At enrollment, willing and able to comply with the study visit schedule and other study 
requirements, as determined by the site investigator or designee 
 
4.1.6 
Confirmed HIV-1 disease based on documented testing of two samples collected from 
two separate blood collection tubes per Sample #1 and Sample #2 requirements, at 
different time points. Test results may be obtained from medical records or from testing 
performed during the study screening period:  
 
• 
For results obtained from medical records, adequate source documentation, including 
the date of specimen collection, date of testing or date of test result, name of 
test/assay performed, and test result, must be available in study records prior to study 
entry. Requirements related to laboratory operations (e.g., CLIA, GCLP, or VQA) 
and related to regulatory authority approvals (e.g., FDA) do not apply to results 
obtained from medical records.  
• 
If adequate source documentation is not available, Sample #1 and/or Sample #2 
should be collected during the study screening period and tested in the study site’s 
designated testing laboratory. At least one of the tests used to confirm HIV-1 status 
must be performed in CLIA- certified or equivalent laboratory (for US sites) or in a 
DAIDS-monitored laboratory that is GCLP compliant and participates in an approved 
external quality assurance proficiency testing program (for non-US sites). 
 
Sample #1 may be tested using any of the following: 
• 
Two rapid antibody tests from different manufacturers or based on different 
principles and epitopes; combination antigen-antibody-based rapid tests may be used. 
• 
One enzyme immunoassay (EIA) OR Western Blot OR immunofluorescence OR 
chemiluminescence 
• 
One HIV DNA polymerase chain reaction (PCR) 
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay) 
• 
One qualitative HIV RNA PCR 
• 
One HIV total nucleic acid test 
 
Sample #2 may be tested using any of the following: 
• 
Rapid antibody test. If this option is used in combination with two rapid tests for 
Sample #1, at least one of the three rapid tests must be FDA-approved, and the third 
rapid test must be from a third manufacturer or based on a third principle or epitope. 
• 
One EIA OR Western Blot OR immunofluorescence OR chemiluminescence 
• 
One HIV DNA PCR 
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay) 
• 
One qualitative HIV RNA PCR 
• 
One HIV total nucleic acid test 
 
All study-specific samples tested to determine HIV status must be whole blood, serum, or 
plasma. Testing methods and algorithms must be approved for each site by the 
IMPAACT Laboratory Center (for NIAID-funded sites) or Westat (for NICHD-funded 
sites). All testing methods should be FDA-approved, if available. If both samples are 


 
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tested using antibody tests, at least one of the samples must be tested in a laboratory that 
operates according to Good Clinical Laboratory Practice (GCLP) guidelines and 
participates in an appropriate external quality assurance program. If nucleic acid testing is 
used, at least one test must be performed in a Clinical Laboratory Improvement 
Amendments CLIA-certified (US sites) laboratory or a VQA-certified laboratory (non-
US sites). For tests performed in other (non-GCLP-compliant) settings, adequate source 
documentation including the date of specimen collection, date of testing or date of test 
result, name of test/assay performed, and test result must be available. 
 
4.1.7 
For at least 3 consecutive months (defined as 90 consecutive days) prior to screening, and 
prior to enrollment, has been on stable unchanged cART consisting of 2 or more drugs 
from 2 or more classes of antiretroviral drugs, ascertainment of this criterion may be 
based on parent or guardian report only, but available medical records should also be 
reviewed in relation to this criterion. 
 
Note: Participants undergoing dose modifications to their antiretroviral regimen for 
growth or who are switching medication formulation(s) are considered to be on a stable 
cART. 
 
4.1.8 
Has at least one documented plasma HIV-1 RNA result less than the lower limit of 
detection of the assay from a specimen collected in the 6 to 12 months (defined as 180 to 
365 days) prior to entry 
 
OR 
 
Has at least one documented plasma HIV-1 RNA result less than the lower limit of 
detection of the assay from a specimen less than 6 months (defined as within 179 days) 
prior to entry and at least one documented plasma HIV-1 RNA result less than the lower 
limit of detection of the assay from a specimen collected in the 12-18 months (defined as 
365 to 545 days) prior to entry. 
 
OR 
 
For Cohort 1 participants enrolling to Cohort 2, has documented plasma HIV-1 RNA 
results less than the lower limit of detection of the assay from all indicated Cohort 1 study 
visits with their Cohort 1 Week 16 visit completed within 28 days prior to Cohort 2 entry. 
 
4.1.9 
At screening, has Grade 2 or lower of all the following laboratory test results: 
• 
ALT (u/l) 
• 
Lipase (u/l) 
• 
Estimated creatinine clearance (CrCl; Schwartz Bedside Pediatrics formula 
mL/min/1.73m2)  
• 
Platelets (cells/mm3) 
• 
Hemoglobin (g/dL) 
• 
AST (u/l) 
• 
Absolute Neutrophil Count (cells/mm3) 
 
See Section 7.3.3 for guidance on severity grading. Laboratory tests may be repeated 
during the study screening period, with the latest result used for eligibility determination. 
 


 
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4.1.10 At screening, is on an atazanavir-containing (ATV) cART regimen and has total bilirubin 
≤ 1.5 mg/dL or normal direct bilirubin 
 
4.1.11 At screening, has documented plasma HIV-1 RNA < 50 copies/mL 
 
4.1.12 At screening, mean value of QTc interval (automated machine readout or calculated 
using either Bazett or Fridericia) on ECG performed in triplicate, < 500 msec.  
 
4.1.13 For females, has a negative (blood or urine) hCG laboratory test result at entry 
 
 
4.1.14 For females of childbearing potential, at entry, currently using at least one allowable 
effective method of contraception, and agrees to use at least one allowable effective 
method of contraception throughout study participation, for at least 30 days after 
discontinuation of oral study product, and for at least 48 weeks after discontinuation of 
CAB LA and/or RPV LA, and intending to delay any planned pregnancies until 30 days 
after last oral study product use or until 48 weeks after last injectable study product use.   
 
Note: See Section 6.13 for details regarding contraceptive counseling, a list of the 
allowed effective contraceptive methods for this study, and the definition of a female of 
childbearing potential.  Hormonal-based contraceptives must have been initiated within 
the prescribed time, per the respective contraceptive method, to be considered effective at 
the time of Entry. The site IoR or designee is responsible for ensuring that 
the contraceptive is used in accordance with the approved product label, and counseling 
participants on proper use of chosen methods of contraception, including barrier methods.  
 
4.1.15 For Cohort 1 participants enrolling to Cohort 2, have completed all scheduled product 
injections and completed Week 16 visit in Cohort 1 Step 2 
 
Note: Cohort 1 participants unable to receive study product injections or complete the 
Week 16 visit due to site limitations or restrictions in response to COVID-19 or 
circumstances beyond the control of the participant/participant’s family and not raising 
concerns of future adherence to protocol requirements are exempt from this inclusion 
criterion. 
 
4.2 
Exclusion Criteria: Cohort 1 Step 1, Cohort 2A Step 3, and Cohort 2B Step 5 
 
Adolescents will be excluded from the study if any of the below specified criteria are identified 
during the screening period. The screening period begins when informed consent is obtained and 
ends immediately prior to enrollment to the applicable cohort. For criteria involving a potential 
participant’s medical history, it is expected that each exclusionary condition will be assessed at 
screening and subsequently reviewed and confirmed on the day of study entry, prior to 
enrollment.  
 
4.2.1 
Within 6 months (defined as within 179 days) prior to entry, two consecutive documented 
HIV-1 RNA values greater than or equal to the lower limit of detection of the assay 
 
Note: Unconfirmed virologic HIV-1 RNA value of greater than the lower limit of 
detection of the assay (transient detectable viremia, or “blip”) prior to screening is not 
exclusionary. 
 


 
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4.2.2 
For Cohort 1 participants enrolling to Cohort 2A Step 3 or to Cohort 2B Step 5, 
occurrence of any Grade 3 or higher adverse event assessed as related to study product or 
permanent discontinuation of study product due to an adverse event of any grade assessed 
as related to study product, during participation in Cohort 1 (including any long-term 
safety and washout PK follow-up visits).  
 
4.2.3 
For participants enrolling to Cohort 1 Step 1, based on available medical records, 
currently on either a cART regimen containing both a PI and an INSTI, or a cART 
regimen containing both an INSTI and a NNRTI. 
 
4.2.4 
As determined by the IoR or designee, and based on available medical records, known or 
suspected resistance to RPV 
 
4.2.5 
As determined by the IoR or designee based on available medical records, known or 
suspected resistance to INSTIs 
 
4.2.6 
History of congestive heart failure, symptomatic arrhythmia, or any clinically significant 
cardiac disease, as determined by the IoR or designee based on available medical records 
 
4.2.7 
At entry, known active tuberculosis infection, as determined by the Investigator of 
Record (IoR) or designee based on available medical records 
 
4.2.8 
Known hepatitis B or hepatitis C infection, as determined by the IoR or designee based 
on available medical records 
 
4.2.9 
Clinically significant hepatic disease, as determined by the IoR or designee based on 
available medical records 
 
4.2.10 Current or anticipated need for chronic anti-coagulation, as determined by the IoR or 
designee, based on available medical records 
 
4.2.11 History of sensitivity to heparin or heparin-induced thrombocytopenia, as determined by 
the IoR or designee, based on available medical records  
 
4.2.12 History of known or suspected bleeding disorder including history of prolonged bleeding, 
as determined by the IoR or designee, based on available medical records 
 
4.2.13 Known or suspected allergy to study product components 
 
Note: For Cohort 1 participants enrolling to Cohort 2, participants who experienced mild 
allergic reactions which resolved whilst on continued study drug or when rechallenged 
with study drug during Cohort 1 may be exempted from this criterion at the discretion of 
the IoR. 
 
4.2.14 More than one seizure within one year (defined as within 365 days) prior to entry, or 
unstable or poorly controlled seizure disorder, as determined by the IoR or designee, 
based on available medical records.  
 
4.2.15 At entry, participant is receiving (or has received in the last 7 days) any disallowed 
medication listed in Section 5.7.  
 


 
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4.2.16 Current inflammatory skin condition that compromises the safety of intramuscular 
injections as determined by the IoR or designee.  
 
4.2.17 Has a tattoo or other dermatological condition overlying the buttock region which, in the 
opinion of the IoR or designee, may interfere with interpretation of injection site 
reactions 
 
4.2.18 Surgically‐placed, or planned, buttock implants, per self‐report 
 
4.2.19 For females, lactating (per self-report and/or parent/guardian report) at entry 
 
4.2.20 Enrolled in another clinical trial of an investigational agent, device, or vaccine  
 
4.2.21 Any other condition or social circumstance situation that, in the opinion of the IoR or 
designee, would make study participation unsafe, complicate interpretation of study 
outcome data, or otherwise interfere with achieving the study objectives 
 
4.3 
Inclusion/Exclusion Criteria, Step 2 (Cohort 1 Progression Criteria, Step 1 to Step 2)  
 
Cohort 1 Step 1 participants will be assessed for eligibility to progress from the oral lead-in phase 
(Step 1) to the injection phase (Step 2) primarily based on the safety assessments from the Cohort 
1 Step 1 Week 4a study visit. Clinical assessments conducted prior to administering the first 
injection at the Week 4b visit will also be used to confirm eligibility to receive the injectable 
study product. See Sections 6.3.3 and 6.3.4 for Week 4a and Week 4b visit scheduling, order of 
procedures, and visit windows, respectively. 
 
All of the following criteria must be met in order for participants to be included in Cohort 1 Step 
2: 
 
4.3.1 
Currently enrolled in Cohort 1, Step 1 
 
4.3.2 
At Cohort 1 Step 1 Week 4a study visit, or from confirmatory repeat testing of Cohort 1 
Step 1 Week 4a study visit laboratory tests, has Grade 2 or lower of all the following 
laboratory test results: 
• 
ALT (u/l) 
• 
Lipase (u/l)  
• 
Estimated creatinine clearance (CrCl; Schwartz Bedside Pediatrics formula 
mL/min/1.73m2)  
• 
Platelets (cells/mm3) 
• 
Hemoglobin (g/dL) 
• 
AST (u/l) 
• 
Absolute Neutrophil Count (cells/mm3) 
 
Note: For a Grade 2 ALT test result from this visit, refer to Section 8.1.6 for required 
participant management. Abnormal laboratory test result values from the Week 4a visit 
may be repeated within the target visit window, and if confirmatory testing results in 
Grade 2 or lower, the participant may be eligible to continue onto the injection phase, 
should all other eligibility criteria be met. 
 


 
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4.3.3 
For females, at Cohort 1 Step 1 Week 4b study visit, has a negative hCG laboratory test 
result 
 
4.3.4 
Assessed by the IoR or designee as sufficiently adherent in Step 1 to permit an adequate 
evaluation of safety and tolerability as part of the oral lead-in phase prior to entry into the 
injection phase 
 
Participants who meet any of the following criteria will be excluded from Cohort 1 Step 2:  
 
4.3.5 
Has permanently discontinued oral study product 
 
4.3.6 
Occurrence of any grade 3 or higher adverse event assessed as related to study product 
during participation in Step 1 
 
4.3.7 
Any other condition or social circumstance that, in the opinion of the IoR or designee, 
would make study participation unsafe, complicate interpretation of study outcome data, 
or otherwise interfere with achieving the study objectives. 
 
4.4 
Inclusion/Exclusion Criteria, Step 4 (Cohort 2A Progression Criteria, Step 3 to Step 4)  
 
Cohort 2A Step 3 participants will be assessed for eligibility to progress from the oral lead-in 
phase (Step 3) to the injection phase (Step 4) primarily based on the safety assessments from the 
Cohort 2A Step 3 Week 4a study visit. Clinical assessments conducted prior to administering the 
first injection at the Week 4b visit will also be used to confirm eligibility to receive the injectable 
study products. See Sections 6.4.3 and 6.4.4 for Week 4a and Week 4b visit scheduling, order of 
procedures, and target visit windows, respectively. 
 
All of the following criteria must be met in order for participants to be included in Cohort 2A 
Step 4: 
 
4.4.1 
Currently enrolled in Cohort 2A, Step 3 
 
4.4.2 
At Cohort 2A Step 3 Week 4a study visit, or from confirmatory repeat testing of Cohort 
2A Step 3 Week 4a study visit laboratory tests, has Grade 2 or lower of the following 
laboratory test results: 
• 
ALT (u/l) 
• 
Lipase (u/l)  
• 
Estimated creatinine clearance (CrCl; Schwartz Bedside Pediatrics formula 
mL/min/1.73m2)  
• 
Platelets (cells/mm3) 
• 
Hemoglobin (g/dL) 
• 
AST (u/l) 
• 
Absolute Neutrophil Count (cells/mm3) 
 
Note: For a Grade 2 ALT test result from this visit, refer to Section 8.1.6 for required 
participant management. Abnormal laboratory test result values from the Week 4a visit 
may be repeated, within the target visit window, and if confirmatory testing results in 
Grade 2 or lower, the participant may be eligible to continue onto the injection phase, 
should all other eligibility criteria be met. 
 


 
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4.4.3 
For females, at Cohort 2 Step 4 Week 4b study visit, has a negative hCG laboratory test 
result 
 
4.4.4 
Assessed by the IoR or designee as sufficiently adherent in Step 3 to permit an adequate 
evaluation of safety and tolerability as part of the oral lead-in phase prior to entry into the 
injection phase 
 
Participants who meet any of the following criteria will be excluded from Cohort 2A Step 4:  
 
4.4.5 
Has permanently discontinued oral study products 
 
4.4.6 
Occurrence of any grade 3 or higher adverse event assessed as related to study product 
during participation in Cohort 2A Step 3 
 
4.4.7 
Any other condition or social circumstance that, in the opinion of the IoR or designee, 
would make study participation unsafe, complicate interpretation of study outcome data, 
or otherwise interfere with achieving the study objectives. 
 
4.5 
Inclusion/Exclusion Criteria: Parents/Caregivers 
 
For U.S. sites only, selected parents or caregivers of adolescents may be enrolled to complete 
qualitative phone interviews. See Appendix IV for more information regarding the selection 
process, and coordination of scheduling the interviews. All of the following criteria must be met 
for the parent/caregiver to be enrolled: 
 
4.5.1 
Selected by the protocol team for participation in the study 
 
4.5.2 
Willing and able to provide informed (verbal or written) consent for study participation 
 
4.5.3 
Per the adolescent participant, has knowledge of how the adolescent participant tolerated 
the study product, and lives with or has regular supportive contact with the adolescent 
participant  
 
4.5.4 
Per parent/caregiver self-report, has knowledge of how the participant tolerated the study 
product, and lives with or has regular supportive contact with the adolescent participant 
 
4.5.5 
Willing and able to complete interview in English by phone 
 
Parents and/or caregivers of participants who meet the following criterion will be excluded from 
study participation:  
 
4.5.6 
Any condition or social circumstance that, in the opinion of the IoR or designee, would 
make study participation unsafe for either the parent/caregiver or the adolescent 
participant, complicate interpretation of study outcome data, or otherwise interfere with 
achieving the study objectives. 
 
4.6 
Co-Enrollment Considerations 
 
Co-enrollment in observational or other studies not involving an investigational agent, device, or 
vaccine may be permitted although careful consideration must be given to visit burden, blood 
draw volumes, and interpretation of outcome data across studies. Requests for co-enrollment must 


 
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be approved in advance by both study teams. Requests for such approval or questions related to 
co-enrollment should be emailed to the IMPAACT 2017 Clinical Management Committee 
(CMC).  
 
4.7 
Recruitment, Screening, and Enrollment Process 
 
This section provides a description of the recruitment methods, screening and enrollment 
processes, and the definition of enrollment for the adolescent participants.  
 
See Appendix IV for recruitment, eligibility confirmation, and enrollment processes, including 
the definition of enrollment, for parents/caregivers to take part in a single qualitative phone 
interview. 
 
4.7.1 
Recruitment and Screening of Cohort 1 (Step 1), Cohort 2A (Step 3), and Cohort 2B (Step 5) 
Participants 
 
Recruitment methods for this study may vary across sites. All participants must be 12 to less than 
18 years of age at the time of enrollment (with the exception of adolescents who previously 
participated in Cohort 1 Step 2 and continuing into Cohort 2, as noted in Section 4.1.1 above). 
Recruitment of participants, for both Cohort 1 and Cohort 2, is expected to rely on current 
patients being seen at a study clinic or from active identification and referral of children and 
adolescents living with HIV-1 who are ART-experienced and virologically suppressed; 
participants may be perinatally or behaviorally infected. 
 
Any advertising materials must undergo approval by each participating site’s IRB/EC. Sites are 
encouraged to solicit input and feedback on recruitment materials from their local Community 
Advisory Board, particularly any adolescent Community Advisory Board members.  
 
Upon identification of a potentially eligible participant, study staff will provide information about 
the study to the parent or guardian and/or the potential participant (as applicable). Each parent or 
guardian and/or potential participant (as applicable) who expresses interest in learning more about 
the study will be provided additional information, education, and counseling as part of the study 
informed consent process. The process will include detailed review of the study informed consent 
and assent forms (as applicable), time to address any questions or concerns the potential 
participant, parent, or guardian may have, and an assessment of understanding, before proceeding 
to informed consent and assent decisions. For potential Cohort 2 participants, the decision of 
Cohort 2A or Cohort 2B selection will be made during the informed consent and assent process; 
see Section 3.2. Study participants enrolled to Cohort 2 under protocol Version 3 and still on-
study will be re-consented to Cohort 2A. Informed consent and assent processes will be fully 
documented, consistent with the DAIDS requirements. Refer to Section 14.3 for further 
information on informed consent procedures for this study.  
 
Each site must establish standard operating procedures (SOPs) for eligibility determination that 
describe where and when screening procedures will be performed; roles and responsibilities for 
performing the required procedures; roles and responsibilities for assessing and confirming 
eligibility; and procedures for documenting the process, taking into consideration the required 
timing of enrollment. Sites are encouraged to minimize the time from screening to enrollment.  
 
Eligibility screening will be initiated after written informed consent and assent (as applicable) is 
provided. See Section 4.7.2 below for use of the Subject Enrollment System (SES) to assist in 
tracking of the screening process and obtaining a study-specific screening number. Screening will 


 
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include confirmatory HIV-1 testing (if needed) and assessment of other entry criteria. If at any 
time it is determined that an individual is not eligible for the study, or that study participation may 
not be feasible or in the participant’s best interest, the eligibility screening process will be 
discontinued; these individuals should be actively referred to non-study sources of care. 
Screening assessments, unless otherwise noted (see Section 6.2), must be completed within 28 
days prior to entry; re-screening is permitted one time per Cohort. For adolescents who are 
screened and found to be ineligible for the study, or who do not enroll in the study for any reason, 
limited demographic information and reasons for non-enrollment will be entered into electronic 
case report forms (eCRFs). Refer to Section 9.5 for more information on monitoring participant 
accrual in this study. Screening numbers for Cohort 2 will only be obtained for participants newly 
enrolling to the study. If a participant was enrolled in Cohort 1, a new screening number is not 
obtained for their Cohort 2 screening attempt(s). 
 
4.7.2 
Enrollment Process for Cohort 1 (Step 1), Cohort 2A (Step 3), and Cohort 2B (Step 5) Participants 
 
Adolescents who are found to meet the study eligibility criteria will be enrolled into the 
applicable Cohort and Step. Screening procedures may be performed on the day of enrollment; 
however, all required screening laboratory test results must be available for eligibility 
determination prior to enrollment.  
 
The IMPAACT Data Management Center’s (DMC) SES will be used to assist with tracking the 
screening and enrollment process. When informed consent and assent (as applicable) are obtained 
for the adolescent, participant identification numbers (PIDs) will be assigned and a study-specific 
screening number will be obtained through the SES. For adolescents found to be eligible, 
enrollment into the study or into a subsequent step will occur upon successful entry of required 
eligibility data into the SES. Successful entry into the SES will generate a study identification 
number (SID) and the prescribing information for the Cohort and Step in which the participant 
has been enrolled.  
 
4.8 
Participant Retention 
 
Once a participant is enrolled in this study, study staff will make every effort to retain him or her 
for the protocol-specified duration of follow-up, thereby maximizing statistical power and 
minimizing potential biases associated with loss to follow-up. Each site must establish and 
implement SOPs that target retention rates that are sufficient to allow the primary study outcomes 
to be reliably estimated (a maximum 10% loss to follow-up is assumed in sample size 
calculations). Additional guidance regarding special considerations for retaining adolescents and 
particularly Cohort 2 participants no longer on pre-study cART regimen, are provided in the 
IMPAACT 2017 MOP. Refer to Section 9.5 for more information on monitoring participant 
retention in this study. 
 
 
5 
STUDY PRODUCT 
 
Site pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS Clinical 
Trials Networks for standard pharmacy operations. Refer to Figure 1 and Figure 2 for an 
overview of the cohorts, and study design, and to the package inserts and investigator’s brochures 
(IBs) for further information about the study products. 
 


 
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5.1 
Study Product Regimen and Administration 
 
Study participants will be assigned to receive (open-label) either CAB (oral CAB followed by 
intramuscular CAB LA) or RPV (oral RPV followed by intramuscular RPV LA) in Cohort 1. 
Study arm assignments in Cohort 1 will be based on participants’ pre-study cART regimen (as 
described in Section 5.1.1 below). 
 
In Cohort 2A, study participants will be assigned to receive (open-label) both CAB and RPV (oral 
CAB + oral RPV, followed by intramuscular CAB LA + intramuscular RPV LA).  
 
In Cohort 2B, study participants will be assigned to receive (open-label) both intramuscular CAB 
LA + intramuscular RPV LA. 
 
5.1.1 
Cohort 1 
 
Participants in Cohort 1 will be assigned to Cohort 1C (oral CAB followed by intramuscular CAB 
LA) or Cohort 1R (oral RPV followed by intramuscular RPV LA) based on their pre-study cART 
regimen:   
 
• 
Participants on a PI-based and/or NNRTI-based cART regimen will be assigned to Cohort 1C 
• 
Participants on a non-boosted INSTI-based cART regimen will be assigned to Cohort 1R 
 
All participants in Cohort 1 will continue their pre-study cART regimen and receive either CAB 
(Cohort 1C) or RPV (Cohort 1R) as shown in Table 5. Participants enrolled under protocol 
Version 2.0 received the Q4W dosing regimen presented in that version; refer to Section 1.3 for 
additional details regarding protocol version history. 
 
Table 5. Cohort 1: Study Product Regimen and Administration 
Cohort 
Step 
Study Product Regimen and Administration (with non-study provided 
cART regimen) 
1C 
1 
CAB administered orally as one 30 mg tablet once daily, beginning at 
the Entry visit, for 4-6 weeks (up to 43 doses), with or without food.  
2 
CAB LA administered as one IM injection in the gluteus medius at 
Week 4b (Step 2 Entry) study visit (600 mg/3 mL), and at Week 8 
(600 mg/3 mL). 
1R 
 
1 
RPV administered orally as one 25 mg tablet once daily, beginning at 
the Entry visit, for 4-6 weeks (up to 43 doses), with a meal. 
2 
RPV LA administered as one IM injection in the gluteus medius at 
Week 4b (Step 2 Entry) study visit (900 mg/3 mL), and at Week 8 
(900 mg/3 mL). 
 
Study participants are generally expected to receive the first dose of intramuscular CAB LA 
(Cohort 1C) or intramuscular RPV LA (Cohort 1R) on the same day as the last dose of oral CAB 
dose or oral RPV, respectively (at the Week 4b Step 2 Entry visit). 


 
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5.1.2 
Cohort 2 
 
All participants in Cohort 2 will discontinue their pre-study cART regimen and receive both CAB 
and RPV as shown in Table 6 (Cohort 2A) and Table 7 (Cohort 2B). Cohort 2 doses may change 
based on experience in Cohort 1, in which case, the new doses will be specified in a letter of 
amendment or full amendment. 
 
Table 6. Cohort 2A: Study Product Regimen and Administration 
Cohort 
Step 
Study Product Regimen and Administration (without cART regimen) 
2A 
3 
CAB administered orally as one 30 mg tablet once daily AND RPV 
administered orally as one 25 mg tablet once daily, taken together and 
with a meal, beginning at the Entry visit for 4-6 weeks (up to 43 doses 
of each). 
4 
 
First and second set of injections: CAB LA administered as one 600 
mg (3 mL) IM injection in the gluteus medius AND RPV LA 
administered as one 900 mg (3 mL) IM injection in the gluteus 
medius, at Week 4b (Step 4 Entry) and at Week 8.  
 
Subsequent injections: starting at the Week 16 visit, CAB LA 
administered as a 600 mg (3 mL) IM injection in the gluteus medius 
muscle AND RPV LA administered as a 900 mg (3 mL) IM injection 
in the gluteus medius, every eight weeks through Week 96. 
 
 
Study participants enrolled into Cohort 2A are generally expected to receive the first doses of 
intramuscular CAB LA and intramuscular RPV LA on the same day as the last doses of oral CAB 
and oral RPV (at the Week 4b Step 4 Entry visit).  
 
Table 7. Cohort 2B: Study Product Regimen and Administration 
Cohort 
Step 
Study Product Regimen and Administration (without cART regimen) 
2B 
5 
 
First and second set of injections: CAB LA administered as one 600 
mg (3 mL) IM injection in the gluteus medius AND RPV LA 
administered as one 900 mg (3 mL) IM injection in the gluteus 
medius, at Entry (Step 5 Entry) and at Week 4.  
 
Subsequent injections: starting at the Week 12 visit, CAB LA 
administered as a 600 mg (3 mL) IM injection in the gluteus medius 
muscle AND RPV LA administered as a 900 mg (3 mL) IM injection 
in the gluteus medius, every eight weeks through Week 92. 
 
 
 
5.1.3 
Dispensing of Oral Study Product (Cohort 1 Step 1, or Cohort 2A Step 3) 
 
A 30-day supply of oral study product will be provided at the Entry visit for Cohort 1 and for 
Cohort 2A. Cohort 1 participants will be provided a 30-day supply of only the oral study product 
to which they are assigned, whereas Cohort 2A participants will be provided a 30-day supply of 
each oral study product. 
 


 
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An additional 30-day supply of oral study product may be dispensed at the Week 2 or Week 4a 
visits (Cohort 1 and Cohort 2A) to ensure sufficient coverage for daily use through the 
participant’s scheduled Week 4b visit and their first study product injection. See Sections 6.3.4 
and 6.4.4 for more details on the Cohort 1 Step 2 Week 4b visit, and Cohort 2A Step 4 Week 4b 
visit, respectively. 
 
5.1.4 
Short-term Oral Bridging for Cohort 2 Participants 
 
In exceptional circumstances and following consultation with the CMC, to address planned 
missed CAB LA + RPV LA injection visits, sites may provide daily oral CAB 30 mg + 
RPV 25 mg as a short-term bridging strategy for Cohort 2 participants who will miss a scheduled 
injection.  Daily oral CAB 30 mg + RPV 25 mg for short-term oral bridging may be dispensed to 
study staff for providing to a participant off-site.  Supply of oral study product for short-term oral 
bridging should ensure sufficient coverage for daily use until the participant can resume study 
product injections. The daily oral CAB 30 mg + RPV 25 mg bridging regimen is ideally to begin 
on the same target visit date (or within the same target visit window) as that of the missed 
injection visit.  The last dose of the daily oral bridging regimen should be taken on the same day 
and prior to resuming injectable study product.   
 
The CMC must be consulted prior to resuming study product injections.  Cohort 2 participants 
may be required to have interim injection visits upon resuming the study product injections to 
appropriately reinitiate the dosing regimen or to realign to the original injection visit dosing 
schedule. 
  
See Section 6.9 for required procedures prior to dispensing oral study products or administering 
study product injections. See Section 6.1 for further guidance on scheduling study visits, and 
Section 6.4.14 for interim injection visits. 
 
5.1.5 
Preparation and Administration of Injections 
 
The Pharmacist of Record must be proficient in the preparation of products requiring aseptic 
technique under a pharmacy biological safety cabinet/isolator. Local regulations and site 
institutional policies and procedures for use of protective equipment, such as gloves, gowns, and 
masks, and safety glasses, must be followed.  
 
All injections will be administered using standard IM injection technique in the gluteus medius. 
The following information must be source documented and entered into eCRFs with each 
injection of study product (e.g., Cohort 2 participants will have information entered for CAB LA, 
and information entered for RPV LA): 
• 
Location (which side) of administration 
• 
Needle length and needle gauge used  
• 
Volume of injectable study product administered  
 
Whenever possible, for Cohort 2 participants, CAB LA is to be administered in the contralateral 
gluteus medius muscle from the RPV LA. However, if the participant prefers, injections can both 
be administered on the same side with the injection sites at least 2cm apart. In these instances, site 
staff must source document where on the gluteus medius muscle each injection has been 
administered for assessing adverse reactions to the injections.  
 


 
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Injectable study product must be administered within the respective study visit windows or per 
CMC guidance (for Cohort 2 participants resuming injections following short-term oral bridging); 
see Section 6.1 for visit window requirements.  
 
Refer to Section 6.4.14 for interim injection visits, Appendix V for detailed instructions on the 
preparation of injectable study products, and to the IMPAACT 2017 MOP for instructions on the 
administration of the study products. 
 
5.2 
Study Product Formulation 
 
5.2.1 
Oral CAB 
 
CAB 30 mg tablets are formulated as white to almost white oval-shaped film-coated tablets for 
oral administration. Cabotegravir 30 mg tablets may also be debossed with the code “SV CTV” 
on one face. The tablets are packaged in high density polyethylene (HDPE) bottles with child-
resistant closures that include induction seal liners. The bottles contain 30 tablets and a desiccant. 
The tablets should be stored up to 30° C (86° F), in the original container with the desiccant, and 
protected from moisture. 
 
5.2.2 
Oral RPV 
 
RPV 25 mg tablets are formulated as white to off-white, film-coated, round, biconvex tablets for 
oral administration. Each tablet is debossed with “TMC” on one side and “25” on the other side. 
Tablets are packaged in bottles containing 30 tablets. Tablets should be stored in their original 
bottles to protect from light. The tablets should be stored at 25° C (77° F) with excursions 
permitted to 15°-30°C (59°-86°F). Further information on the study product is available in the 
EDURANT® Prescribing Information. 
 
5.2.3 
Injectable CAB LA 
 
CAB LA is formulated as a sterile white to slightly pink suspension containing 200mg/mL of 
cabotegravir free acid for administration by IM injection. The product is packaged in single-use 
vials, containing a nominal fill volume of 2 mL (400 mg of CAB LA) or 3 mL (600 mg of CAB 
LA). Dilution is not required prior to administration. Vials should be stored up to 30° C (86° F); 
do not freeze.  
 
5.2.4 
Injectable RPV LA 
 
RPV LA is formulated as a sterile white suspension containing 300 mg/mL of RPV free base for 
administration by IM injection. The product is packaged in single-use vials, containing a nominal 
fill volume of 2 mL (600 mg of RPV LA) or 3 mL (900 mg of RPV LA). Dilution is not required 
prior to administration. Vials should be stored refrigerated at 2° to 8° C (36° to 46° F); protect 
from light and do not freeze. 
 
 
5.3 
Study Product Supply 
 
CAB and CAB LA (oral and injectable formulations), and RPV and RPV LA (oral and injectable 
formulations) will be supplied by ViiV Healthcare. 
 


 
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The above-listed study products will be made available to study sites through the National 
Institute of Allergy and Infectious Diseases (NIAID) Clinical Research Products Management 
Center (CRPMC). Upon successful completion of protocol registration procedures, these study 
products may be obtained by the site pharmacist by following instructions provided in the 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks.  
 
5.4 
Study Product Accountability 
 
Site pharmacists must maintain complete records of all study products received from the CRPMC 
and subsequently dispensed to study participants. All study products must be stored in the 
pharmacy.  
 
5.5 
Final Disposition of Study Product 
 
 
Participants who temporarily or permanently discontinue oral study product during Step 1 or Step 
3, or during oral bridging in Step 4 or Step 5, will be instructed to return all oral study products to 
the site clinic as soon as possible. 
 
All unused study products remaining at US sites after the study is completed or terminated will be 
returned to the CRPMC (unless otherwise directed by DAIDS). At non-US sites, any remaining 
unused study products will be quarantined for destruction. Study products may also be returned to 
the CRPMC for other reasons, as requested by DAIDS. Site pharmacists will follow the relevant 
instructions for return or destruction of unused study products provided in the Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks.  
 
5.6 
Concomitant Medications 
 
All concomitant medications received by enrolled participants must be source documented as part 
of the medical and medication histories obtained at each study visit. This includes prescription 
and non-prescription (over-the-counter) medications; vaccines and other preventive medications; 
therapeutic foods and nutritional supplements; and alternative, complementary, and traditional 
medications and preparations. All concomitant medications (except herbal or traditional) are to be 
entered into eCRFs, per Section 6.10.  
 
cART, other than CAB and RPV (oral and injectable formulations), will not be provided through  
the study. 
 
5.7 
Prohibited Medications  
 
Any study participant who requires a medication considered prohibited while on study product 
must have the study product held or permanently discontinued. A list of prohibited medications 
may be found on the IMPAACT 2017 protocol-specific website 
(http://impaactnetwork.org/studies/IMPAACT2017.asp). Upon identification of the need for a 
prohibited medication, the site investigator should consult the CMC for further guidance on study 
product management, and per Section 8.  
 
5.8 
Precautionary Medications  
 
A list of medications that should be used with caution while on study product may be found on 
the IMPAACT 2017 protocol-specific website. 


 
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6 
STUDY VISITS AND PROCEDURES 
 
All visits and procedures must be performed at the approved clinical research site or approved 
associated facilities unless otherwise noted (specified visits or visit procedures may be conducted 
off-site; see Section 6.1.3). All visits and procedures must be documented in accordance with 
DAIDS requirements for source documentation; refer to Section 12 for more information on data 
handling and record keeping. Refer to Section 7 for information on expedited adverse event 
(EAE) reporting, which may be required at any time during follow-up.  
 
In addition to the protocol-specified procedures listed in this section, study staff may complete 
other tasks including but not limited to collecting, reviewing, and updating demographic and 
locator information; reviewing elements of informed consent and/or assent; scheduling telephone 
contacts and visits; providing instructions for contacting study staff between visits; providing visit 
reminders; and following up on missed visits. All such tasks should be conducted and 
documented consistent with site SOPs. Study staff should inform participants (or 
parents/guardians, if applicable) of clinically meaningful physical exam findings and laboratory 
test results, when available. See Section 14.9 for additional considerations of disclosing test 
results to the parents/guardians of adolescent participants.  
 
Information relating to study visit windows, split and interim visits, and off-site visits is described 
in Section 6.1, including additional considerations for scheduling injection visits. See Section 
6.4.14 for additional considerations for scheduling and conducting interim injection visits for 
Cohort 2 participants following short-term oral bridging. Detailed information related to specific 
visits, such as target visit dates, individual visit windows, required procedures per scheduled 
visits, and further guidance for select procedures are presented in Sections 6.2–6.16. See Section 
5.1.5 for source documentation and eCRF requirements for any study product injection. 
Procedures required to continue oral and injectable study product administration at scheduled 
follow-up visits are described in Section 6.9.  
 
PK sample collections are required at visits throughout Cohort 1, Cohort 2, and LSFU. All pre-
dose PK sample collections should be performed prior to and on the same day as administration 
of the specified study product. The date and time of each PK sample collection must be source 
documented and entered into eCRFs for all PK samples. Additional source documentation, eCRF 
requirements, and scheduling considerations for PK sample collections during Weeks 2, and 4b 
(for both Cohorts 1 and 2A) are provided in the relevant visit sections below.    
 
Site staff collecting specimens for PK evaluations must prepare workspace and supplies with 
regards to protecting all PK specimens from light, as specified in the laboratory processing chart 
(LPC). As Cohort 2 participants will receive both CAB and RPV, the PK sample collection must 
be sufficient for the number of aliquots specified in the LPC for CAB and for RPV. Albumin 
(g/dL) will be obtained as part of blood collection for chemistries, but only at visits in which both 
chemistries and a PK sample are collected. See Section 6.16 for details on specimen collection 
considerations and processing, and Appendix I for required blood volumes.  
 
For sites experiencing disruptions or limitations of usual operations due to COVID-19, 
operational guidance is provided in Appendix VI. All sites should follow applicable government, 
health authority, and institutional policies with respect to conduct of study visits and procedures, 
with utmost importance placed on the health and well-being of study participants and study staff. 
 


 
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6.1 
Study Visit Windows, Split and Interim Visits, and Off-site Visits 
 
6.1.1 
Study Visit Windows and Injection Visit Spacing Requirements 
 
For follow-up study visits, a target visit date and a target visit window are specified. Study visits 
should be scheduled to occur on the respective target visit date. If it is not possible to conduct a 
visit on the respective target visit date, the visit may be scheduled within the target visit window.  
 
For select non-injection visits, broader allowable visit windows are provided. If the participant is 
unable to attend the scheduled non-injection study visit on the target visit date or within the target 
window, the non-injection study visit may be conducted within the allowable window.  
 
For study product injection visits, target visit dates and target visit windows are provided and 
established based on the participant’s first study product injection administered for the applicable 
Step. In addition to scheduling study product injection visits per the above, Cohort 2A Step 4 and 
Cohort 2B Step 5 study product injections should be scheduled to occur and administered within 
each respective target visit window as follows: 
 
Cohort 2A Step 4 Injection Spacing Requirements 
• 
For the Step 4 Week 8 injection, a minimum of 3 weeks (21 days) and a maximum of 4 
weeks and 3 days (31 days) from the Step 4 Week 4b injection. 
• 
For the Step 4 Week 16 injection, a minimum of 7 weeks (49 days) and a maximum of 8 
weeks and 3 days (59 days) from the Step 4 Week 8 injection. 
• 
For the Week 24 and all subsequent injections, a minimum of 7 weeks (49 days) and a 
maximum of 9 weeks (63 days) from the previous regularly scheduled injection. 
 
Cohort 2B Step 5 Injection Spacing Requirements 
• 
For the Step 5 Week 4 injection, a minimum of 3 weeks (21 days) and a maximum of 4 
weeks and 3 days (31 days) from the Entry visit. 
• 
For the Step 5 Week 12 injection, a minimum of 7 weeks (49 days) and a maximum of 8 
weeks and 3 days (59 days) from the Step 5 Week 4 injection. 
• 
For the Week 20 and all subsequent injections, a minimum of 7 weeks (49 days) and a 
maximum of 9 weeks (63 days) from the previous regularly scheduled injection. 
 
Depending on when the previous injection was administered within the previous target visit 
window, the minimum and maximum spacing requirements may impact the availability of a 
target visit window (including the target visit date).  Scheduled injection visits which do not occur 
within the target window are considered missed, and the CMC must be consulted regarding 
clinical considerations and study product management.  
 
Sites are expected to make every effort to schedule and conduct each study visit on the respective 
target visit date, or, when necessary, within the target visit window. Further guidance on 
scheduling study visits are provided in the IMPAACT 2017 MOP. 
 
6.1.2 
Split and Interim Visits 
 
All visit procedures specified to be performed at scheduled visits should ideally be performed on 
the same day. Unless otherwise noted, if it is not possible to conduct all visit procedures on the 
same day (e.g., if a participant must leave the clinical research site before all procedures can be 
performed), visits may be split, with procedures performed on more than one day within the 


 
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target visit window or allowable visit window (if applicable). See Section 6.9 for required study 
visit procedures to be performed on the same day as and prior to administration of study product. 
 
Interim contacts and visits (those between regularly scheduled follow-up visits) may be 
performed at participant request or as deemed necessary by the site investigator or designee at 
any time during the study, and without prior approval from the CMC. Some interim visits may 
occur for administrative reasons or retention purposes. Interim visits at which no data are 
collected should be source documented but not entered into eCRFs. Other interim contacts and 
visits may occur in response to AEs experienced by study participants. In some instances, and per 
CMC guidance, a PK sample should also be collected. When interim contacts or visits are 
completed in response to participant reports of adverse events, study staff will assess the reported 
event clinically, enter the event into eCRFs per Section 7.2, and provide or refer the participant to 
appropriate medical care. See Section 8 for participant management and specified AE 
management. 
 
For Cohort 2 participants initiating short-term oral bridging, an interim visit may be conducted to 
dispense oral study products and conduct required procedures per Section 6.9.  See Section 5.1.4 
for details regarding initiating short-term oral bridging and Section 6.1.3 below regarding 
conducting non-injection study visits at an off-site location. See Section 6.4.14 for interim 
injection visit scheduling and considerations for Cohort 2 participants. 
 
6.1.3 
Off-Site Visit Considerations for Non-Injection Study Visits 
 
Sites are expected to make every effort to conduct each study visit at the clinical research site.  
However, if allowed per local law and regulations and/or institutional policies, participants may 
have non-injection follow-up study visits or non-injection interim visits conducted in their home 
or in other off-site locations. Off-site visits must be completed within the respective visit’s target 
window or allowable window.  Additionally, off-site visits should only be conducted if sites are 
able to collect and transport any PK samples required for the applicable non-injection follow-up 
study visit; see further guidelines below regarding off-site specimen collection. 
 
At sites where off-site visits are permitted, study staff will discuss this option with participants 
(and parent or legal guardian, as applicable) in advance and agree on where and when such visits 
may take place, with adequate protections for participant privacy and confidentiality. Prior to 
each off-site visit, study staff will again confirm the date, location, and time of each visit with the 
participant (and parent or legal guardian, as applicable) to indicate permission for this activity and 
record any special instructions for the study staff. 
 
At off-site visits when specimen collection is required, the procedures specified in Section 6.16 
must be followed. Off-site visits may only be conducted by designated study staff who are 
qualified to perform all protocol-specified procedures and have undergone study-specific and all 
other applicable training relevant to the procedures they will perform off-site (e.g., Human 
Subject Protection [HSP], Good Clinical Practices [GCP], International Air Transport Association 
[IATA]). These staff should also be adequately trained and qualified to immediately manage any 
adverse events and/or social impacts that may occur during off-site visits (e.g., fainting during 
phlebotomy, family dispute in the home). If adverse events requiring further evaluation or 
management are identified during an off-site visit, study staff conducting the visit will arrange for 
the participant to return to the study site as soon as possible.   
 


 
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6.2 
Cohort 1 Step 1, Cohort 2A Step 3, and Cohort 2B Step 5 Screening Visit  
 
Refer to Section 4.7 for a description of the study recruitment, screening, and enrollment process. 
 
Screening may be initiated after written informed consent/assent is obtained. All screening 
procedures must be performed within 28 days prior to study entry. Hematology, chemistries, 
HIV-1 RNA, pregnancy testing, and confirmation of HIV status (if necessary) are required, in 
relation to the eligibility criterion in Sections 4.1–4.2; as soon as the required laboratory 
screening test results are obtained, all results should be graded for severity as specified in Section 
7.3.3. Multiple visits may be conducted within the 28-day time frame to complete all required 
procedures and to repeat laboratory tests for confirmation, if necessary. 
 
For potential Cohort 2 participants, the Cohort 2A or Cohort 2B determination will be made as 
part of the informed consent or assent process and by the potential study participant, the 
parent/legal guardian (as applicable), and in consultation with the IoR.  
 
Potential Cohort 2 participants should be counseled to continue their pre-study cART regimen 
during the screening window, with their last pre-study cART regimen dose(s) administered on the 
day prior to the scheduled Cohort 2A Step 3 Entry visit or the Cohort 2B Step 5 Entry visit.  
Cohort 1 Step 1 participants will continue their pre-study cART regimen throughout Cohort 1 
participation.  
 
Cohort 1 Step 1, Cohort 2A Step 3, and Cohort 2B Step 5 Screening Visit Procedures 
Administrative 
and Regulatory 
• Obtain written informed consent/assent 
• Assign PID to adolescent, if indicated 
• Obtain screening number from SES 
• Obtain available documentation of participant’s HIV status  
• Collect demographic and locator information 
Behavioral and 
Counseling 
• Provide HIV pre-/post-test counseling, if indicated 
• Provide contraceptive counseling 
Clinical 
• Obtain available medical records and medical and medications history  
• Assess documentation of HIV status 
• Assess ARV history 
• Assess HIV-1 RNA test result history 
• Perform complete physical exam 
• Perform Sexual Maturity Rating 
• Perform an electrocardiogram (ECG) in triplicate 
• For Cohort 1 participants screening for Cohort 2, confirm completion of all 
study product injections and the Week 16 visit in Cohort 1 Step 2  
Laboratory 
Blood  
Collect blood for: 
• Confirmatory HIV testing, if needed per Section 4.1.6 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN) 
• HIV-1 RNA 
 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for 
pregnancy test 
 


 
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For potential participants who do not meet the eligibility criteria, screening should be 
discontinued once ineligibility is determined and these individuals should be actively referred to 
non-study sources of care. See Section 4.7.1 for documentation requirements for adolescents who 
are found to be ineligible. 
 
Participants may rescreen once per Cohort (i.e. total of two screening attempts for Cohort 1 and 
two screening attempts for Cohort 2 are allowed). If any participant is re-screened, all screening 
procedures listed above must be repeated, with the exception that: 
 
• 
A new PID should not be assigned (Note: Obtain new screening number from SES for second 
screening attempt) 
• 
Confirmatory HIV testing, if conducted during first screening attempt, need not be repeated 
• 
Previously documented medical and medications history information should be reviewed and 
updated through the date of re-screening (it is not necessary to re-record history information 
that was previously documented) 
 
The Cohort 1 Entry Visit (Step 1 – oral phase) is described in Section 6.3.1. The Cohort 2 Entry 
Visits (for both Cohort 2A Step 3 Entry and Cohort 2B Step 5 Entry) are described in Section 
6.4.1.  
 
Additional Considerations for Cohort 1 Step 2 Participants Screening for Cohort 2  
 
Cohort 2 will initially open to accrual limited to Cohort 1 participants. These participants must 
undergo screening procedures to determine Cohort 2 Step 3 or Step 5 eligibility, should they wish 
to participate in Cohort 2. The timing of screening and, if eligible, enrolling into Cohort 2 may 
occur prior to completing all scheduled LSFU study visits. In the event Cohort 1 Step 2 
participants complete all scheduled LSFU study visits and exit the study (as described in Section 
6.5 below), these former Cohort 1 Step 2 participants may undergo screening procedures to 
determine eligibility for resuming study participation in Cohort 2. 
 
Any adolescent screening for Cohort 2 is required to meet eligibility criteria per Sections 4.1–4.2. 
Clinical assessments, evaluations, and laboratory values obtained during Cohort 1 Step 2 or 
LSFU study visits may be used to screen for Cohort 2 eligibility, if obtained within 28 days of the 
Cohort 2 Entry Visit. Otherwise, all screening visit procedures as described above must be 
completed for the applicable Cohort 2A or Cohort 2B eligibility determination. For previous 
Cohort 1 Step 2 participants, a new screening number will not be obtained from SES for the 
Cohort 2 screening attempt. 
 
Any adolescent found to meet the applicable eligibility criteria will be enrolled into either Cohort 
2A Step 3 or Cohort 2B Step 5, per Section 4.7 and Section 6.4.1. Previous Cohort 1 Step 2 
participants will retain their PID as assigned during Cohort 1 procedures and a new SID will be 
assigned upon successful enrollment using the SES. 
 
Additional guidance and eCRF completion processes for (former) Cohort 1 Step 2 participants 
enrolling into Cohort 2 may be found in the IMPAACT 2017 MOP. 
 
6.3 
Cohort 1  
 
6.3.1 
Cohort 1 Entry Visit (Step 1 – oral phase) 
 


 
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Refer to Section 4.7 for a description of the study recruitment, screening, and enrollment 
processes. The Cohort 1 Step 1 Entry visit must occur within 28 days (inclusive) from the Cohort 
1 Screening Visit. Cohort 1 Step 1 Entry visit procedures that may provide information relevant 
to study eligibility should be performed first, prior to final eligibility determination and 
enrollment. In the event a participant is found to be ineligible on the day of enrollment, 
enrollment should not occur.  
 
The Cohort 1 Step 1 Entry visit may not be conducted over a multi-day split visit, and the 
following visit procedures must be conducted in the sequence specified below:  
• 
Complete final eligibility determination and confirmation (medical and medications history 
including ARV history assessment, symptom-directed physical exam, and, for participants 
assigned female at birth, pregnancy testing); for participants assigned female at birth, 
pregnancy test results must be available for eligibility confirmation 
• 
Complete a paper-based Step 1 eligibility checklist  
• 
Enroll the participant on Cohort 1 Step 1 and obtain SID 
• 
Prescribe assigned oral study product  
• 
Dispense assigned oral study product 
• 
Facilitate and observe administration of assigned oral study product 
 
Cohort 1R participants should be provided a meal with the observed oral study product dose; see 
Section 5.1 regarding RPV oral dosing regimen and food intake requirements 
 
Note that acceptability and tolerability questionnaires must be administered relative to other Entry 
visit procedures as specified in the IMPAACT 2017 MOP. Visit procedures not otherwise 
specified may be conducted at any timepoint during the Cohort 1 Step 1 Entry visit. Operational 
guidance on the order of Entry visit procedures may be found in the IMPAACT 2017 MOP. 
 
Cohort 1 Step 1 Entry Visit Procedures 
Administrative 
and Regulatory 
• Complete final eligibility determination and confirmation* 
• Complete paper-based eligibility checklist*, enter checklist data into SES to 
enroll the participant and generate SID; print and file a copy of the 
confirmation file 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires 
• Assess willingness for participation in qualitative phone interview (U.S. 
sites only), see Section 11 
Clinical 
• Update medical and medications history since last visit* 
• Perform symptom-directed physical exam*  
• Assess ARV history* 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN)  
• CD4 count and percentage 
• HIV-1 RNA 
• Store whole blood for genotypic resistance testing 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test* 


 
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Study Product 
• Prescribe, dispense, facilitate and observe administration of the assigned oral 
study product, see Section 5.1 
*Perform prior to enrollment 
 
6.3.2 
Cohort 1 Week 2 Visit (Step 1 – oral phase) 
 
The Cohort 1 Week 2 visit is targeted to be conducted on day 14, counted from the day of entry, 
with a target window of +7 days from the target date. If necessary, this visit may be conducted 
within the allowable window of +14 days from the target date and the CMC notified. 
 
PK samples will be collected at the Week 2 visit (intensive PK); Cohort 1C and Cohort 1R will 
have different PK sample collection timepoints at the Week 2 visit only. The pre-dose PK sample 
collection should be performed prior to and on the same day as the oral study product dose 
observed at the site. See the procedural table below for the specific PK collection time points and 
collection windows.  
 
After the Entry visit and through the Week 2 visit, participants should be recommended to take 
the oral study product at the same time of day (morning or evening) as the Week 2 visit pre-dose 
PK collection time point. At minimum, for the three days prior to the Week 2 visit, participants 
should take their oral study product at the same time of day (morning or evening) as the 
scheduled pre-dose PK collection time point and be fully adherent to their assigned daily oral 
study product regimen. In preparation for the Week 2 visit, sites may contact participants or 
parents and guardians, to reinforce adherence within the three days prior to the scheduled PK 
evaluation using retention methods as described in Section 4.8, as well as to remind the 
participant to hold the oral study product dose due on the day of the Week 2 visit. For example, 
sites may call or visit the participant and/or parent/guardian prior to the scheduled PK evaluation 
to reinforce adherence.  
 
If, for the three days prior to the Week 2 visit, either a missed dose is reported or the participant 
has not adjusted the timing of their oral study product dosing to align with the pre-dose PK 
collection time point, the Week 2 visit should be rescheduled. Additional guidelines for 
scheduling and conducting the Cohort 1 Week 2 visit are below.  
• 
Participants and their parents/guardians should be reminded to hold administration of the 
daily oral study product due on the day of the Week 2 visit, to allow for a pre-dose PK 
sample collection and for the dose to be observed at the site. The Week 2 visit should be 
rescheduled if the oral study product dose was already taken and not observed at the site. 
• 
Participants and their parents/guardians should also be reminded to return all oral study 
product at the Week 2 visit, such that the adherence assessment may be performed. 
• 
Height and weight must be obtained on the same day as initiating the Week 2 PK evaluation.  
• 
Cohort 1R participants should be provided a meal with the observed oral study product dose; 
see Section 5.1 regarding RPV oral dosing regimen and food intake requirements 
• 
The oral study product dose dates, times, dose amounts, and food intake around the oral doses 
must be source documented and entered into eCRFs for the oral doses observed at the Week 2 
visit in addition to the previous three doses.  
• 
For participants who report intercurrent illness immediately prior to or on the day of the 
scheduled PK visit that may have interfered with study product administration or resulted in 
malabsorption of study product (e.g., fever, vomiting, diarrhea), the Week 2 visit should be 
rescheduled. 
• 
If the observed oral study product dose is not retained within 30 minutes (inclusive) of 
administration (e.g., vomiting), the Week 2 visit should be rescheduled.  


 
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• 
Depending on site capacity and participant preferences, participants and their parents or 
guardians may stay at the clinical research facility overnight for the intensive PK sampling. 
 
Additional oral study product, as assigned per Cohort 1C or Cohort 1R, may be dispensed at this 
visit if needed to provide coverage until the Week 4a visit, per Section 5.1.3. Pregnancy test 
results must be obtained prior to any dispensing of additional oral study product. 
 
Following the Week 2 visit, timing of taking the oral study product may be changed, if desired. 
However, participants should be encouraged to maintain the timing of taking their oral study 
product (morning or evening) through the Week 4b visit. Additional guidance regarding the 
timing of oral study product dosing prior to the Week 2 visit is provided in the IMPAACT 2017 
MOP. 
 
Cohort 1 Week 2 Visit Procedures (Step 1 – oral phase) 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam (including height and weight) 
• Perform adherence assessment 
• Identify/review/update adverse events  
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3) , ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance 
(CrCl; Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT 
(u/l), Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
Blood 
(Intensive 
PK 
evaluation) 
Collect blood for: 
• Cohort 1C: Pre-dose, 1, 2, 3, 4, and 8 hours post-dose (6 PK collection 
timepoints) 
• Cohort 1R: Pre-dose, 4, and 8 hours post-dose (3 PK collection timepoints) 
 
± a 15-minute window is allowed for the 1, 2, and 3-hours post-dose; ± a 30-
minute window is allowed for the 4-hours post-dose; ± 1 hour window is 
allowed for the 8 hours post-dose 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for 
pregnancy test; result must be obtained before observed dose of oral study 
product 
Study Product 
• Facilitate and observe administration of the assigned study product 
following pre-dose blood collection 
• Prescribe and dispense assigned oral study product, if indicated, see Section 
5.1 
 
6.3.3 
Cohort 1 Week 4a Visit (Step 1 – oral phase) 
 
The Cohort 1 Week 4a visit is targeted to be conducted on day 28, counted from the day of entry, 
with a target window of +7 days from the target date, and an allowable window of -7 days/+10 
days from the target date.    
 


 
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Participants and their parents/guardians should be reminded to return all oral study product at the 
Week 4a visit, such that the adherence assessment may be performed. Additional oral study 
product, as assigned per Cohort 1C or Cohort 1R, may be dispensed at this visit if needed to 
provide coverage until the Week 4b visit, per Section 5.1.3. Pregnancy test results must be 
obtained prior to any dispensing of additional oral study product. 
 
Data collected through the Week 4a study visit will be assessed to determine eligibility to enter 
Step 2 and receive injectable CAB LA or RPV LA, per Cohort 1C or Cohort 1R, respectively. 
Week 4a visit laboratory test results should be reviewed as soon as they are available, for 
determining Step 2 eligibility and scheduling the Week 4b visit. Abnormal laboratory test result 
values from the Week 4a visit may be repeated prior to scheduling the Week 4b visit. If repeat 
laboratory test results confirm Step 2 eligibility, and all other eligibility criteria are met, the Week 
4b visit may be scheduled within the target visit window (see Section 6.3.4 below) for Step 2 
Entry and injectable study product administration, and may be combined with the Week 4a visit. 
See Section 4.3 for Cohort 1 Step 2 eligibility criteria.  
 
If Cohort 1 participants are ineligible to receive injectable study product in Step 2, they will 
permanently discontinue oral study product use and complete an Early Termination visit 28 days 
after their last oral study product dose (see Section 0). 
 
Cohort 1 Week 4a Visit Procedures (Step 1 – oral phase) 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Perform adherence assessment 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN) 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test; result must be obtained before dispensing oral study product, if 
dispensing is indicated at this visit 
Study product 
• Prescribe, dispense, and facilitate administration of the assigned oral study 
product, if indicated, see Section 5.1 
 
6.3.4 
Cohort 1 Week 4b Visit (Step 2 Entry – injection phase) 
 
The Week 4b visit must take place after Week 4a laboratory test results are available, and with 
the target visit window of day 21-42, counted from the day of Step 1 entry. This visit should be 
scheduled to minimize the time between the Week 4a visit and initiation of the injectable study 
products in Step 2. Additionally, the Week 4b visit must occur within 42 days (inclusive) of Step 
1 entry so as not to exceed the intended maximum of 6 weeks on oral study product (up to 43 
doses).  
 
Cohort 1 participants who meet eligibility criteria to progress to Step 2, per Section 4.3, are 
generally expected to receive their last oral dose of CAB or RPV on the same day as their first 


 
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injection of CAB LA or RPV LA at the Week 4b study visit, which also serves as the Step 2 
Entry visit.  PK samples will be collected at the Week 4b visit.  Participants who report taking an 
oral study product dose within 12 hours (inclusive) of the scheduled Week 4b pre-dose sample 
collection will not take the oral study product dose during the Week 4b study visit; see below for 
further details regarding PK sampling and flexibility in study visit scheduling. Note that HIV-1 
RNA test results collected at the Week 4b visit are not required to be obtained or reviewed prior 
to administering injectable study product.  
 
After the Week 2 visit and through the Week 4b visit, participants should be recommended to 
take the oral study product at the same time of day (morning or evening) as the Week 4b visit pre-
dose PK collection time point. For the three days prior to the Week 4b visit, participants should 
ideally take their oral study product at the same time of day (morning or evening) as the 
scheduled pre-dose PK collection time point, and be fully adherent to their assigned daily oral 
study product regimen. However, the Week 4b visit may continue as scheduled if a missed dose is 
reported, or the participant has not adjusted the timing of their oral study product dosing to align 
with the pre-dose PK collection time point. 
 
In preparation for the Week 4b visit, sites may contact participants or parents and guardians, to 
reinforce adherence and oral study product dose timing within the three days prior to the 
scheduled PK evaluation using retention methods as described in Section 4.8. For example, sites 
may call or visit the participant and/or parent/guardian prior to the scheduled PK evaluation to 
reinforce adherence. Participants and their parents/guardians should be reminded to hold 
administration of the daily oral study product due on the day of the Week 4b visit, to allow for a 
pre-dose PK sample collection and for the dose to be observed at the site. Participants and their 
parents/guardians should also be reminded to return all oral study product at the Week 4b visit, 
such that the adherence assessment may be performed. 
 
Prior to initiating the pre-dose PK sample collection, study staff should ascertain when the 
participant’s most recent oral study product dose was administered to determine whether oral 
study product should be administered during Week 4b visit:   
• 
If the participant’s most recent oral study product dose was taken more than 12 hours from 
the Week 4b pre-dose PK sample collection, the pre-dose PK sample should be collected 
prior to observing the participant’s last oral study product dose administered (and observed) 
at the site. Sites should provide Cohort 1R participants a meal with the observed oral study 
product dose; see Section 5.1 regarding RPV oral dosing regimen and food intake 
requirements. 
 
• 
If the participant’s most recent oral study product dose was taken within 12 hours (inclusive) 
of the Week 4b pre-dose PK sample collection, an oral study product dose may not be 
administered during Week 4b visit. The Week 4b visit may still occur as scheduled and the 
pre-dose PK sample collection will be prior to the participant’s first study product injection. 
 
The Cohort 1 Week 4b visit may not be conducted over a multi-day split visit with the following 
procedures conducted as specified below: 
• 
Contraceptive and adherence counseling must be provided prior to enrolling the participant 
into Step 2 to confirm the participant is willing to receive the injectable study product. 
• 
Final eligibility determination and confirmation must be completed prior to completing the 
Step 2 eligibility checklist: medical and medications history, symptom-directed physical 
exam (must include height and weight), adherence assessment, and, for participants assigned 


 
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female at birth, pregnancy testing; for participants assigned female at birth, pregnancy test 
results must be available for eligibility confirmation. 
• 
The pre-dose PK sample must be collected prior to the participant’s first study product 
injection. See guidance above regarding whether the pre-dose PK sample is collected prior to 
an oral study product dose administered (and observed) at the site, or whether no oral study 
product dose is administered at this visit. 
• 
The Step 2 paper-based eligibility checklist must be completed prior to enrolling the 
participant to Step 2. 
• 
Enrollment to Step 2 must occur prior to prescribing the assigned injectable study product.  
• 
Prescribing must occur prior to dispense assigned injectable study product. 
• 
Administration of the assigned injectable study product must occur after enrollment into Step 
2, and after prescribing and dispensing the participant’s assigned injectable study product. 
• 
The post-dose PK sample must be collected after administration of both the oral study 
product and the injectable study product. 
 
Note that acceptability and tolerability questionnaires must be administered relative to other 
Week 4b visit procedures as specified in the IMPAACT 2017 MOP.  Visit procedures not 
otherwise specified may be conducted at any timepoint during the Week 4b visit. Operational 
guidance on the order of Week 4b visit procedures may be found in the IMPAACT 2017 MOP. 
 
Cohort 1 Week 4b Visit Procedures (Step 2 Entry - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling* 
• Provide adherence counseling* 
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Administrative 
and Regulatory 
• Complete final eligibility confirmation for Step 2 Entry, see Section 4.3* 
• Complete paper-based eligibility checklist*, enter checklist data into SES to 
enroll the participant and generate SID; print and file a copy of the 
confirmation file 
Clinical 
• Update medical and medications history since last visit* 
• Perform symptom-directed physical exam* 
• Identify/review/update adverse events* 
• Perform adherence assessment* 
Laboratory 
Blood 
 
Collect blood for: 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Pre-dose and 2 hours post-dose (2 PK collection timepoints), 
± 30 minutes window is allowed for the 2-hours post-dose  
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test* 
Study product 
• Facilitate and observe administration of the assigned oral study product, if 
indicated, see above 
• Prescribe, prepare, and administer assigned injectable study product, see 
Section 5.1 
*Perform prior to completing the Step 2 eligibility checklist and prior to prescribing injectable study 
product. 
 
6.3.5 
Cohort 1 Week 5 Visit (Step 2 – injection phase) 
 


 
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The Week 5 visit is targeted to be conducted 3 days after completion of the Week 4b Step 2 Entry 
visit (the first administration of injectable study product), with a target window of +4 days from 
the target date, and an allowable window of -1 day/+5 days from the target date. 
 
Cohort 1 Week 5 Visit Procedures (Step 2 - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• PK evaluation: Single sample  
 
6.3.6 
Cohort 1 Week 8 Visit (Step 2 – injection phase) 
 
The Week 8 visit is targeted to be conducted 28 days after the Week 4b Step 2 Entry visit (the 
first administration of injectable study product), with a target window of -7 days/+3 days from the 
target date.     
 
Cohort 1 Week 8 Visit Procedures (Step 2 - injection phase) 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test; result must be obtained before administering injectable study product 
Study product 
• Prescribe, prepare, and administer assigned injectable study product, see 
Section 5.1 
 
6.3.7 
Cohort 1 Week 9 Visit (Step 2 – injection phase) 
 
The Week 9 visit is targeted to be conducted 3 days after completion of the Week 8 visit, with a 
target window of +7 days from the target date, and an allowable window of -1 day/+10 days from 
the target date. 


 
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Cohort 1 Week 9 Visit Procedures (Step 2 - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
• Perform an ECG 
Laboratory 
Blood 
Collect blood for: 
• PK evaluation: Single sample 
 
6.3.8 
Cohort 1 Week 12 Visit (Step 2 – injection phase) 
 
The Week 12 visit is targeted to be conducted 28 days after completion of the Week 8 visit, with 
a target window of +4 days from the target date, and an allowable window of -1 day/+5 days from 
the target date. 
 
Cohort 1 Week 12 Visit Procedures (Step 2 - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• PK evaluation: Single sample 
 


 
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6.3.9 
Cohort 1 Week 16 Visit (Step 2 – injection phase) 
 
The Week 16 visit is targeted to be conducted 56 days after completion of the Week 8 visit, with 
a target window of ±7 days from the target date, and an allowable window of ±14 days from the 
target date. 
 
Cohort 1 Week 16 Visit Procedures (Step 2 - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling 
• Perform acceptability/tolerability assessment questionnaires 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Identify/review/update adverse events 
• Perform Sexual Maturity Rating 
• Perform an ECG 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• CD4 count and percentage 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation:  Single sample 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test 
 
Participants completing the Cohort 1 Week 16 visit will be followed according to the LSFU visit 
schedule beginning with the LSFU Week 24 Visit (see Section 6.5 and Appendix I-D), or may 
screen for Cohort 2 eligibility if Cohort 2 has been opened to accrual. 
 
6.4 
Cohort 2 
 
6.4.1 
Cohort 2 Entry Visits (Cohort 2A Step 3 and Cohort 2B Step 5) 
 
Refer to Section 4.7 for a description of the study recruitment, screening, and enrollment 
processes. The Cohort 2 Entry visit (for either Cohort 2A Step 3 or Cohort 2B Step 5) must occur 
within 28 days (inclusive) from the Cohort 2 Screening Visit. Potential Cohort 2 Step 3 or Step 5 
participants should be counseled to continue their pre-study cART regimen during the screening 
window, with their last dose administered on the day prior to the scheduled Cohort 2 Step 3 or 
Step 5 Entry visit. Cohort 2 Entry visit procedures that may provide information relevant to 
eligibility for the study should be performed first, prior to final eligibility determination and 
enrollment. In the event a potential participant is found to be ineligible on the day of enrollment, 
enrollment should not occur.  
 
The Cohort 2A Step 3 and Cohort 2B Step 5 Entry visits may not be conducted over multi-day 
split visits. 
 
Cohort 2A Step 3 Entry Visit 


 
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The following Cohort 2A Step 3 Entry visit procedures must be conducted in the sequence 
specified below: 
• 
Complete final eligibility determination and confirmation (medical and medications history, 
symptom-directed physical exam, and, for participants assigned female at birth, pregnancy 
testing); for participants assigned female at birth, pregnancy test results must be available for 
eligibility confirmation. Contraceptive and adherence counseling must also be provided prior 
to enrolling the participant to confirm the participant is willing to enter Cohort 2A Step 3 and 
receive the oral study products. 
• 
Complete a paper-based Step 3 eligibility checklist.  
• 
Enroll the participant on Cohort 2A Step 3 and obtain SID. 
• 
Prescribe oral study product.  
• 
Dispense oral study product. 
• 
Facilitate and observe administration of oral study product. 
 
Participants should be provided a meal with the observed oral study product doses; see Section 
5.1 regarding RPV oral dosing regimen and food intake requirements. 
 
Cohort 2B Step 5 Entry Visit 
The following Cohort 2B Step 5 Entry visit procedures must be conducted in the sequence 
specified below: 
• 
Complete final eligibility determination and confirmation (medical and medications history, 
symptom-directed physical exam (must include height and weight), and, for participants 
assigned female at birth, pregnancy testing); for participants assigned female at birth, 
pregnancy test results must be available for eligibility confirmation. Contraceptive and 
adherence counseling must be provided prior to enrolling the participant to confirm the 
participant is willing to enter Cohort 2B Step 5 and receive the injectable study products. 
• 
Complete a paper-based Step 5 eligibility checklist.  
• 
Enroll the participant on Cohort 2B Step 5 and obtain SID. 
• 
Prescribe injectable study products.  
• 
Dispense injectable study products. 
• 
Administer injectable study products. 
• 
The post-dose PK sample must be collected after administration of both injectable study 
products. 
• 
The ECG must be performed after administration of both injectable study products. 
 
Note that acceptability and tolerability questionnaires must be administered relative to other Entry 
visit procedures as specified in the IMPAACT 2017 MOP. Visit procedures not otherwise 
specified may be conducted at any timepoint during the Cohort 2 Step 3 or Step 5 Entry visit. 
Operational guidance on the order of Entry visit procedures may be found in the IMPAACT 2017 
MOP. Upon enrolling into Cohort 2, Step 3 or Step 5, study participants will discontinue their 
pre-study oral cART regimen.  
 


 
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Cohort 2A Step 3 Entry Visit and Cohort 2B Step 5 Entry Visit Procedures 
Administrative 
and Regulatory 
• Complete final eligibility determination and confirmation* 
• Complete paper-based eligibility checklist*, enter checklist data into SES to 
enroll the participant and generate SID; print and file a copy of the 
confirmation file 
Behavioral and 
Counseling 
• Provide adherence counseling* 
• Provide contraceptive counseling* 
• Perform acceptability/tolerability assessment questionnaires 
• Assess willingness for participation in qualitative phone interview (U.S. 
sites only), see Section 11 
Clinical 
• Update medical and medications history since last visit* 
• Perform symptom-directed physical exam*  
• Perform an ECG, 2 hours post-injection dose, ± 1 hour window is allowed 
(Cohort 2B only) 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN) 
• CD4 count and percentage 
• HIV-1 RNA 
• Store whole blood for genotypic resistance testing 
• PK evaluation: 2-hours post-injection dose PK sample, ± 30 minutes window 
(Cohort 2B only) 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test* 
Study 
Product 
Step 3 
• For Cohort 2A Step 3 participants: Prescribe, dispense, facilitate, and observe 
administration of oral study products, see Section 5.1 
Step 5  
• For Cohort 2B Step 5 participants: Prescribe, prepare, and administer 
injectable study products, see Section 5.1 
*Perform prior to enrollment 
 
Participants enrolled to Cohort 2A Step 3 will follow the applicable study visit schedule, as 
outlined in Appendix I-B and as described in Sections 6.4.2 – 6.4.4 below. Participants enrolled 
to Cohort 2B Step 5 will follow the applicable study visit schedule outlined in Appendix I-C and 
as described in Sections 6.4.5– 6.4.14 below.  
 
6.4.2 
Cohort 2A Week 2 Visit (Step 3 – oral phase) 
 
The Cohort 2 Week 2 visit is targeted to be conducted on day 14, counted from the day of entry, 
with a target window of +7 days from the target date, and an allowable window of +14 days from 
the target date. 
 
PK samples will be collected at the Week 2 visit. The pre-dose PK sample collection should be 
performed prior to and on the same day as the oral study product dose observed at the site.      
 
After the Entry visit and through the Week 2 visit, participants should be recommended to take 
the oral study product at the same time of day (morning or evening) as the Week 2 visit pre-dose 
PK collection time point. At minimum, for the three days prior to the Week 2 visit, participants 
should take their oral study product at the same time of day (morning or evening) as the 
scheduled pre-dose PK collection time point and be fully adherent to the daily oral study product 


 
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regimen. In preparation for the Week 2 visit, sites may contact participants or parents and 
guardians, to reinforce adherence within the three days prior to the scheduled PK evaluation using 
retention methods as described in Section 4.8, as well as to remind the participant to hold the oral 
study product dose due on the day of the Week 2 visit. For example, sites may call or visit the 
participant and/or parent/guardian prior to the scheduled PK evaluation to reinforce adherence.  
 
If, for the three days prior to the Week 2 visit, either a missed dose is reported or the participant 
has not adjusted the timing of their oral study product dosing to align with the pre-dose PK 
collection time point, the Week 2 visit should be rescheduled. Additional guidelines for 
scheduling and conducting the Cohort 2 Week 2 visit are below.  
• 
Participants and their parents/guardians should be reminded to hold administration of the 
daily oral study product due on the day of the Week 2 visit, to allow for a pre-dose PK 
sample collection and for the dose to be observed at the site. The Week 2 visit should be 
rescheduled if the oral study product dose was already taken and not observed at the site. 
• 
Participants and their parents/guardians should also be reminded to return all oral study 
product at the Week 2 visit, such that the adherence assessment may be performed. 
• 
Height and weight must be obtained on the same day as initiating the Week 2 PK evaluation. 
• 
Participants should be provided a meal with the observed oral study product doses; see 
Section 5.1 regarding RPV oral dosing regimen and food intake requirements. 
• 
The oral study product dose dates, times, dose amounts, and food intake around the oral doses 
must be source documented and entered into eCRFs for the oral doses observed at the Week 2 
visit in addition to the previous three doses.  
• 
For participants who report intercurrent illness immediately prior to or on the day of the 
scheduled PK visit that may have interfered with study product administration or resulted in 
malabsorption of study product (e.g., fever, vomiting, diarrhea), the PK evaluation should be 
rescheduled.  
• 
If the observed oral study product dose is not retained within 30 minutes (inclusive) of 
administration (e.g., the vomiting), the Week 2 visit should be rescheduled.  
• 
Depending on site capacity and participant preferences, participants and their parents or 
guardians may stay at the clinical research facility overnight for the PK sampling. 
 
Additional oral study product may be dispensed at this visit if needed to provide coverage until 
the Week 4a visit, per Section 5.1.3. Pregnancy test results must be obtained prior to any 
dispensing of additional oral study product. 
 
Following the Week 2 visit, timing of taking the oral study product may be changed, if desired. 
However, participants should be encouraged to maintain the timing of taking their oral study 
product (morning or evening) through the Week 4b visit. Additional guidance regarding the 
timing of oral study product dosing prior to the Week 2 visit is provided in the IMPAACT 2017 
MOP. 


 
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Cohort 2A Week 2 Visit Procedures (Step 3 – oral phase) 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam (including height and weight) 
• Perform adherence assessment 
• Identify/review/update adverse events  
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Pre-dose and 3 hours post-dose (2 PK collection timepoints), 
± 1 hour window is allowed for the 3 hours post-dose 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test; result must be obtained before observed dose of oral study product 
Study Product 
• Facilitate and observe administration of oral study products following pre-
dose blood collection 
• Prescribe and dispense oral study products, if indicated, see Section 5.1 
 
6.4.3 
Cohort 2A Week 4a Visit (Step 3 – oral phase) 
 
The Cohort 2 Week 4a visit is targeted to be conducted on day 28, counted from the day of entry, 
with a target window of +7 days from the target date, and an allowable window of -7 days/+10 
days from the target date.    
 
Participants and their parents/guardians should also be reminded to return all oral study product at 
the Week 4a visit, such that the adherence assessment may be performed. Additional oral study 
products may be dispensed if needed to provide coverage until the Week 4b visit, per Section 
5.1.3. Pregnancy test results must be obtained prior to any dispensing of additional oral study 
products. 
 
Data collected through the Week 4a study visit will be assessed to determine eligibility to enter 
Step 4 and receive injectable CAB LA + RPV LA. Week 4a visit laboratory test results should be 
reviewed as soon as they are available, for determining Step 4 eligibility and scheduling the Week 
4b visit. See Section 4.4 for Cohort 2 Step 4 eligibility criteria. Abnormal laboratory test result 
values from the Week 4a visit may be repeated prior to scheduling the Week 4b visit. If repeat 
laboratory test results confirm Step 4 eligibility, and all other eligibility criteria are met, the Week 
4b visit may be scheduled within the target visit window (see Section 6.4.4 below) for Step 4 
Entry and injectable study products administration, and may be combined with the Week 4a visit.    
 
If Cohort 2 participants (who had not previously participated in Cohort 1 Step 2) are ineligible to 
receive injectable study products in Step 4, they will permanently discontinue oral study product 
use and complete an Early Termination visit 28 days after their last oral study product dose (see 
Section 0).  Cohort 1 Step 2 participants who continue in Cohort 2 Step 3 but are not eligible to 
progress to Cohort 2 Step 4 will be followed per the LSFU visit schedule (see Section 6.5).  
 


 
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Cohort 2A Week 4a Visit Procedures (Step 3 – oral phase) 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Identify/review/update adverse events 
• Perform adherence assessment 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN) 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test; result must be obtained before dispensing oral study product, if 
dispensing is indicated at this visit 
Study product 
• Prescribe, dispense, and facilitate administration of oral study products, if 
indicated, see Section 5.1 
 
 
6.4.4 
Cohort 2A Week 4b Visit (Step 4 Entry – injection phase) 
 
The Week 4b visit must take place after Week 4a laboratory test results are available, and with 
the target visit window of day 21-42, counted from the day of Step 3 entry. This visit should be 
scheduled to minimize the time between the Week 4a visit and initiation of the injectable study 
products in Step 4. Additionally, the Week 4b visit must occur within 42 days (inclusive) of Step 
3 entry so as not to exceed the intended maximum of 6 weeks on oral study product (up to 43 
doses of each oral study product).  
 
Cohort 2 participants who meet eligibility criteria to progress to Step 4, per Section 4.4, are 
generally expected to receive their last oral dose of CAB + RPV on the same day as their first 
injection of CAB LA + RPV LA at the Week 4b study visit, which also serves as the Step 4 Entry 
visit. PK samples will be collected at the Week 4b visit.  Participants who report taking oral study 
product doses within 12 hours (inclusive) of the scheduled Week 4b pre-dose sample collection 
will not take the oral study product doses during the Week 4b study visit; see below for further 
details regarding PK sampling and flexibility in study visit scheduling. Note that HIV-1 RNA test 
results collected at the Week 4b visit are not required to be obtained or reviewed prior to 
administering injectable study products.  
 
After the Week 2 visit and through the Week 4b visit, participants should be recommended to 
take the oral study product at the same time of day (morning or evening) as the Week 4b visit pre-
dose PK collection time point. For the three days prior to the Week 4b visit, participants should 
ideally take their oral study product at the same time of day (morning or evening) as the 
scheduled pre-dose PK collection time point and be fully adherent to the daily oral study product 
regimen. However, the Week 4b visit may continue as scheduled if a missed dose is reported, or 
the participant has not adjusted the timing of their oral study product dosing to align with the pre-
dose PK collection time point. 
 
In preparation for the Week 4b visit, sites may contact participants or parents and guardians, to 
reinforce adherence and oral study product dose timing within the three days prior to the 


 
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scheduled PK evaluation using retention methods as described in Section 4.8. For example, sites 
may call or visit the participant and/or parent/guardian prior to the scheduled PK evaluation to 
reinforce adherence. Participants and their parents/guardians should be reminded to hold 
administration of the daily oral study product due on the day of the Week 4b visit, to allow for a 
pre-dose PK sample collection and for the dose to be observed at the site. Participants and their 
parents/guardians should also be reminded to return all oral study product at the Week 4b visit, 
such that the adherence assessment may be performed. 
 
Prior to initiating the pre-dose PK sample collection, study staff should ascertain when the 
participant’s most recent oral study product dose was administered to determine whether oral 
study product should be administered during Week 4b visit:   
• 
If the participant’s most recent oral study product dose was taken more than 12 hours from 
the Week 4b pre-dose PK sample collection, the pre-dose PK sample should be collected 
prior to observing the participant’s last oral study product dose administered (and observed) 
at the site. Sites should provide participants a meal with the observed oral study product dose; 
see Section 5.1 regarding RPV oral dosing regimen and food intake requirements. 
 
• 
If the participant’s most recent oral study product dose was taken within 12 hours (inclusive) 
of the Week 4b pre-dose PK sample collection, an oral study product dose may not be 
administered during Week 4b visit. The Week 4b visit may still occur as scheduled and the 
pre-dose PK sample collection will be prior to the participant’s first study product injection. 
 
The Cohort 2 Week 4b visit may not be conducted over a multi-day split visit with the following 
procedures conducted as specified below: 
• 
Contraceptive and adherence counseling must be provided prior to enrolling the participant 
into Step 4 to confirm the participant is willing to receive the injectable study products. 
• 
Final eligibility determination and confirmation must be completed prior to completing the 
Step 4 eligibility checklist: medical and medications history, symptom-directed physical 
exam (must include height and weight), adherence assessment, and, for participants assigned 
female at birth, pregnancy testing; for participants assigned female at birth, pregnancy test 
results must be available for eligibility confirmation. 
• 
The pre-dose PK sample must be collected prior to the participant’s first study product 
injection. See guidance above regarding whether the pre-dose PK sample is collected prior to 
an oral study product dose administered (and observed) at the site, or whether no oral study 
product dose is administered at this visit. 
• 
The Step 4 paper-based eligibility checklist must be completed prior to enrolling the 
participant to Step 4. 
• 
Enrollment to Step 4 must occur prior to prescribing injectable study products.  
• 
Prescribing must occur prior to dispensing injectable study products. 
• 
Administration of injectable study products must occur after enrollment into Step 4, and after 
prescribing and dispensing the injectable study products. 
• 
The post-dose PK sample must be collected after administration of both the oral study 
product and the injectable study products. 
 
Note that acceptability and tolerability questionnaires must be administered relative to other 
Week 4b visit procedures as specified in the IMPAACT 2017 MOP. Visit procedures not 
otherwise specified may be conducted at any timepoint during the Week 4b visit. Operational 
guidance on the order of Week 4b visit procedures may be found in the IMPAACT 2017 MOP. 


 
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Cohort 2A Week 4b Visit Procedures (Step 4 Entry - injection phase) 
Behavioral and 
Counseling 
• Provide contraceptive counseling* 
• Provide adherence counseling* 
• Perform acceptability/tolerability assessment questionnaires 
Administrative 
and Regulatory 
• Complete final eligibility confirmation for Step 4 Entry, see Section 4.4* 
• Complete paper-based eligibility checklist*, enter checklist data into SES to 
enroll the participant and generate SID; print and file a copy of the 
confirmation file 
Clinical 
• Update medical and medications history since last visit* 
• Perform symptom-directed physical exam* 
• Identify/review/update adverse events* 
• Perform adherence assessment* 
• Perform ECG: 2 hours post-injection dose, ± 1 hour window is allowed 
Laboratory 
Blood 
 
Collect blood for: 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Pre-dose and 2 hours post-injection dose (2 PK collection 
timepoints), ± 30 minutes window is allowed for the 2-hours post-dose 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test* 
Study product 
• Facilitate and observe administration of oral study products, if indicated, see 
above 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
*Perform prior to completing the Step 4 eligibility checklist and prior to prescribing injectable study 
products. 
 
6.4.5 
Cohort 2A Week 5 Visit (Step 4 – injection phase) and Cohort 2B Week 1 Visit (Step 5 - injection 
phase) 
 
The Cohort 2A Week 5 and Cohort 2B Week 1 visits are targeted to be conducted 3 days after 
completion of the first administration of injectable study products – Week 4b Step 4 Entry visit 
(for Cohort 2A) and the Step 5 Entry visit (for Cohort 2B). The Cohort 2A Week 5 and Cohort 2B 
Week 1 visits have a target window of +4 days from the target date, and an allowable window of 
-1 day/+5 days from the target date. 
 
Cohort 2A Week 5 (Step 4 - injection phase) and Cohort 2B Week 1 (Step 5 – injection phase) Visit 
Procedures 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• PK evaluation: Single sample 
 


 
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6.4.6 
Cohort 2A Week 8 Visit (Step 4 – injection phase) and Cohort 2B Week 4 Visit (Step 5 - injection 
phase) 
 
The Cohort 2A Week 8 and Cohort 2B Week 4 visits are targeted to be conducted 28 days after 
completion of the first administration of injectable study products – Week 4b Step 4 Entry visit 
(for Cohort 2A) and the Step 5 Entry visit (for Cohort 2B). The Cohort 2A Week 8 and Cohort 2B 
Week 4 visits have a target window of -7 days/+3 days from the target date.   
 
Cohort 2A Week 8 Visit Procedures (Step 4 - injection phase) and Cohort 2B Week 4 (Step 5 – 
injection phase) Visit Procedures 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test; result must be obtained before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 
6.4.7 
Cohort 2A Week 16 Visit (Step 4 – injection phase) and Cohort 2B Week 12 Visit (Step 5 - injection 
phase) 
 
The Cohort 2A Week 16 visit target date is 84 days after completion of the Week 4b visit with a 
target window of -7 days/+3 days from the target date. Additionally, the Cohort 2A Week 16 visit 
and the third injection of study product should be scheduled a minimum of 7 weeks (49 days) and 
a maximum of 8 weeks and 3 days (59 days) from the previous injection. 
 
The Cohort 2B Week 12 visit target date is 84 days after completion of the Step 5 Entry visit with 
a target window of -7 days/+3 days from the target date. Additionally, the Cohort 2B Week 12 
visit and the third injection of study product should be scheduled a minimum of 7 weeks (49 
days) and a maximum of 8 weeks and 3 days (59 days) from the previous injection.   
 


 
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Cohort 2A Week 16 Visit Procedures (Step 4 – injection phase) and Cohort 2B Week 12 (Step 5 – 
injection phase) Visit Procedures 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
•  Perform acceptability/tolerability assessment questionnaires, if indicated 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam  
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test; result must be obtained before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 
6.4.8 
Cohort 2A Week 24 Visit (Step 4 – injection phase) and Cohort 2B Week 20 Visit (Step 5 - injection 
phase) 
 
The Cohort 2A Week 24 visit target date is 140 days after completion of the Cohort 2A Week 4b 
visit, with a target window of ±7 days.  Additionally, the Cohort 2A Week 24 visit should occur a 
minimum of 7 weeks (49 days) and a maximum of 9 weeks (63 days) from the previous injection. 
 
The Cohort 2B Week 20 visit target date is 140 days after completion of the Step 5 Entry visit, 
with a target window of ±7 days.  Additionally, the Cohort 2B Week 20 visit should occur a 
minimum of 7 weeks (49 days) and a maximum of 9 weeks (63 days) from the previous injection. 
 


 
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Cohort 2A Week 24 Visit Procedures (Step 4 – injection phase) and Cohort 2B Week 20 (Step 5 – 
injection phase) Visit Procedures 
Behavioral and 
Counseling 
• Provide adherence counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Identify/review/update adverse events 
• Sexual Maturity Rating assessment 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• CD4 count and percentage 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation:  Single pre-dose sample 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test; result must be obtained before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 
6.4.9 
Cohort 2A Week 25 Visit (Step 4 – injection phase) and Cohort 2B Week 21 Visit (Step 5 - injection 
phase) 
 
The Cohort 2A Week 25 visit is targeted to be conducted 3 days after completion of the Cohort 
2A Week 24 visit, with a target window of +4 days from the target date, and an allowable 
window of -1 day/+5 days from the target date. 
 
The Cohort 2B Week 21 visit is targeted to be conducted 3 days after completion of the Cohort 
2B Week 20 visit, with a target window of +4 days from the target date, and an allowable 
window of -1 day/+5 days from the target date. 
 
Cohort 2A Week 25 Visit Procedures (Step 4 – injection phase) and Cohort 2B Week 21 (Step 5 – 
injection phase) Visit Procedures 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• PK evaluation: Single sample 
 
6.4.10 Cohort 2A Weeks 32 and 40 Visits (Step 4 – injection phase) and Cohort 2B Weeks 28 and 36 Visits 
(Step 5 - injection phase) 
 
The Cohort 2A Week 32 study visit is targeted to occur 196 days after the Cohort 2A Week 4b 
visit, with a target window of ±7 days from the target date.  The Cohort 2A Week 40 study visit is 


 
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targeted to occur 252 days after the Cohort 2A Week 4b visit, with a target window of ±7 days 
from the target date.  Additionally, the Cohort 2A Weeks 32 and 40 visits should occur a 
minimum of 7 weeks (49 days) and a maximum of 9 weeks (63 days) from the previous injection. 
 
The Cohort 2B Week 28 study visit is targeted to occur 196 days after the Cohort 2B Step 5 Entry 
visit, with a target window of ±7 days from the target date.  The Cohort 2B Week 36 study visit is 
targeted to occur 252 f window of ±7 days from the target date.  Additionally, the Cohort 2B 
Weeks 28 and 36 visits should occur a minimum of 7 weeks (49 days) and a maximum of 9 
weeks (63 days) from the previous injection. 
 
Cohort 2A Weeks 32 and 40 (Step 4 – injection phase) and  
Cohort 2B Weeks 28 and 36 (Step 5 – injection phase) Visit Procedures 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test; result must be obtained before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 
6.4.11 Cohort 2A Week 48 Visit (Step 4 – injection phase) and Cohort 2B Week 44 Visit (Step 5 - injection 
phase) 
 
The Cohort 2A Week 48 study visit is targeted to occur 308 days after the Cohort 2A Week 4b 
visit, with a target window of ±7 days from the target date.  Additionally, the Cohort 2A Week 48 
visit should occur a minimum of 7 weeks (49 days) and a maximum of 9 weeks (63 days) from 
the previous injection. 
 
The Cohort 2B Week 44 study visit is targeted to occur 308 days after the Cohort 2B Step 5 Entry 
visit, with a target window of ±7 days from the target date.  Additionally, the Cohort 2B Week 44 
visit should occur a minimum of 7 weeks (49 days) and a maximum of 9 weeks (63 days) from 
the previous injection. 
 


 
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Cohort 2A Week 48 Visit Procedures (Step 4 – injection phase) and Cohort 2B Week 44 (Step 5 – 
injection phase) Visit Procedures 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling 
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• CD4 count and percentage 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test; result must be obtained before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 
6.4.12 Cohort 2A Weeks 56, 64, 72, 80, 88 Visits (Step 4 – injection phase) and Cohort 2B Weeks 52, 60, 68, 
76, 84 Visits (Step 5 - injection phase) 
 
The Cohort 2A Weeks 56, 64, 72, 80, and 88 study visits have the following target dates as 
counted from completion of the Cohort 2A Week 4b visit: 
• 
Cohort 2A Week 56 visit target date is 364 days after Week 4b  
• 
Cohort 2A Week 64 visit target date is 420 days after Week 4b  
• 
Cohort 2A Week 72 visit target date is 476 days after Week 4b  
• 
Cohort 2A Week 80 visit target date is 532 days after Week 4b 
• 
Cohort 2A Week 88 visit target date is 588 days after Week 4b 
 
These Cohort 2A visits each have a target window of ±7 days from the respective target date. 
Additionally, each of these Cohort 2A visits should occur a minimum of 7 weeks (49 days) and a 
maximum of 9 weeks (63 days) from the previous injection. 
 
The Cohort 2B Weeks 52, 60, 68, 76, and 84 study visits have the following target dates as 
counted from completion of the Cohort 2B Step 5 Entry visit: 
• 
Cohort 2B Week 52 visit target date is 364 days after Step 5 Entry 
• 
Cohort 2B Week 60 visit target date is 420 days after Step 5 Entry 
• 
Cohort 2B Week 68 visit target date is 476 days after Step 5 Entry 
• 
Cohort 2B Week 76 visit target date is 532 days after Step 5 Entry 
• 
Cohort 2B Week 84 visit target date is 588 days after Step 5 Entry 
 
These Cohort 2B visits each have a target window of ±7 days from the respective target date. 
Additionally, each of these Cohort 2B visits should occur a minimum of 7 weeks (49 days) and a 
maximum of 9 weeks (63 days) from the previous injection. 
 


 
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Cohort 2A Weeks 56, 64, 72, 80, 88 Visit Procedures (Step 4 – injection phase) and  
Cohort 2B Weeks 52, 60, 68, 76, 84 (Step 5 – injection phase) Visit Procedures 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling (Cohort 2A Week 72 only; Cohort 2B Week 
68 only) 
• Perform acceptability/tolerability assessment questionnaires, if indicated 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin* (g/dL)  
• CD4 count and percentage (Cohort 2A Week 72 only; Cohort 2B Week 68 
only) 
• HIV-1 RNA (Cohort 2A Weeks 64 and 80 only; Cohort 2B Weeks 60 and 76 
only) 
• Store plasma for genotypic and phenotypic resistance testing (Cohort 2A 
Weeks 64 and 80 only; Cohort 2B Weeks 60 and 76 only) 
• Cohort 2A PK evaluation: For all Cohort 2A participants, a single pre-dose 
sample is collected at Weeks 64, 80, and 88 visits only  
• Cohort 2B PK evaluation: For all Cohort 2B participants, a single pre-dose 
sample is collected at Weeks 60, 76, and 84 visits only  
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for 
pregnancy test; result must be obtained before administering injectable study 
products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
*For Cohort 2A, Albumin (g/dL) is required at Weeks 64, 80, and 88 only; for Cohort 2B, Albumin (g/dL) 
is required at Weeks 60, 76, and 84 only 
 
6.4.13 Cohort 2A Week 96 Visit (Step 4 – injection phase) and Cohort 2B Week 92 Visit (Step 5 - injection 
phase) 
 
The Cohort 2A Week 96 visit target date is 644 days after completion of the Cohort 2A Week 4b 
visit, with a target window of ±7 days from the target date. Additionally, the Cohort 2A Week 96 
visit should occur a minimum of 7 weeks (49 days) and a maximum of 9 weeks (63 days) from 
the previous injection. 
 
The Cohort 2B Week 92 visit target date is 644 days after completion of the Cohort 2B Step 5 
Entry visit, with a target window of ±7 days from the target date. Additionally, the Cohort 2B 
Week 92 visit should occur a minimum of 7 weeks (49 days) and a maximum of 9 weeks (63 
days) from the previous injection. 
 
Cohort 2 participants completing these visits who will continue to receive injectable CAB LA + 
RPV LA external to the protocol will exit the study. See Section 6.8 for more information on 
post-study contacts, and Section 14.11 for more information regarding post-trial access to study 
products. Participants who do not wish to continue receiving the injectable CAB LA + RPV LA 
beyond the Week 96 or Week 92 visit will not exit the study but will be followed per the LSFU 
visit schedule as described in Section 6.5 below. 


 
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Cohort 2A Week 96 Visit Procedures (Step 4 – injection phase) and Cohort 2B Week 92 (Step 5 – 
injection phase) Visit Procedures 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling  
• Provide instructions for cART administration and adherence counseling to the 
participant, parent or guardian, (if study exit visit only)  
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam  
• Identify/review/update adverse events 
• Sexual Maturity Rating assessment 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• CD4 count and percentage  
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test; result must be obtained before administering injectable study products 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1 
 
6.4.14 Interim Injection Visit (Step 4 or Step 5 – injection phase) 
 
For Cohort 2A Step 4 or Cohort 2B Step 5 participants resuming injectable study products 
following short-term oral bridging, in consultation with and per CMC guidance, an interim 
injection visit may be required to administer study product injections outside of a regularly 
scheduled injection visit window.  In consultation with the CMC, one or more interim injection 
visits may be necessary to appropriately reinitiate a participant on the dosing regimen or to 
realign to the original injection visit dosing schedule (as established based on the administration 
of the first injections).  Regularly scheduled visits may be missed to maintain adequate spacing 
requirements between interim injection visits.  The CMC must be consulted prior to initiating 
short-term oral bridging and prior resuming study product injections regarding clinical 
considerations, and injectable study product management and scheduling.  It is generally expected 
that, in consultation with the CMC, the following guidelines will apply when resuming injectable 
study products following short-term oral bridging: 
• 
If a participant will be on short-term oral bridging for ≤ 8 weeks (56 days) and is able to 
receive their study product injections with ≥ 3 weeks (21 days) before the next regularly 
scheduled injection visit, then an interim injection visit may be conducted; the next regularly 
scheduled injection visit will be conducted as originally scheduled. 
• 
If a participant will be on short-term oral bridging for ≤ 8 weeks (56 days) but there are < 3 
weeks (21 days) until the next regularly scheduled injection visit, then oral bridging should 
continue until the next regularly scheduled injection visit.  No interim injection visit will be 
conducted; and the regularly scheduled injection visit should occur early within the window 
to facilitate the shortest course of oral bridging necessary. 


 
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• 
If a participant will be on short-term oral bridging for more than 8 weeks (56 days), the CMC 
must be consulted for guidance on resuming the injections versus premature discontinuation 
of study products. 
 
An interim injection visit may also occur, in consultation with and per CMC guidance, to ensure 
the full injectable treatment for Cohort 2 participants and in accordance with the intended total 
injectable study product dosage/volumes per visit. Interim injection visit procedures are provided 
below, and study data will be entered into eCRFs per Section 5.1.5 and Section 7.2.  Section 6.9 
must also be followed prior to administering any study product injection.  Further details and 
guidance on scheduling and conducting study injection visits, including interim injection visits, 
are provided in the IMPAACT 2017 MOP. 
 
Cohort 2 Step 4 and Step 5 Interim Injection Visit Procedures (Step 4 or Step 5 - injection phase) 
Behavioral and 
Counseling 
• Provide adherence counseling* 
• Provide contraceptive counseling* 
Clinical 
• Update medical and medications history since last visit* 
• Perform symptom-directed physical exam* 
• Identify/review/update adverse events* 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA* 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: Single pre-dose sample* 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test; result must be obtained before administering injectable study product* 
Study product 
• Prescribe, prepare, and administer injectable study products, see Section 5.1^ 
*Perform prior to administration of injectable study products 
^Alternate dosing may be required, per CMC guidance, to ensure full injectable treatment. 
 
6.5 
Long-Term Safety and Washout PK Follow-Up (LSFU) Visits  
 
As noted in Section 3, the below specified participants will be followed according to the long-
term safety and washout PK follow-up (LSFU) visit schedule:  
• 
For Cohort 1 Step 2 participants: upon premature permanent discontinuation of injectable 
study product, or completion of the Cohort 1 Step 2 Week 16 visit but not enrolling to Cohort 
2 
 
• 
For Cohort 1 Step 2 participants who enroll to Cohort 2A Step 3 but are ineligible for Step 4: 
upon premature permanent discontinuation of oral study product in Cohort 2A Step 3 (the 
LSFU visit schedule will be based on the date of their last study product injection, i.e., their 
Cohort 1 Step 2 Week 8 visit) 
 
• 
For Cohort 2 participants: upon premature permanent discontinuation of injectable study 
products, or completion of the Cohort 2A Step 4 Week 96 or Cohort 2B Step 5 Week 92 
study visit but do not wish to receive injectable CAB LA + RPV LA external to the protocol 
(see Section 6.4.13 above)  


 
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• 
Participants assigned female at birth who discontinue study product use (either oral or 
injectable study product) due to pregnancy during Steps 1-5 
 
For participants permanently discontinuing injectable study product (not due to pregnancy), the 
LSFU visit schedule is based on the date of the participant’s last study product injection. Cohort 1 
Step 2 participants who complete their Week 16 visit will skip the LSFU Week 8 Visit.  
 
Participants assigned female at birth who permanently discontinue study product (either oral or 
injectable study product and during Steps 1 through 5) due to pregnancy will be followed for 48 
weeks, based on the date of the positive confirmatory pregnancy test result, per the LSFU visit 
schedule. For participants who become pregnant during LSFU visits, the LSFU visits will 
continue as scheduled and not restart. All LSFU visit procedures will be conducted, with the 
exception that pregnancy testing will not be required for participants who are currently pregnant. 
See Section 8.3 for further details on management of pregnant participants and pregnancy 
outcome.  
 
Cohort 2A Step 3 participants should resume (non-study provided) cART as soon as possible and 
within 4 weeks from their last oral study product use. Cohort 2 participants should resume (non-
study provided) cART at 8 weeks (±7 days) after their last study product injections. See the 
IMPAACT 2017 MOP for further guidance on scheduling LSFU study visits. 
 
During LSFU, a single random PK sample will be collected at each visit as shown in the 
procedural tables below. Participants must have sufficient blood volume collection for their 
assigned study product(s), as specified in the LPC. See Section 6.16 for additional considerations 
for laboratory procedures, and Appendix I-D for blood volume ranges during LSFU visits. 
 
6.5.1 
LSFU Week 8 Visit 
 
The LSFU Week 8 visit is targeted to be conducted 56 days after the last administration of 
injectable study product (or confirmatory positive pregnancy test result), with a target window of 
-14 days/+28 days from the target visit date. For Cohort 1 Step 2 participants completing the 
Week 16 visit, the LSFU Week 8 Visit will be skipped. Cohort 2 participants will resume (non-
study provided) oral cART at 8 weeks (±7 days) of discontinuing study product.  


 
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LSFU Week 8 Visit Procedures (LSFU) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling 
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: single sample 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test (unless currently pregnant) 
 
Sites may conduct interim safety visits between the LSFU Week 8 and LSFU Week 24 visits to 
clinically assess participants as they initiate their cART regimen, per standard of care or site 
SOPs. 
 
6.5.2 
LSFU Week 24 Visit 
 
The LSFU Week 24 Visit is targeted to take place 168 days after the last administration of 
injectable study product (or confirmatory positive pregnancy test result), with a target window of 
±42 days from the target visit date. 
 
LSFU Week 24 Visit Procedures (LSFU) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: single sample 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test (unless currently pregnant) 
 


 
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6.5.3 
LSFU Week 36 Visit 
 
The LSFU Week 36 Visit is targeted to take place 252 days after the last administration of 
injectable study product (or confirmatory positive pregnancy test result), with a target window of 
±42 days from the target visit date. 
 
LSFU Week 36 Visit Procedures (LSFU) 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing 
• PK evaluation: single sample 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test (unless currently pregnant) 
 
6.5.4 
LSFU Week 48 / Early Termination Visit 
 
The LSFU Week 48 Visit is targeted to take place 336 days after the last administration of 
injectable study product (or confirmatory positive pregnancy test result), with a target window of 
±42 days from the target visit date. These same visit procedures will be conducted as an Early 
Termination visit for participants withdrawing or terminating from the study prior to scheduled 
completion of study follow-up, instead of their regularly scheduled study visit, for a final series of 
evaluations. All participants completing this visit, whether as the LSFU Week 48 Visit (per the 
LSFU visit schedule) or as an Early Termination visit, will exit the study.  
 
Scheduling and completion of Early Termination visits will be in consideration of participant 
withdrawal or termination; visit procedures may be combined with an ongoing study visit. Any 
procedures conducted within 14 days of an Early Termination visit need not be repeated, with the 
following target dates for completing the Early Termination visit:   
• 
For Cohort 1 Step 1 and Cohort 2A Step 3 participants not progressing to the injection phase, 
an Early Termination visit is targeted to be completed 28 days after the participant’s last oral 
study product use; the Early Termination visit may be completed sooner, if necessary. For 
these participants, a PK evaluation will not be performed at this visit.  Cohort 2A Step 3 
participants should resume (non-study provided) cART as soon as possible and within 4 
weeks from their last oral study product use. 
 
• 
For Cohort 1 Step 2, Cohort 2A Step 4, Cohort 2B Step 5, and any participant being followed 
per the LSFU visit schedule, an Early Termination visit is targeted to be completed within 28 
days (inclusive) of the previous study visit.  Cohort 2 participants should resume (non-study 
provided) cART at 8 weeks (±7 days) after their last study product injections.    
 


 
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Participants completing an Early Termination visit will be followed until resolution (return to 
baseline) or stabilization of any adverse events per Section 8.  
 
Refer to Section 6.7 for the definition of scheduled completion of follow-up, and additional 
considerations for participants exiting the study (whether scheduled completion of follow-up or 
an early termination visit). Refer to Section 8.8 for criteria for participant withdrawal or 
premature termination from the study. The IMPAACT 2017 MOP provides further guidance on 
Early Termination visit scheduling considerations. 
 
LSFU Week 48 /Early Termination Visit Procedures  
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling 
• Perform acceptability/tolerability assessment questionnaires 
• Conduct qualitative phone interview, if indicated, see Section 11 
Clinical 
• Update medical and medications history since last visit 
• Perform complete physical exam 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC if indicated) 
• Sexual Maturity Rating assessment 
Laboratory 
Blood 
 
Collect blood for: 
• Hematology: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• Chemistries: Creatinine, Creatine kinase (CPK), Creatinine Clearance (CrCl; 
Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), 
Lipase (u/l), Blood Urea Nitrogen (BUN), Albumin (only if PK is also 
collected at this visit, g/dL) 
• HIV-1 RNA 
• Store plasma for genotypic and phenotypic resistance testing (LSFU Week 48 
visit only) 
• Store whole blood for genotypic resistance testing (Early Termination visit 
only) 
• PK evaluation: single sample, (except for participants completing an Early 
Termination visit during Cohort 1 Step 1 or Cohort 2 Step 3) 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test (unless currently pregnant) 
 
6.6 
Confirmation of Virologic Failure Visit 
 
Virologic failure is defined as two consecutive plasma HIV-1 RNA test results ≥200 copies/mL, 
from two separate specimens. Any participant with a plasma HIV-1 RNA level ≥200 copies/mL 
after enrollment should be recalled to the clinic for confirmatory testing 2-4 weeks after specimen 
collection for the initial test. Refer to Section 8.4 for more information on monitoring HIV-1 viral 
load, definitions of virologic failure, and managing virologic failure.  
 
Scheduling of confirmatory testing should be in consideration of potential causes for virologic 
failure such as intercurrent illness, recent immunizations, inadequate adherence or interruptions to 
cART (for Cohort 1 or LSFU participants), interruptions of study product due to toxicity 
management, or other extenuating circumstances. For Cohort 1 Step 2 or Cohort 2 participants 
receiving injectable study product, confirmatory test results should ideally be obtained and 
reviewed prior to the next scheduled administration of injectable study product. While injection 


 
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study visits for these participants may be delayed within the respective target visit window, 
injectable study product must not be withheld for pending confirmatory testing or results. 
  
Confirmation of Virologic Failure visit procedures may be combined with regularly scheduled 
visit procedures if they are performed within the target window of a regularly scheduled visit. In 
addition to the protocol-specific procedures listed in this section, study staff may complete other 
tasks and assessments consistent with local standards of care and site SOPs. Viral load results 
should be provided to participants and may be used to guide adherence counseling. See Section 
6.14 for additional details on adherence counseling. 
 
Confirmation of Virologic Failure Visit Procedures 
Behavioral and 
Counseling 
• Provide contraceptive counseling 
• Provide adherence counseling, if indicated 
• Provide instructions for cART administration and adherence counseling to the 
participant, parent or guardian, if indicated 
Clinical 
• Obtain interval medical and medications history  
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC if indicated) 
Laboratory 
Blood 
Collect blood for: 
• HIV-1 RNA 
• Plasma for genotypic and phenotypic resistance testing 
• PK evaluation: single sample 
 
Blood or 
Urine 
• For participants assigned female at birth, collect blood or urine for pregnancy 
test (unless currently pregnant) 
 
6.7 
Study Exit 
 
Participants may exit the study at different timepoints, with the following considered as scheduled 
study completion of follow-up: 
• 
Participants following the LSFU visit schedule will exit the study at their LSFU Week 48 
study visit (see Section 6.5 above) 
 
• 
Cohort 2 participants who complete the Step 4 Week 96 or Step 5 Week 92 visit and wish 
to receive injectable CAB LA + RPV LA external to the protocol will exit the study; see 
Section 14.11 
 
Any participant withdrawing or terminating from the study prior to these timepoints is considered 
as prematurely terminating from the study and the LSFU Week 48 study visit will be conducted 
as an Early Termination visit, instead of their regularly scheduled study visit, for a final series of 
evaluations. All visit procedures as described in and applicable to Section 0 will be completed for 
an Early Termination visit, with additional procedures and exceptions as noted.  
 
At any study exit visit (scheduled completion of follow-up or an early termination visit), 
arrangements should be made to provide all clinically meaningful results to the participant and 
the participant’s parent or guardian. The participant and parent or guardian should be provided 
information on how to remain in contact with study staff (if desired) and how to learn about the 
results of the study when available. The participant and the participant’s parent or guardian 
should also be provided information, counseling, and referrals to non-study sources of care and 
treatment for the participant, as applicable. Cohort 2A Step 3 participants should resume (non-


 
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study provided) cART as soon as possible and within 4 weeks from their last oral study product 
use.  Cohort 2 participants should resume (non-study provided) cART at 8 weeks (±7 days) after 
their last study product injections. See Section 8.1 regarding management of adverse events at 
study exit, and Section 8.8 for additional considerations regarding participant withdrawal or 
termination. 
 
6.8 
Post-Study Contacts 
 
Planning for transition to non-study care and treatment for participants exiting the study should 
begin prior to the participant’s scheduled study exit visit, and the transition should be 
implemented at the participant’s scheduled study exit visit. Study staff will complete a final study 
contact, with the participant and the participant’s parent or guardian, if applicable, within 4 to 8 
weeks of the participant’s study exit visit to confirm the transition and should be documented in 
each participant’s study chart. These contacts are not expected to be entered into eCRFs. 
However, eCRF data collection is required after the participant’s study exit visit in the following 
scenarios:  
• 
If a participant becomes pregnant while on study:  Refer to Section 8.3; the pregnancy 
outcome must be ascertained and the relevant eCRFs entered after the participant exits the 
study to record the pregnancy outcome. 
 
• 
If confirmation of virologic failure is pending after the LSFU Week 48 visit: A Confirmation 
of Virologic Failure Visit should be conducted (refer to Section 6.6) with all relevant eCRFs 
entered. 
 
• 
If the participant has any Grade 3 or higher adverse event at the study exit visit: participants 
should be asked to be continued on study for up to 56 days or until resolution (return to 
baseline) or stabilization (i.e., Grade 2 or lower), whichever is sooner, with the frequency of 
visits determined by the site investigator. 
 
6.9 
Procedures for Continued Oral and Injectable Study Product Administration 
 
The following procedures must be performed on the same day as and prior to either dispensing 
oral study product or administering study product injection to assess for any indication of study 
product hold or permanent discontinuation: 
• 
Clinical evaluations per the respective study visit (see Section 6 and Appendix I) 
• 
Laboratory test results from the previous study visit obtained and reviewed for indication of 
study product hold or permanent discontinuation (see Section 8) 
• 
For participants assigned female at birth, a negative pregnancy test result  
• 
For participants childbearing potential, confirmation (per participant report) of effective 
contraception, per Section 6.13 
 
See Section 8.1 for details regarding participant management. See Section 8.6 for details 
regarding deferring study product due to managing adverse events and other indications.  
 


 
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6.10 
Medical and Medications History  
 
Collection of medical and medication history information is required at each scheduled visit. A 
baseline history is established at Screening and Entry, and interval (since the last visit) histories 
are obtained at subsequent follow-up visits. All history information may be obtained based on 
participant self-report or as reported by the parent or guardian, but available medical records 
should be obtained when possible to supplement self-reported information. Refer to the 
IMPAACT 2017 MOP for additional guidance regarding establishing baseline history. 
 
Documented medical conditions will be assessed for severity as described in Section 7.3.3, and 
new conditions occurring during follow-up will also be assessed for relationship to study product 
as described in Section 8.1. Relevant dates will be recorded for all conditions and medications; 
see Section 5.6 for more information on concomitant medications.  
 
Table 8 specifies the baseline and interval medical and medications history elements that must be 
source documented for participants, as well as associated eCRF entry requirements.  
 
Table 8. Documentation Requirements for Medical and Medication Histories 
Assess for and Source Document 
Enter into eCRFs or SES 
Baseline Medical and Medication History Elements 
Age, sex at birth, and other socio-
demographics 
 
Yes (all) 
HIV diagnosis, mode of transmission, and 
ARV treatment history (including all prior 
ARV use) 
Yes (all, including start/stop dates, dates and 
values of results, as applicable) 
History of allergy and/or hypersensitivity 
(including to ARVs) 
Yes (all) 
Medical conditions (including malignancies) 
occurring during the 28 days prior to entry, 
ongoing at entry, as well as all prior 
significant central nervous system disorders 
(including seizures and migraines/headaches), 
mood disorders (such as depression), and 
significant liver disease resulting in 
hospitalization or interfering with daily 
activities.  
Yes (all, including start/stop dates, and dates 
of diagnosis, as applicable) 
Medications, (other than ARVs, see above) 
taken within the 28 days prior to enrollment 
and/or ongoing at enrollment 
Yes (all, except herbal or traditional 
medications are not be captured on eCRFs) 
Assessment of sexual activity 
Yes 


 
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Assess for and Source Document 
Enter into eCRFs or SES 
Contraceptives ongoing at enrollment, 
including start date and most recent date of 
administration of current contraceptive 
method. 
 
Note:  Hormonal-based contraceptives must 
have been initiated within the prescribed time, 
per the respective contraceptive method, to be 
considered effective at the time of Entry. The 
site IoR or designee is responsible for 
ensuring that the contraceptive is used in 
accordance with the approved product label 
Yes 
Any other information needed to determine 
eligibility for the study 
— 
Interval Medical and Medication History Elements 
Current status of conditions that were ongoing 
at the previous visit 
Any updates of previous entries 
(e.g., resolution dates) 
Occurrence of any new conditions since the 
last visit 
Any newly identified adverse events that meet 
criteria in Section 7.2 
Current status of medications (including 
contraceptives) that were ongoing at the 
previous visit 
Any updates of previous entries  
(e.g., stop dates) 
Use of any new medications since the last 
visit (see Section 5.6 for more information on 
concomitant medications) 
 
Note: For participants in Cohort 1 and LSFU, 
ARVs would be considered concomitant 
medications.  
 
 
• Any concomitant ARVs taken 
• Any new use of concomitant medications, 
including contraceptives  
• All medications taken at onset of or in 
response to adverse events that are specified 
to be entered into eCRFs per Section 7.2 
 
Note: herbal or traditional medications taken 
during follow-up should not be captured on 
eCRFs. 
Oral Study Product since the last visit (for 
Cohort 1 Step 1, Cohort 2A Step 3 
participants, and any Cohort 1 or Cohort 2 
participants on oral bridging)   
 
Note: Injectable study product information is 
not considered as part of medical and 
medications history since last visit, and will 
be collected as per Section 5. See Section 6 
above for details regarding study product 
dosing documentation requirements for PK 
evaluations. 
• Oral study product doses taken from time of 
enrollment through completion of follow-up 
Assessment of sexual activity since the last 
visit 
— 
 


 
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6.11 
Physical Examinations 
 
A physical examination is required at each scheduled visit, either as a complete physical exam or 
as a symptom-directed physical exam, per the specified procedures for each visit. Table 9 below 
outlines the visits when a complete physical exam is required; symptom-directed exams are 
required at all other scheduled visits. 
 
Table 9. Visits Requiring Complete Physical Examination 
Cohort 1 
Screening, Week 4a, and Week 16 Visits 
Cohort 2A 
Screening, Week 4a, Week 24, Week 48,  
and Week 96 
Cohort 2B 
Screening, Week 20, Week 44,  
and Week 92 
LSFU 
LSFU Week 4, and LSFU Week 48/Early 
Termination Visit 
 
Complete exams should include the following: 
• 
Height and weight 
• 
Vital signs, including heart rate, temperature and blood pressure 
• 
Examination of: 
– General appearance 
– Head 
– Eyes  
– Ears  
– Nose  
– Neck 
– Mouth and throat 
– Lymph nodes 
– Lungs 
– Heart 
– Abdomen 
– Musculoskeletal system 
– Skin 
– Neuro 
• 
Sexual Maturity Rating (SMR) (at Screening for both Cohort 1 and Cohort 2, Cohort 1 Week 
16, Cohort 2A Week 24 and 96, Cohort 2B Week 20 and 92, and LSFU Week 48/Early 
Termination visits)  
• 
Examination of other body systems driven by other identified signs or symptoms 
 
Symptom-directed exam should include the following:  
• 
Height and weight 
• 
Vital signs, including heart rate, temperature and blood pressure 
• 
Examination of body systems driven by identified signs or symptoms 
 
At all visits, additional assessments may be performed at the discretion of the examining site 
investigator. All exam findings should be source documented, with vital signs and any abnormal 
findings entered into eCRFs, as specified in Section 7.2. Additionally, height and weight must be 
obtained on the same day as any PK sample collection, and source documented and entered into 
eCRFs, even if a physical exam was already conducted as part of that visit.  
 


 
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6.12 
Performing an Electrocardiogram (ECG/EKG)  
 
Electrocardiogram (ECG) readings are required as specified in Sections 6.2 through 6.5 above. 
For all ECG readings, a 12-lead ECG should be performed with the participant in a semi-supine 
position. An ECG machine that automatically calculates the heart rate and measures QTc 
intervals is preferred, and the automated calculations can be used for reporting purposes. The IoR 
or designee can review the ECG reading and a cardiologist reading is not required. Otherwise, an 
appropriately qualified ECG reader must interpret the results.  
 
At the Cohort 1 Screening and Cohort 2 Screening visits, the ECG reading should be done in 
triplicate such that three, single automated QTc readings will be done, each separated by at least 2 
minutes, with the mean value establishing baseline. Once the QT correction formula of either 
Bazett or Fridericia has been chosen for a participant’s eligibility, the same formula must 
continue to be used for that participant for ECG monitoring and all QTc data being collected for 
data analysis. This formula may not be changed or substituted once the participant has been 
enrolled. For example, if a participant is eligible for the protocol based on QTcB (calculated 
using Bazett’s formula), then QTcB must be used for this individual participant during study 
follow-up.  During follow-up, single automated readings will be compared to the baseline value, 
with the following requiring two repeat readings (for a total of three readings separated by at least 
2 minutes): 
• 
For QTcB (using Bazett’s formula), a result of > 500 msec or ≥ 60 msec increase from 
baseline. 
• 
For QTcF (using Fridericia formula), a result of ≥ 500 msec or > 60 msec increase from 
baseline. 
 
All ECG readings should be source documented and entered into eCRFs. See Section 8.2 for 
Management of QTc Prolongation. 
 
6.13 
Pregnancy Testing and Contraceptive Counseling 
 
Pregnancy testing is required for all participants assigned female at birth, at specified study visits 
and prior to administration of study product, regardless of self-reported sexual activity or 
childbearing potential. See Section 8.3 for details on participant and study product management 
relating to Management of Contraception and Pregnancy.  
 
As stated in Section 4.1.14, participants of childbearing potential are required to use at least one 
allowable effective method of contraception to enroll to the study. For participants who become 
of childbearing potential during the study, an allowable effective contraceptive method must be 
initiated prior to administration of study product (oral or injectable study product). A participant 
assigned female at birth is considered of childbearing potential following the initiation of puberty 
(Tanner stage 2 based on genitalia and/or breast assessment) or onset of menarche, whichever is 
noted first, until becoming post-menopausal, unless permanently sterile or with medically 
documented ovarian failure. Participants assigned female at birth are considered to be in a 
postmenopausal state when they are > 54 years of age with cessation of previously occurring 
menses for > 12 months without an alternative cause. Permanent sterilization includes 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a participant of any age 
assigned female at birth. 
 
The effective methods of contraception allowed for this study are listed below.  


 
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• 
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the participant’s preferred and usual 
lifestyle 
 
OR 
 
• 
Consistent and correct use of 1 of the following methods of birth control listed below.  
o Intrauterine device (IUD) with a failure rate of < 1% per year  
o Intrauterine hormone-releasing system (IUS) with a failure rate of < 1% per year  
o Tubal sterilization  
o Essure micro-insert system (provided confirmation of success 3 months after procedure)  
o Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)  
 
OR 
 
• 
Consistent and correct use of one hormonal method AND one barrier method  
o Barrier methods  
▪ 
Diaphragm with spermicide  
▪ 
Cervical cap with spermicide  
▪ 
Male condom (with or without spermicide)  
o Hormonal methods  
▪ 
Oral contraceptives (either combined or progesterone only)  
▪ 
Injectable progesterone  
▪ 
Implants of levonorgestrel  
▪ 
Transdermal contraceptive patch  
▪ 
Contraceptive vaginal ring  
 
For any methods of contraception not included in the listing which have a < 1% failure rate, per 
the product label, may be allowed in consultation with the CMC. 
 
Study staff will provide contraception counseling to all participants (regardless of gender, self-
reported sexual activity, or childbearing potential) at all study visits. Counseling will include 
maintaining contraceptive use for 30 days after the last oral study product use and for 48 weeks 
after any single injection of study product. Participants assigned female at birth should also be 
encouraged to delay pregnancy for at least 30 days following oral study product use, or 48 weeks 
following any single injection of study product. 
 
At any point during study participation, additional counseling on correct use of chosen 
contraceptive methods should also be offered according to site SOPs; this will include 
information on correct use of barrier methods. For Cohort 1 and all LSFU participants, 
contraceptive counseling will also reflect the ARVs which participants are currently taking for the 
potential interactions between these ARVs and available contraceptive methods. Contraceptive 
counseling may be tailored to be age-appropriate and will be provided by clinic and/or pharmacy 
staff consistent with local standards of care and site SOPs. Study sites should ideally integrate 
provision of contraceptive methods with other services offered to study participants and should 
provide referrals to non-study sources of methods that cannot be provided at the study site. Study 
staff should confirm (per participant report) effective contraception with one of the study-required 
contraceptive methods for all participants of childbearing potential at each visit in which study 
product is administered.  
 


 
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Pregnancy test results will be disclosed to participants and their parent/guardians consistent with 
local standards of care; local standard procedures will be noted in site-specific informed consent 
and assent forms. 
 
6.14 
Study Product Adherence Assessment and Adherence Counseling (Study Product, cART 
Regimen, Study Visits) 
 
Prior to progressing to the injection phase, Cohort 1 and Cohort 2A participants should be 
assessed for adherence to oral study product and whether sufficient evaluations of safety and 
tolerability were permitted to be conducted during the oral lead-in phase. Pill counts will be 
conducted at the Week 2, Week 4a and Week 4b visits (for both Cohort 1 and Cohort 2A) but will 
not be used as a basis for counseling participants on oral study product adherence. Information 
obtained through the pill counts, participant self-report, and adherence counseling discussions 
should be used in combination as a broader adherence assessment evaluation when assessing each 
participant for eligibility to receive injectable study product. The IoR, or designee, should source 
document all contributing information leading to and final determination of Step 2 or Step 4 
eligibility with regards to Sections 4.3.4 and 4.4.4.  
 
Adherence counseling will be provided to all study participants and parents/guardians throughout 
study participation at specified study visits, and as needed based on IoR discretion. Topics 
discussed during adherence counseling will vary depending on the Cohort, Step and whether 
participants are also taking a (non-study provided) cART regimen: 
• 
For Cohort 1 participants, adhering to the (non-study provided) cART regimen and 
instructions on cART administration will be provided. These topics will also be discussed 
prior to participants transitioning to the LSFU visit schedule (if permanently 
discontinuing injectable study product), during specified LSFU visits, and at Early 
Termination visits. 
• 
For Cohort 1 Step 1 and Cohort 2A Step 3 participants, counseling on adhering to the oral 
study product will be provided in relation to the purpose of the oral lead-in phase and 
allowing for sufficient evaluations of safety and tolerability. 
• 
For Cohort 1 Step 2, Cohort 2A Step 4, and Cohort 2B Step 5 participants, counseling 
will include discussion with participants regarding the importance of adhering to the 
intended injectable study product dosing regimen and adhering to the study visit 
schedule. 
• 
For all Cohort 2 participants, counseling will include confirmation of the decision to 
enroll to the selected Cohort 2 group (Cohort 2A versus Cohort 2B), and discussion on 
the importance of adhering to the study visit schedule as these participants are no longer 
receiving a (non-study provided) cART regimen. 
• 
For participants exiting the study at the Cohort 2A Week 96 or Cohort 2B Week 92 visit 
(to continue injectable CAB LA + RPV LA external to the protocol), counseling will 
include the importance of adhering to the intended injectable dosing regimen and 
schedule. 
 
Counseling may be provided by clinic and/or pharmacy staff consistent with local standards of 
care and site SOPs. Counseling should be provided in a client-centered manner, tailored as 
needed to the information, skills building, and support needs of each participant. Information on 
correct use of oral study products will be provided. Counseling will also address challenges to 
consistent use of oral study product or attending injectable study visits over time, with the aim of 
supporting participants in identifying strategies to address any such challenges. 
 


 
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6.15 
Acceptability and Tolerability Assessments 
 
Acceptability and tolerability of the study products will be assessed at specified study visits, and 
at visits during which permanent study product discontinuation is initiated. These assessments 
will be administered to participants by site staff via questionnaires covering topics on participant 
perceptions of the study product injections, reasons for switching from daily oral cART to long-
acting study products, satisfaction with treatment, quality of life, and treatment preferences. A 
shortened assessment battery will be utilized for individuals who are unable to complete the 
questionnaires in English or Spanish. Prior to the participant leaving the clinic, questionnaires 
should be reviewed, and any potential adverse events reported in the participant’s responses 
should be clinically assessed. Further guidance and considerations for conducting and reviewing 
the acceptability and tolerability assessments, the timing of administering the assessments relative 
to other visit procedures, as well as guidance regarding the appropriate site staff to administer 
specified assessments is provided in the study-specific MOP. 
 
6.16 
Additional Considerations for Laboratory Procedures 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy on 
Requirements for DAIDS Funded and/or Sponsored Laboratories in Clinical Trials Policy, which 
is available at: https://www.niaid.nih.gov/research/daids-clinical-research-laboratory-specimens-
management. 
 
6.16.1 Specimen Collection 
 
Specimens will be collected for this study as indicated in the Schedule of Evaluations and per 
detailed guidance provided in the LPC, which will be posted on the study-specific webpage: 
http://impaactnetwork.org/studies/IMPAACT2017.asp. Site staff collecting specimens for PK 
evaluations must prepare the workspace and supplies with regards to protecting all specimens 
from light, as specified in the LPC.  
 
In accordance with US National Institutes of Health (NIH) recommendations, pediatric (less than 
18 years) blood collection will not exceed 5 mL/kg in a single day or 9.5 mL/kg over any eight-
week period. Adult (18 years and older) blood collection will not exceed 10.5 mL/kg or 550 mL, 
whichever is smaller, over any eight-week period.  
 
In the event blood collection must be limited, available specimens will be prioritized for use in 
the following order: (1) safety (chemistries, hematology, pregnancy testing), (2) PK, (3) HIV-1 
viral load, and (4) genotypic and phenotypic resistance storage sample.  
 
6.16.2 Specimen Preparation, Testing, Storage, and Shipping 
 
All specimens collected for this study will be labeled, transported, processed, tested, stored and/or 
shipped in accordance with the DAIDS policy referenced above, site and local laboratory SOPs, 
and the LPC. The frequency of specimen collection and testing will be directed by the Schedules 
of Evaluations in Appendix I and specifications for clinical management provided in Section 8. 
The Laboratory Data Management System (LDMS) will be used to document specimen 
collection, testing, storage, and shipping as specified in the LPC. Any specimens stored at the 
Screening Visit for participants who do not subsequently enroll in the study will be destroyed. 


 
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The following will be performed in real time at local laboratories that are CLIA-certified or 
equivalent (for US sites) or at any network-approved non-US laboratory that operates in 
accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate 
external quality assurance programs: 
• 
Pregnancy tests  
• 
Hematology laboratory testing: complete blood counts, with platelets (cells/mm3), ANC 
(cells/mm3), and hemoglobin (g/dL) 
• 
Chemistry laboratory testing:  Creatinine, Creatine kinase (CPK), Creatinine Clearance 
(CrCl; Schwartz formula mL/min/1.73m2), Total bilirubin, AST (u/l), ALT (u/l), Lipase (u/l), 
Blood Urea Nitrogen (BUN), Albumin (g/dL) 
• 
CD4 count and percentage tests 
• 
Plasma HIV-1 RNA assays 
 
HIV genotypic and phenotypic resistance samples for storage (collected at study visits other than 
the Confirmation of Virologic Failure visit) must be processed and stored per the LPC.  
 
HIV genotypic and phenotypic resistance samples collected at the Confirmation of Virologic 
Failure visit must be processed with plasma retained at the site laboratory, as specified in the 
LPC, pending HIV-1 RNA test results to confirm virologic failure. For participants with 
confirmed virologic failure, aliquots of plasma stored for resistance testing collected during the 
Confirmation of Virologic Failure visit, the visit in which the participant had an initial elevated 
viral load test result, the whole blood sample stored at the Entry visit, and any other study visits 
as requested by the CMC, will be shipped with testing performed in real time at a designated 
CLIA-certified or equivalent testing laboratory, as specified in the LPC. If failure is not 
confirmed, resistance samples collected during the Confirmation of Virologic Failure visit will 
remain stored at the site laboratory. 
 
Specimens collected, processed, and stored at site laboratories for PK evaluations are generally 
expected to be shipped to the designated testing laboratory as follows, or as otherwise requested 
by the protocol team:   
• 
For Cohort 1: PK samples from Week 2 through Week 8 visits should be shipped upon 
completion of the Week 8 visit.  Cohort 1 PK samples from Week 9 through Week 16 visits 
should be shipped upon completion of the Week 16 visit. Samples from all LSFU visits 
should be batched and shipped quarterly. 
• 
For Cohort 2A: PK samples from Week 2 through Week 16 should be shipped upon 
completion of the Week 16 visit.  PK samples from the Week 24 visit should be shipped in 
real time and upon completion of the Week 24 visit.  Samples from Week 25 through Week 
48 visits should be shipped upon completion of the Week 48 visit. Samples from Week 56 
through Week 96 visits and all LSFU visits should be batched and shipped quarterly. 
• 
For Cohort 2B: PK samples from Entry through Week 20 should be shipped in real time and 
upon completion of the Week 20 visit.  Samples from Week 21 through Week 44 visits 
should be shipped upon completion of the Week 44 visit. Samples from Week 52 through 
Week 92 visits and all LSFU visits should be batched and shipped quarterly. 
• 
All Confirmation of Virologic Failure visits (from both Cohorts 1 and 2) should be batched 
and shipped quarterly. 
 
After all protocol-specified laboratory testing has been performed, residual specimens may be of 
interest for future research use. Participants and participants’ parents or guardians (if applicable) 
will be asked to provide written informed consent/assent for future research use of these 


 
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specimens, if permitted by IRBs/ECs and other applicable review bodies. Parents or guardians (or 
participants) may choose to provide or to decline informed consent for future research use of 
residual specimens with no impact on other aspects of participation in the study. If informed 
consent for future research use of residual specimens is initially provided but if participants or 
their parent/guardian subsequently change their mind and withdraw that consent, all remaining 
residual samples will be destroyed.  
 
6.16.3 Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study as currently recommended by the US Centers for Disease Control and 
Prevention, NIH, and other applicable agencies. All specimens will be shipped using packaging 
that meets requirements specified by the International Air Transport Association Dangerous 
Goods Regulations for UN 3373, Biological Substance, Category B, and Packing Instruction 650. 
Culture isolates, if obtained in this study, are to be shipped as specified for UN 2814 Category A 
Infectious Substances. 
 
 
7 
SAFETY ASSESSMENT, MONITORING, AND REPORTING 
 
Participant safety will be carefully assessed, monitored, and reported at multiple levels 
throughout this study. Sections 7.1–7.3 describe safety-related roles, responsibilities, and 
procedures for site investigators. The safety monitoring roles of the Clinical Management 
Committee (CMC) and the IMPAACT Study Monitoring Committee (SMC) are briefly 
referenced in Section 7.1 and described in greater detail in Sections 9.5.1 and 9.5.2. 
 
Unless otherwise noted, the specifications of this section only apply to adolescent participants in 
Cohort 1, Cohort 2, and LSFU. 
 
7.1 
Safety-Related Roles and Responsibilities 
 
7.1.1 
Site Investigators 
 
Site investigators are responsible for continuous monitoring of all study participants and for 
alerting the CMC if unexpected concerns arise. Site investigators will enter safety-related data 
into eCRFs as indicated in Section 7.2 and complete expedited adverse event (EAE) reporting as 
indicated in Section 7.3. Site investigators are also responsible for prompt reporting of any 
unanticipated problems involving risks to participants or others to all applicable IRBs/Ecs and 
other applicable review bodies, per the procedures of each applicable review body.  
  
Importantly, site investigators must inform the CMC of any of the following:  
• 
New onset seizure  
• 
Grade 3 or higher absolute neutrophil count (ANC), alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), creatine kinase (CPK), total bilirubin (unless isolated 
atazanavir related hyperbilirubinemia with normal direct bilirubin), or lipase  
• 
Grade 3 or higher adverse events assessed as related to study product 
• 
Missed scheduled study product injection visit 
• 
Suspected maladministration and/or post-injection reaction 


 
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For new onset of seizure and suspected maladministration and/or post-injection reactions, the 
CMC should be informed within 24 hours of awareness of the event. For all other events 
specified above, the CMC should be informed as soon as possible and within 48 hours of 
awareness of the event. 
 
For participants who miss a scheduled study product injection, or who have a temporary hold 
which will cause the participant to miss a scheduled study product injection, the CMC should be 
consulted as soon as possible and within 48 hours of site awareness.  
 
7.1.2 
Clinical Management Committee (CMC) 
 
The following Protocol Team members comprise the CMC: Co-Chairs, Medical Officers, 
Statisticians, Data Managers, Clinical Research Managers, Laboratory Center Representatives, 
protocol Pharmacologists, at least one protocol Investigator, at least one Statistician 
representative from ViiV, at least one medical (or designee) representative from each ViiV and 
Janssen, and at least one Pharmacologist representative from each ViiV and Janssen. The CMC 
will provide guidance as needed to site investigators regarding all aspects of participant 
management, including but not limited to questions of participant eligibility, management of 
adverse events, study product administration, cART regimens, and other concomitant 
medications. Refer to Section 8 for more information on participant management. 
 
On behalf of the full Protocol Team, the CMC will monitor participant safety through routine 
review of study data reports as described in Section 9.5.1.  
 
Detailed toxicity management algorithms including criteria for discontinuation of study product 
can be found in Section 8 below. 
 
7.1.3 
Study Monitoring Committee (SMC) 
 
An independent IMPAACT Study Monitoring Committee (SMC) will monitor participant safety 
through routine and as needed reviews of study data. Refer to Section 9.5.2 for more information 
on the composition and role of the SMC in monitoring of this study.  
 
7.2 
Safety-Related Data Collection 
 
This section describes eCRF data collection for pre-existing conditions and adverse events. 
Criteria for expedited reporting of specified adverse events are further detailed in Sections 7.3.2 
and 7.3.3 below.  
 
The definition of the term adverse event provided in Version 2.0 of the Manual for Expedited 
Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) will be used in this study. This 
definition will be applied only to the adolescent participants, beginning at the time of enrollment 
(as defined in Section 4.7), regardless of subsequent administration of or exposure to study 
product. Any untoward medical conditions (including abnormal laboratory test results, signs, 
symptoms, or diseases) identified prior to enrollment will be considered pre-existing conditions. 
 
Pre-Existing Conditions  
 
The following pre-existing conditions will be entered into medical history eCRFs: 


 
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• 
All conditions identified during the 28 days prior to study entry  
• 
All conditions ongoing at the time of enrollment 
• 
All prior significant central nervous system disorders (including seizures and 
migraines/headaches), mood disorders (such as depression), and significant liver disease 
resulting in hospitalization or interfering with daily activities  
 
Adverse Events  
 
The following adverse events will be entered into the adverse events eCRFs: 
• 
Grade 1 and higher clinical adverse events (including all signs, symptoms, and associated 
laboratory test results of the clinical adverse event) 
• 
Grade 3 or higher laboratory-only adverse events 
• 
All adverse events that result in temporary study product hold or permanent discontinuation 
of study product 
• 
All adverse events that meet criteria for expedited reporting per protocol Section 7.3.2 
• 
For Cohort 1 participants enrolling to Cohort 2, all Grade 1 or higher clinical adverse events 
ongoing at the time of Cohort 2 Entry as well as any event that occurred within the 28 days 
prior to Cohort 2 Entry (i.e., Cohort 2A Step 3 Entry or Cohort 2B Step 5 Entry, as 
applicable) 
 
Laboratory Test Results  
 
All protocol-required laboratory test results will be entered into laboratory eCRFs. 
 
7.3 
Expedited Adverse Event (EAE) Reporting 
 
7.3.1 
EAE Reporting to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of adverse events are outlined in 
Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE 
Manual), which is available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-
research-sites/manual-expedited-reporting-adverse-events-daids. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system, must be used for EAE reporting to DAIDS. In the event of system outages or technical 
difficulties, EAEs may be submitted using the DAIDS EAE Form. This form is available on the 
DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. 
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Queries may also be sent from within the DAERS application 
itself.  
 
For questions about expedited reporting, please contact the DAIDS RSC Safety Office at 
DAIDSRSCSafetyOffice@tech-res.com. 
 


 
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7.3.2 
EAE Reporting Requirements for this Study 
 
The SAE (serious adverse event) reporting category, as defined in Version 2.0 of the DAIDS 
EAE Manual, will be used for this study. In addition, the following must also be reported in an 
expedited manner (i.e., as EAEs), regardless of severity or relationship to study product:   
• 
ALT ≥3x ULN with total bilirubin ≥2x ULN 
• 
ALT ≥8x ULN  
• 
ALT ≥3x baseline ALT with signs/symptoms of acute hepatitis  
• 
ALT ≥5x ULN that persists >2 weeks   
• 
Any seizure event 
 
The study agents for which expedited reporting are required are oral cabotegravir (CAB), long-
acting injectable cabotegravir (CAB LA), and oral rilpivirine (RPV), and long-acting injectable 
rilpivirine (RPV LA). 
 
Information on Aes will be included in reports to the US FDA, and other government and 
regulatory authorities, as applicable. 
 
7.3.3 
Grading Severity of Events (applies to EAEs and all other adverse events) 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017, will be used in this study.  
This table is available at:  
 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables 
 
The DAIDS AE Grading Table provides grading for creatinine and creatinine clearance (or 
eGFR) values based on both absolute value and change from baseline. For this study, for 
creatinine, only the comparison to upper limit of normal (ULN) will be used and not change from 
baseline. For creatinine clearance (or eGFR), only the absolute value will be used, and not percent 
change from baseline, using the Bedside Schwartz formula. 
 
The DAIDS AE Grading Table provides grading for prolonged QTc interval assessed per Bazett’s 
formula (QTcB); protocol-specific grading for prolonged QTc interval assessed per Fridericia’s 
formula (QTcF) is as follows: 
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
QTc Prolongation Interval 
(using the Fridericia 
formula) 
QTc ≥ 460msec, 
but < 480msec 
QTc ≥ 480msec, 
but < 500msec 
QTc ≥ 500msec  
OR 
 
QTc > 60 msec 
greater than 
baseline  
AND  
QTc ≥ 480 msec 
Life-threatening 
consequences  
(e.g., Torsades de 
pointes, other 
serious ventricular 
dysrhythmias) 
 


 
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7.3.4 
EAE Reporting Period 
 
The EAE reporting period for this study is the protocol-specific period of follow-up, beginning at 
the time of study entry and ending on the date of the final follow-up visit. For all participants who 
continue per the LSFU visit schedule, EAE reporting requirements continue throughout LSFU 
follow-up. For Cohort 1 participants who may enter Cohort 2 after having exited the study, EAE 
reporting requirements resume upon re-entry into the study. 
 
After this reporting period, unless otherwise noted, only Suspected, Unexpected Serious Adverse 
Reactions (SUSARs) as defined in Version 2.0 of the EAE Manual will be reported to DAIDS if 
the study staff become aware of the events on a passive basis (from publicly available 
information). 
 
 
8 
PARTICIPANT MANAGEMENT 
 
8.1 
Management of Adverse Events 
 
All adverse events identified in this study will be source documented in participant research 
records, consistent with the policies and procedures referenced in Section 12. Among other 
details, source documentation will include the severity of each event (graded as described in 
Section 7.3.3) and its relationship to study product, assessed by the site clinician according to the 
following categories and definitions: 
 
Related 
There is a reasonable possibility that the adverse event may be related to the 
study agents: oral cabotegravir (CAB), long-acting injectable cabotegravir (CAB 
LA), and oral rilpivirine (RPV), and long-acting injectable rilpivirine (RPV LA) 
 
Not related 
There is not a reasonable possibility that the adverse event may be related to the 
study agents: oral cabotegravir (CAB), long-acting injectable cabotegravir (CAB 
LA), and oral rilpivirine (RPV), and long-acting injectable rilpivirine (RPV LA) 
 
Further standardized guidance on determining whether there is a reasonable possibility of a 
relationship is available in the DAIDS EAE Manual, referenced in Section 7.3.1 above. 
  
Adverse events identified in enrolled participants will be managed based on their severity and 
assessed relationship to study product, as described in greater detail below. Unless otherwise 
specified below, AEs (clinical as well as abnormal laboratory values) should be managed per 
general management guidelines in Section 8.1.1. 
 
Individual dose adjustments or reductions of study products for management of toxicity-related 
AEs are not allowed. For Cohort 2 participants, in the event of a temporary study product hold or 
a permanent discontinuation of study product, both study products will always be held (or 
discontinued). For additional considerations regarding Cohort 2 participants and resuming (non-
study provided) cART, see Section 8.6 regarding temporary product holds, and Section 8.7 
regarding permanent discontinuation of study product.  
 
Unless otherwise noted in the protocol, laboratory values obtained and clinical assessments 
performed at the Entry visit for the applicable cohort will be used as baseline. Laboratory 
values obtained and clinical assessments performed as part of screening procedures for the 


 
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applicable cohort may be used as baseline if not available from the Entry visit or per CMC 
guidance. Refer to the IMPAACT 2017 MOP for additional guidance. All adverse events must be 
followed to resolution (return to baseline) or stabilization, with the frequency of repeat 
evaluations determined by the clinical significance of each event. Additional evaluations beyond 
those listed in the Schedules of Evaluations (see Appendix I) may be performed at the discretion 
of the site investigator to determine the etiology of a given event and/or further assess its severity 
or relationship to study product. In some instances, and per CMC guidance, a PK sample should 
also be collected. Clinical management of all adverse events should be provided consistent with 
the best medical judgment of the site investigator and local clinical practice standards.  
 
Adverse events that are ongoing at the time of the final study visit, particularly those of Grade 3 
or higher severity, should generally be followed to resolution or stabilization by the site 
investigator; if this is not possible, the site investigator should actively facilitate referral to local 
non-study sources of appropriate medical care and treatment. Unless otherwise specified, when 
management of an adverse event requires consultation with the CMC, the CMC should be 
contacted as soon as possible and within two business days of site awareness of the event. 
 
8.1.1 
General Management of Adverse Events 
 
Sections 8.1.2–8.1.10 provide detailed participant and study product management on specified 
adverse events and abnormal laboratory test result values. If an observed adverse event or 
abnormal laboratory test result value is not listed in those sections below, the guidance in this 
section (General Management of Adverse Events) should be followed.  
 
In general, the IoR or designee has the discretion to temporarily hold study product at any time if 
s/he feels that continued product use would be harmful to the participant or interfere with 
treatment deemed clinically necessary. See Sections 8.6 and 8.7 below. 
 
• 
Grade 1 or Grade 2, regardless of relationship to study product:  continue study product 
and manage participant according to standard of care practice at the site. 
 
• 
Grade 3 assessed as not related:  continue study product and re-evaluate participant at least 
weekly until improvement to Grade 2 or lower. If improvement to Grade 2 or lower cannot be 
documented in 2 weeks, consult the CMC. 
 
• 
Grade 3 assessed as related:  temporarily hold study product use, notify the CMC, and re-
evaluate the participant at least weekly until improvement to Grade 2 or lower. If within 2 
weeks the AE has improved to Grade 2 or lower, study product may be resumed. Consult the 
CMC if improvement to Grade 2 or lower cannot be documented within 2 weeks 
o If study product use is resumed and the same Grade 3 AE deemed related to study 
product, recurs at any time, the IoR/designee must temporarily hold study product and 
consult the CMC for further guidance on continuing the temporary hold or progressing 
to permanent discontinuation of the study product. 
 
• 
Grade 4 regardless of relationship to study product:  temporarily hold study product, re-
evaluate the participant as soon as possible or within 2 business days, and consult the CMC.  
Continue the temporary product hold until a recommendation is obtained from the CMC 
  


 
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8.1.2 
Injection Site Reactions (ISRs)  
 
An ISR is defined as an adverse event which, in the opinion of the IoR or designee, results in pain 
out of proportion of what would be expected when a person gets an intramuscular injection, 
tenderness, erythema, redness, induration or swelling, or pruritis, regardless of when it occurs 
after administration of an injection. ISRs should be assessed and reported per the Site Reactions 
to Injections and Infusions section of the DAIDS toxicity tables. 
 
Participants with ISRs should be managed as follows, regardless of relationship to study product: 
• 
Grade 1 or Grade 2:  continue study product, and manage the participant symptomatically 
(e.g. cold/warm compress, acetaminophen, ibuprofen)  
 
• 
Grade 3 or 4:  consult the CMC to determine etiology and study product management  
 
Procedural pain and/or discomfort from the needle or from the volume of the suspension entering 
the tissue at the time of injection that is normal and expected with an intramuscular (IM) 
injection, in the opinion of the investigator, is not considered an adverse event or an ISR. See the 
IMPAACT 2017 MOP for more details related to procedural pain and Injection Site Reactions 
(ISRs). 
 
8.1.3 
Suspected Maladministration of Injectable Study Product and/or Post-Injection Reaction 
 
In the event that a participant experiences a serious post-injection reaction or IM 
maladministration is suspected at any time (e.g., suspected under or overdose or inadvertent IV 
dosing), the investigator should request that the participant stay onsite for approximately 2-3 
hours post-dose for safety monitoring. An ECG or any other supportive testing may be obtained 
at the discretion of the investigator. Additionally, a PK sample (4 mL) should be drawn 
approximately 2 hours post-dosing for evaluation of CAB and RPV plasma concentrations. The 
CMC should be consulted for additional guidance on participant safety management within 24 
hours after a suspected maladministration and/or suspected post-injection reaction event. 
Additional safety labs may be requested by the CMC or collected per investigator discretion. 
 
8.1.4 
Creatine Kinase (CK/CPK) Elevation  
 
All participants with elevated CPK results from baseline should be assessed for a history of use of 
drugs known to cause increase of CPK (such as statins), and/or physical activity or exercise 
preceding the CPK sample collection. Participants should abstain from exercise for more than 24 
hours and be well hydrated prior to any repeat sample collection. 
 
• 
Grade 1 or 2:  continue study product. 
 
• 
Grade 3:  continue study product and repeat testing from a new sample within 14 days. If the 
repeat test result is Grade 3 or higher, consult the CMC within 48 hours. 
 
• 
Grade 4, with no signs/symptoms of rhabdomyolysis:  continue study product and repeat 
testing from a new sample within 7 days, and after the participant has abstained from exercise 
for >24 hours. If the repeat test result is Grade 2 or lower, manage per grade. If the repeat test 
result is Grade 3 or higher, consult the CMC within 48 hours for further guidance on study 
product and participant management.  
 


 
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• 
Grade 4, with signs/symptoms of rhabdomyolysis: For Grade 4 CPK elevations that are in 
the opinion of the IoR associated with signs/symptoms of rhabdomyolysis (such as myalgias, 
muscle pain, dark urine, or clinically significant changes in creatinine clearance), temporarily 
hold study product, repeat testing from a new sample within 7 days, and consult the CMC 
within 48 hours for further guidance on study product and participant management.  
 
8.1.5 
Lipase Elevations and Pancreatitis  
 
Participants with asymptomatic elevations in lipase should be managed as follows, regardless of 
relationship to study product: 
 
• 
Grade 1 or 2:  continue study product, and be followed for development of symptoms (i.e. 
pancreatitis) according to standard of care practice at the site.  
 
• 
Grade 3 or higher:  temporarily hold study product, and repeat testing on a newly obtained 
sample within 2 weeks. If the repeat test result is Grade 2 or lower, resume study product. If 
upon resuming study product lipase elevation is Grade 3 or higher, permanently discontinue 
study product. If the repeat test result is Grade 3 or higher, and in the absence of other 
diagnoses, permanently discontinue study product.  
 
Participants with a confirmed diagnosis of clinical pancreatitis (i.e., symptomatic elevations in 
lipase) should be managed as follows:  
 
• 
Grade 2 or higher assessed as not related:  temporarily hold study product, notify the CMC 
within 48 hours, and re-evaluate the participant weekly until complete resolution (i.e. return 
to baseline). Upon returning to baseline, resume study product and re-evaluate the participant 
every 2 weeks for at least 6 weeks. If after resuming study product, any elevation of lipase of 
Grade 2 or higher, or any recurrence of symptoms, then permanently discontinue study 
product. 
 
• 
Grade 2 or higher assessed as related:  permanently discontinue study product, and notify 
the CMC.  
 
8.1.6 
Elevations in ALT (or AST), Bilirubin 
 
This section provides guidance on study product and participant management due to elevations in 
ALT (or AST), including considerations of accompanying bilirubin test results. Participants with 
an abnormal total bilirubin test result should have serum bilirubin fractionation (i.e. direct 
bilirubin) testing requested (ideally from the same sample - i.e. automatic fractionation - if raised 
bilirubin results), regardless of whether they are on an atazanavir-containing regimen.  
Confirmatory repeat testing should be performed, at the timepoints indicated below (if ALT or 
AST is also elevated) or per CMC consultation (if ALT or AST is normal).  
 
In all cases of elevated ALT (or AST) and/or elevated bilirubin (total or direct), possible 
alternative etiology should be assessed, and the underlying illness treated, or the likely causative 
agent removed. 
 
As noted in Section 7.1.1, the CMC must be informed of any Grade 3 or higher total bilirubin, 
unless isolated atazanavir related hyperbilirubinemia with normal direct bilirubin. Note that to 
assess total hyperbilirubinemia as atazanavir-related, demonstration of a normal direct bilirubin is 


 
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needed. Asymptomatic Cohort 1 participants on an atazanavir-containing cART regimen, who 
present with hyperbilirubinemia (any grade) with a normal direct bilirubin, normal ALT (or 
normal AST), and no other alternate etiology for the unconjugated hyperbilirubinemia, may 
continue study product use in consultation with the CMC.  
 
ALT or AST SEVERITY GRADE WITH 
ACCOMPANYING BILIRUBIN SEVERITY 
GRADE (TOTAL OR DIRECT) 
PARTICIPANT AND STUDY PRODUCT 
MANAGEMENT 
Grade 1 ALT (or AST), and/or Grade 1 
bilirubin 
Continue study product use, and repeat testing at 
the next scheduled study visit, or more frequently 
at the discretion of site investigator. 
 


 
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ALT or AST SEVERITY GRADE WITH 
ACCOMPANYING BILIRUBIN SEVERITY 
GRADE (TOTAL OR DIRECT) 
PARTICIPANT AND STUDY PRODUCT 
MANAGEMENT 
 
Grade 2 ALT (or AST) 
 
• 
With ≤ Grade 1 bilirubin (at the Week 4a 
visit): Continue study product use, and repeat 
testing within 72 hours. If repeat test results 
return to baseline, continue per study visit 
schedule (see Sections 6.3.3, and 6.4.3). If 
repeat test results in Grade 2, consult the 
CMC immediately and manage per CMC 
guidance. 
 
• 
With ≤ Grade 1 bilirubin (all visits except the 
Week 4a visit):  Continue study product use, 
and repeat testing weekly. If still Grade 2 
ALT (or AST) after 4 weeks, consult the 
CMC. 
 
• 
With Grade 2 or higher bilirubin:  Hold study 
product, and repeat testing weekly. If repeat 
test results of both ALT (or AST) and 
bilirubin return to baseline, resume study 
product use, inform the CMC, and continue to 
monitor per applicable Schedule of 
Evaluations. If after 4 weeks repeat test results 
of ALT (or AST) is still ≥ Grade 2, and/or 
bilirubin is still ≥ Grade 1, continue to hold 
study product and consult the CMC. 
 
• 
If baseline ALT (or AST) was ≤ ULN and 
participant is symptomatic (i.e. has nausea, 
abdominal discomfort or anorexia), regardless 
of accompanying bilirubin test results:  Hold 
study product, and repeat testing weekly. If 
repeat test results of ALT (or AST) return to 
baseline, resume study product use, inform the 
CMC, and continue to monitor per applicable 
Schedule of Evaluations. If after 4 weeks 
repeat test results are still Grade 2 ALT (or 
AST), continue to hold study product and 
consult the CMC. 
 


 
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ALT or AST SEVERITY GRADE WITH 
ACCOMPANYING BILIRUBIN SEVERITY 
GRADE (TOTAL OR DIRECT) 
PARTICIPANT AND STUDY PRODUCT 
MANAGEMENT 
Grade 3 ALT (or AST), regardless of 
accompanying bilirubin test result 
Hold study product, inform the CMC within 24 
hours, and repeat testing within 72 hours.  
 
Reinforce participant awareness and knowledge 
about signs and symptoms of hepatotoxicity. 
Participants should be advised to notify the study 
site immediately if they develop any concerning 
signs or symptoms: new or worsening nausea, 
vomiting, unexplained loss of appetite; yellowing 
of the skin or eyes; increased weakness or fatigue; 
pain in the upper abdomen (liver tenderness or 
hepatomegaly); pale or clay-colored stools; and/or 
unexplained weight loss. Participants should be 
advised to seek immediate medical attention and 
contact the site as soon as possible. 
 
• 
If repeat test results in ≤ Grade 2 without 
addressing possible alternative etiology, 
manage as per Grade 2 above.  
 
• 
If upon addressing possible alternative 
etiology repeat test results in ≤ Grade 2, 
consult CMC. If CMC agrees, resume study 
product. If event recurs at ≥ Grade 3, 
permanently discontinue study product and 
inform CMC. 
 
• 
If repeat test results in ≥ Grade 3, continue to 
hold study product and consult the CMC. If no 
possible alternative cause identified, 
permanently discontinue study product. 
 


 
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ALT or AST SEVERITY GRADE WITH 
ACCOMPANYING BILIRUBIN SEVERITY 
GRADE (TOTAL OR DIRECT) 
PARTICIPANT AND STUDY PRODUCT 
MANAGEMENT 
Grade 4 ALT (or AST), regardless of 
accompanying bilirubin test result 
Hold study product, inform the CMC within 24 
hours, and repeat testing within 72 hours.  
 
Reinforce participant awareness and knowledge 
about signs and symptoms of hepatotoxicity. 
Participants should be advised to notify the study 
site immediately if they develop any concerning 
signs or symptoms: new or worsening nausea, 
vomiting, unexplained loss of appetite; yellowing 
of the skin or eyes; increased weakness or fatigue; 
pain in the upper abdomen (liver tenderness or 
hepatomegaly); pale or clay-colored stools; and/or 
unexplained weight loss. Participants should be 
advised to seek immediate medical attention and 
contact the site as soon as possible. 
 
• 
If repeat test results in ≤ Grade 2, manage as 
per Grade 2 above. 
 
• 
If repeat test results in Grade 3, manage as per 
Grade 3 above. 
 
• 
If repeat test result is still Grade 4, inform 
CMC and permanently discontinue study 
product. 
 
 
8.1.7 
Hypersensitivity Reaction 
 
Hypersensitivity includes a constellation of symptoms such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia. 
 
If the IoR or designee suspects hypersensitivity reaction, regardless of relationship to study 
product, the participant should be managed as follows: 
 
• 
Grade 1 or higher:  temporarily hold study product, and within 24 hours of site awareness 
repeat hematology and chemistries testing on newly obtained samples, and notify the CMC. 
Continue to re-evaluate the participant, and repeat testing on newly obtained samples at least 
twice weekly until the abnormal laboratory test results return to baseline values, or stabilize. 
Refer participant to a specialist or hepatology consultation, at the discretion of the site 
investigator, and in consultation with the CMC. 
 
8.1.8 
Allergic Reaction  
 
Participants with allergic reactions should be managed as follows: 
 


 
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• 
Grade 1 or higher assessed as not related, and Grades 1 or 2 assessed as related:  
continue study product, and antihistamines, topical corticosteroids, or antipruritic agents may 
be prescribed at the discretion of the IoR or designee. The participant should be advised to 
contact the site immediately if there is any worsening of symptoms or if further systemic 
signs or symptoms develop.  
 
• 
Grade 3 or higher assessed as related:  permanently discontinue study product, and notify 
the CMC within 24 hours. Manage as clinically appropriate including antihistamines, topical 
corticosteroids, or antipruritic agents. Admission to hospital may be required for severe 
allergic reactions. Following clinical stabilization, re-evaluate the participant weekly, and 
manage according to standard of care practice at the site until resolution to baseline. 
  
8.1.9 
Skin Rash 
 
All participants experiencing a rash should be assessed for systemic symptoms, laboratory 
abnormalities, or mucosal involvement.  
 
Participants with skin rash should be managed as follows, regardless of relationship to study 
product: 
 
• 
Grade 1 (regardless of systemic involvement), or Grade 2 without evidence of systemic 
involvement:  continue study product use at the discretion of the site investigator.  
 
• 
Grade 2 with evidence of systemic involvement, or Grade 3 or higher (regardless of 
systemic involvement):  permanently discontinue study product, and consult the CMC 
within 48 hours. Re-evaluate daily for at least 5 days for systemic symptoms, laboratory 
abnormalities, mucosal involvement, and for any progression of the rash or increase in 
severity. Cohort 1 participants should also discontinue their cART regimen, at the discretion 
of the site investigator and in consultation of the CMC. Participants may be referred to a 
dermatologist, at the discretion of the site investigator. 
 
Additionally, for any rash determined to be related to study product and presenting prior to the 
Week 4b visit (for both Cohort 1 and Cohort 2A participants), the CMC must be consulted prior 
to administering injectable study product at the Week 4b visit.  
 
8.1.10 Depression, Suicidal Ideation or Attempt 
 
Participants with HIV may occasionally present with symptoms of depression and/or suicidal 
ideation or behavior. Participants who experience symptoms of depression and/or suicidal 
ideation or behavior, or report delusions and inappropriate behavior, regardless of relationship to 
study product, should be managed and re-evaluated according to standard of care practice at the 
site, or more frequently, or referred for specialist evaluation and treatment, at the discretion of the 
site investigator. Refer to the IMPAACT 2017 MOP for additional guidance regarding 
establishing a baseline screening assessment for depression. Participants reporting new symptoms 
of depression will be asked to contact the study IoR or designee immediately if symptoms of 
severe acute depression (including suicidal ideation/attempts) develop. All sites should have a 
plan in place for managing possible risks for suicide related events.  
 
• 
Grades 1 or 2: manage per site standard of care and SOPs.  


 
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• 
Grade 3 or higher: manage per site standard of care and SOPs, and consult the CMC within 
24 hours 
 
8.2 
Management of QTc Prolongation 
 
Management of QTc Prolongation 
 
See Section 6.12 for QTc intervals requiring repeat readings.  
• 
If any one of the repeated readings confirm a QTc interval (for QTcB: > 500 msec or a ≥ 60 
msec increase from baseline; for QTcF: ≥ 500 msec or > 60 msec increase from baseline), 
temporarily hold study product and assess participant for concomitant medications known to 
cause prolonged QT or Torsades de pointes.  
• 
If the prolonged QTc is assessed as not related, study product may be resumed in consultation 
with the CMC. 
• 
If the prolonged QTc is assessed as related, or no other likely cause identified, permanently 
discontinue study product.  
 
For any other abnormality or irregularity reported by the automated read during follow-up that is 
considered clinically significant by the qualified site clinician, a cardiologist should be consulted, 
and the CMC notified. 
 
8.3 
Management of Contraception and Pregnancy 
 
Participants of childbearing potential must agree to maintain use of an allowable effective 
contraceptive method throughout study participation, in addition to: 
 
• 
at least 30 days after discontinuation of oral study products (if terminating early from the 
study during Cohort 1 Step 1 or Cohort 2A Step 3), and  
• 
at least 48 weeks after discontinuation of injectable study products.    
 
Counseling should begin during the screening visit and continue for each participant throughout 
their participation in the study.  See Section 6.13 for more details on pregnancy testing, 
contraceptive counseling, and a list of the allowable effective contraception methods.  
 
For all participants assigned female at birth, a negative pregnancy test result must be obtained on 
the same day and prior to administration of study product. For participants of childbearing 
potential, confirmation of contraceptive use (per participant report) must also be obtained on the 
same day and prior to administration of study product. If effective contraception cannot be 
confirmed, and in the opinion of the investigator early pregnancy cannot be excluded, then study 
product should be temporarily held, and the CMC consulted for further guidance on study product 
use and participant management.  
 
Participants with a positive pregnancy test result will temporarily discontinue study product, with 
confirmatory testing conducted within 48 hours. Upon a confirmatory positive pregnancy test 
result, study product will be permanently discontinued; Cohort 2 participants will resume an oral 
cART regimen. The choice of cART regimen is at the site investigator’s discretion and in 
accordance with the local standard of care and available resistance profiles, and appropriate for 
use in pregnancy. Sites should actively refer pregnant participants to antenatal standard of care, 
and to engage in antenatal care as early in the pregnancy as possible. Additionally, the CMC 
should be notified within 2 weeks of obtaining the initial positive pregnancy test result. 


 
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Pregnant participants will be followed per the LSFU visit schedule based on the date of the 
positive confirmatory test result. Pregnant participants already being followed per the LSFU visit 
schedule will continue their scheduled visits, however any pregnancy outcome occurring after 
study exit will be entered into eCRFs, as further described below.    
 
Pregnancy test results and pregnancy outcomes will be ascertained and entered into eCRFs. 
Pregnancy outcomes should be ascertained based on medical records; when medical records are 
unavailable, maternal report may be used. For participants who are pregnant at the time of study 
exit, or early study termination, additional post-study contacts should be completed to ascertain 
their pregnancy outcomes (see Section 6.8). If the site becomes aware of a pregnancy 
complication occurring after the participant has exited the study, and the pregnancy complication 
is assessed as related to study product, the CMC should be notified within 2 weeks of site 
awareness. 
 
Study sites will also be encouraged to prospectively register the participant’s pregnancy in the 
Antiretroviral Pregnancy Registry: http://www.apregistry.com/ (in US: 1-800-258-4263).  
 
8.4 
Monitoring and Management of HIV Viral Load 
 
Monitoring 
 
HIV-1 RNA (viral load) will be monitored closely with frequent testing as specified in the 
Schedules of Evaluations in Appendix I. All HIV-1 RNA assays must be performed in a CLIA-
certified or equivalent (US sites) or VQA-certified (non-US) laboratory using the testing platform 
specified in the LPC.  
 
Site investigators should review the results of each test as well as trends over time and consult 
with the CMC regarding any individual test results or trends of concern. As noted in Section 6.6, 
viral load results should be provided to participants and may be used to guide adherence 
counseling. 
 
Definition and Confirmation of Virologic Failure 
 
Virologic failure is defined as two successive plasma HIV-1 RNA test results ≥200 copies/mL. 
 
Any participant with a plasma HIV-1 RNA level ≥200 copies/mL after enrollment should be 
recalled to the clinic for confirmatory testing 2-4 weeks after specimen collection for the initial 
test. Specimen collection for antiretroviral resistance testing and other procedures will also be 
performed at the time of specimen collection for confirmatory HIV-1 RNA testing. Refer to 
Section 6.6 for more details regarding the visit procedure and scheduling of the Confirmation of 
Virologic Failure visit. 
 
Management of Confirmed Virologic Failure 
 
The CMC should be consulted regarding any participant with confirmed virologic failure. All 
participants with confirmed virologic failure will be permanently discontinued from study 
product. Refer to Section 8.7 for participant management regarding permanent discontinuation of 
study product, and Section 6.5 for those participants who will be followed per the LSFU visit 
schedule upon permanent discontinuation of study product. 
 


 
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HIV genotypic and phenotypic resistance samples will be processed, stored, and shipped per 
Section 6.16.2 and the LPC. Upon confirmation of virologic failure, testing of resistance samples 
will be performed in real time, per Section 6.16.2 and the LPC. These resistance test results will 
be reviewed by the site investigator of record, or designee, and used to inform a recommended 
cART regimen, in consultation with the CMC. Cohort 1 participants may be recommended to 
change their ongoing cART regimen, based on these results. Cohort 2 participants should resume 
the recommended non-study provided oral cART as soon as possible and within 4 weeks. 
 
8.5 
Substitution or Dose Modification of cART for Cohort 1 Participants 
 
Cohort 1 participants will continue their pre-study cART regimen while receiving study products 
in both Step 1 and Step 2. Dose changes for growth are permitted. In the event that a change or 
substitution is required for an acute safety event that requires regimen changes (e.g., renal 
compromise on TDF for which alternative NRTI is sought), sites should consult CMC for 
guidance for drugs that can be co-administered. Cohort 1 participants will be permanently 
discontinued from study product use if a cART regimen change is required that would affect 
Cohort 1C vs Cohort 1R assignment.  
 
8.6 
Deferring Study Product and Criteria for Temporary Hold of Study Product 
 
At each study product administration time point, the site investigator or designee must confirm 
participant eligibility to receive study product based on review of medical and medications 
history, physical examination findings, and prior laboratory test results (see Section 6.9). Study 
product administration must be deferred consistent with the guidance provided in Section 8.  
 
For any other significant medical condition that, in the opinion of the investigator, would make it 
unsafe to administer study product or make it difficult to assess for subsequent product related 
adverse events, if present on the scheduled day of study product administration, administration 
must be deferred, and the CMC should be consulted on next steps and continued study product 
management. 
 
For Cohort 2 participants who have a temporary hold, both study products should be held, and the 
CMC should be consulted as soon as possible and within 48 hours of site awareness; the CMC 
may recommend resuming a (non-study provided) cART regimen in these situations. For 
participants resuming a cART regimen for the duration of a temporary study product hold, site 
staff should provide the participant and the participant’s parent or guardian with referrals to non-
study sources of treatment for the participant, as applicable. See the IMPAACT 2017 MOP for 
operational consideration and guidance. 
  
Study product will be temporarily held from a participant for any of the following reasons: 
 
• 
Study product management per Sections 8.1 through 8.5. 
 
• 
Report of use of prohibited concomitant medications (as listed in Section 5.7). Study product 
use may resume upon consultation with the CMC and when the participant reports that he/she 
is no longer taking the prohibited medication, provided other reasons for temporary study 
product hold/permanent discontinuation do not apply. The CMC should be consulted in all 
cases of a participant reporting taking a prohibited concomitant medication during the course 
of the study. 
 


 
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• 
The participant is unable or unwilling to comply with required study procedures, such as 
protocol-required laboratory assessments or injectable study product visits, or otherwise 
might be put at undue risk to their safety and well-being by continuing study product use, 
according to the judgment of the site investigator. The site investigator must consult the CMC 
on all temporary study product holds instituted for this reason, for further guidance on 
resuming study product use, continuing the temporary hold, or progressing to permanent 
discontinuation. 
 
Participants who temporarily or permanently discontinue oral study product during the oral phase 
(Step 1 or Step 3), or during oral bridging (in Step 4 or Step 5) will be instructed to return all oral 
study products to the site clinic as soon as possible.  
 
8.7 
Criteria for Premature Permanent Discontinuation of Study Product  
 
See Section 8.8 for guidance regarding participant management in the event of early termination 
or withdrawal from study participation. Administration of study product will be permanently 
discontinued in the following circumstances:  
 
• 
Participant intention to discontinue study product or study follow-up 
• 
During the oral phase (Cohort 1 Step 1, or Cohort 2A Step 3), sustained non-adherence to 
oral regimen (study product, or non-study provided cART for Cohort 1 participants) that, in 
the opinion of the investigator and in consultation with the CMC, warrants early study 
product discontinuation. 
• 
Sustained non-adherence to injection visit schedule that, in the opinion of the investigator and 
in consultation with the CMC, warrants early study product discontinuation (per IoR 
discretion, a temporary product hold may be initially implemented; see Section 8.6). 
• 
The participant requires treatment with prohibited medications (see Section 5.7). 
• 
Pregnancy (see Section 8.3) 
• 
The participant experiences an adverse event that requires discontinuation as defined in 
Sections 8.1 through 8.5. 
• 
Virologic failure as described in Section 8.4. 
• 
The site investigator determines that further administration of study product would be 
detrimental to the participant’s health or well-being. 
• 
New data become available that indicate study products should be discontinued as determined 
by the CMC.  
 
In the event of premature permanent discontinuation of study product, participants will either be 
followed per the LSFU visit schedule or complete an Early Termination visit, as described below. 
For Cohort 2 participants, in the event of a permanent discontinuation of study product, both 
study products will always be discontinued, and participants should immediately resume (non-
study provided) oral cART.  
 
See Section 6.5 for the specified participants who will be followed per the LSFU visit schedule 
upon permanent discontinuation of study product. 
 
Cohort 1 Step 1 and Cohort 2A Step 3 participants (without prior Cohort 1 Step 2 participation) 
not eligible to progress to their respective injection phase will complete an Early Termination 
visit upon permanent discontinuation of study product.   
 


 
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8.8 
Participant Withdrawal or Termination from the Study 
 
Regardless of the participant retention procedures referenced in Section 4, participants may 
voluntarily withdraw from the study. Participants may also be terminated from the study by the 
site investigator or designee under the following circumstances: 
 
• 
Participant re-locates away from the study site, is otherwise determined to be lost-to-follow-
up, or withdraws consent/assent 
• 
Investigator or designee determines that continued participation in the study would be unsafe 
or otherwise not in the best interest of the participant, after consultation with the CMC 
• 
The study is stopped or canceled at the discretion of the FDA, IMPAACT, the site IRB or 
EC, US Office for Human Research Protection (OHRP), NIAID, NICHD, or other country-
specific governmental agencies 
 
A participant may voluntarily discontinue study participation at any time, and the site investigator 
may also, at their discretion, discontinue the participant from the study at any time. Participants 
who are withdrawn from the study will not be replaced.  
 
Should the consenting parent or guardian of an enrolled participant die or no longer be available 
for any reason, study product should be temporarily held and no further study products should be 
administered, cART resumed for Cohort 2 participants, and no further study-specific evaluations 
should be performed until informed consent for continued study participation is obtained from an 
authorized guardian, as defined locally. Study sites may continue to provide care for the 
participant as needed and as appropriate (outside of the study), consistent with the local standard 
of care, but no study-specific procedures may be performed. If an authorized guardian cannot be 
identified, or if the authorized guardian does not consent to continued study participation, the 
participant must be terminated from the study. Refer to Section 8.6 for additional guidance on 
communication with the CMC for temporary study product holds, and Section 14.3 for guardian 
consent for study participation. 
 
For any participant who withdraws/is withdrawn or is terminated from the study prior to 
scheduled completion of follow-up, study staff will document the reason for the withdrawal or 
termination in detail and will make every effort complete final evaluations as described in Section 
0. In the event that the circumstances that led to a participant’s withdrawal or termination change 
(e.g., he or she returns to the study site area after having re-located previously), the site 
investigator or designee should contact the CMC to discuss options for resumption of follow-up. 
 
 
9 
STATISTICAL CONSIDERATIONS 
 
For all PK-related matters, including PK endpoints, outcome measures and analyses, refer to 
Section 10. 
 
9.1 
General Design Issues 
 
This is a Phase I/II, multi‐center, open‐label, non‐comparative dose-finding study with the 
primary objective of evaluating the safety, acceptability, tolerability, and pharmacokinetics of 
oral CAB and CAB LA as well as RPV LA in children and adolescents 12 to <18 years of age 
living with HIV who are virologically suppressed. 
 


 
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This statistical section describes the methodology and analyses planned for the primary endpoints 
and outcome measures with respect to safety and the secondary endpoints and outcome measures 
other than PK. Please refer to Section 10 for all matters which deal with pharmacokinetics (PK), 
including the outcome measures and primary analyses, in more detail.  
 
It is expected that up to 55 participants will be enrolled into Cohort 1 to achieve approximately 
15-20 dose-evaluable for CAB and approximately 15 dose-evaluable for RPV, with CAB and 
RPV to be evaluated separately in this stage of the study. Most (or all) of these participants are 
expected to proceed to Cohort 2, where they will take the full regimen (CAB + RPV), consisting 
of both products. There is not a restriction (minimum or maximum) on the number of eligible 
Cohort 1 participants allowed to proceed to Cohort 2, to provide the most flexibility in study 
design. It is expected that 100 additional participants will need to be enrolled directly into Cohort 
2 to achieve an approximate additional 70 evaluable participants receiving the final recommended 
dose of CAB and RPV. This sample of participants (approximately 100 for 70 evaluable) will be 
treated as the primary subgroup of Cohort 2 participants, since their results will generalize to the 
population of patients who would be treated by simultaneous exposure to the two study products 
without a prior period of exposure to one or the other as in Cohort 1.  
 
For analysis purposes, evaluable participants will be defined as having been treated exclusively 
on the final recommended dose for a given cohort and (1) having either completed all treatment 
regimen through the said week periods (Week 4, Week 16 for Cohort 1, Week 24 for Cohort 2A, 
Week 20 for Cohort 2B), or (2) having experienced any of the following:  
•     death that is attributable to the study product/s, OR 
•     study product-related Grade 3+ events (excluding injection-site Aes) OR 
•     permanently discontinued from treatment due to study product-related toxicities (regardless 
of grade) during these weeks of treatment.  
 
Dose-evaluable participants for dose-finding purposes are defined in Section 9.5.1.3.  
 
Although oral bridging in Cohort 2 will not be counted as a substitute for an injection, the 
participant will be considered evaluable following the definition given above as long as the 
recommended injectable total dosing has been given through Week 24 (for Cohort 2A) and 
through Week 20 (for Cohort 2B), even if they were out of window. For participants requiring 
more than one injection visit to receive full injectable treatment dosing, the participant will also 
be considered evaluable following the definition given above, if the recommended injectable total 
dosing has been given through Week 24 (for Cohort 2A) and through Week 20 (for Cohort 2B) 
within the injection visit window. 
 
In making dosing decisions, the protocol team will review Cohort 1 safety data, as well as the 
results of PK data (modeling data as needed). Please refer to Section 9.5.1.3 (Dose 
Finding/Confirmation) for the dose-finding algorithm and the safety guidelines for making dosing 
decisions. 
 
To assess the acceptability and tolerability of the study products based on the perceptions of 
parents and caregivers, up to 60 parents or caregivers of the adolescent participants, as selected 
by the protocol team, will be accrued to complete a single qualitative phone interview. 
 
9.2 
Outcome Measures 
 
For all PK-related matters, including PK outcome measures and analyses, refer to Section 10. 
 


 
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For safety monitoring and reporting purposes, a study product related AE is defined as an adverse 
event that is judged (based on attribution by the site with concurrence from the CMC) to be 
related to the study products (CAB/RPV). To document the attribution concurrence or lack 
thereof, the CMC assessment will be collected.  
 
Primary and secondary outcome measures listed below will be addressed in the study’s primary 
Statistical Analysis Plan, which will define the content of the Primary Analysis Report. This 
report will form the basis for the primary study manuscript, results reporting to 
ClinicalTrials.gov, and supporting the drug development in adolescence population. Outcomes of 
interest intended for subsequent publications are listed under “Other Outcome Measures”. 
 
9.2.1 Primary Endpoints and Outcome Measures 
9.2.1.1 
Safety through Week 4 for oral CAB, through Week 16 (CAB LA or RPV LA) for 
Cohort 1 
• Safety Outcome: All adverse events, regardless of grade 
• Number of participants who: 
o Had Grade 3 or higher adverse events 
o Had Grade 3 or higher adverse events assessed as related to study 
product/s 
o Had serious adverse events meeting ICH criteria assessed as related to 
study product/s 
o Permanently discontinued study product due to adverse events assessed as 
related to study product/s   
o Died due to adverse events assessed as related to study product/s 
9.2.1.2 
Safety through Week 24 for Cohort 2A (oral followed by injectable); through Week 
20 for Cohort 2B (injectable only) 
• Safety Outcome: All adverse events, regardless of grade 
• Number of participants who: 
o Had Grade 3 or higher adverse events 
o Had Grade 3 or higher adverse events assessed as related to study 
product/s 
o Had serious adverse events meeting ICH criteria assessed as related to 
study product/s 
o Permanently discontinued study product due to adverse events assessed as 
related to study product/s   
o Died due to adverse events assessed as related to study product/s 
9.2.2 Secondary Endpoints and Outcome Measures 
9.2.2.1 
HIV-1 RNA through Week 16 for Cohort 1 
• Number of participants with HIV-1 RNA < 50 copies/mL  
9.2.2.2 
Tolerability of CAB LA or RPV LA through Week 16 for Cohort 1 
• Tolerability measures will include measures of side effects, pain during and after 
injections, injection site reactions, and perceptions of injections from 
comprehensive surveys of adolescents 
 
Acceptability of CAB LA or RPV LA through Week 16 for Cohort 1 
• Acceptability measures will include assessments of motivation for changing 
regimens, satisfaction with treatment, preferences for injectable versus oral 
regimen, quality of life, changes in attitudes towards the study products from 
comprehensive surveys of adolescents  


 
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9.2.2.3 
Safety through Week 48 for Cohort 2A (oral followed by injectable); through Week 
44 for Cohort 2B (injectable only) 
• Safety Outcome: All adverse events, regardless of grade 
• Number of participants who: 
o Had Grade 3 or higher adverse events 
o Had Grade 3 or higher adverse events assessed as related to study 
product/s 
o Had serious adverse events meeting ICH criteria assessed as related to 
study product/s 
o Permanently discontinued study product due to adverse events assessed as 
related to study product/s   
o Died due to adverse events assessed as related to study product/s 
9.2.2.4 
Virologic activity of CAB LA+RPV LA through Weeks 24 and 48 for Cohort 2A 
(oral followed by injectable); through Week 20 and 44 for Cohort 2B (injectable 
only) 
• Outcome: Plasma HIV-1 RNA  
• Number of participants with HIV-1 RNA ≥50 copies/mL, HIV-1 RNA ≥200 
copies/mL, per snapshot algorithm  
9.2.3 Other Endpoints and Outcome Measures  
9.2.3.1 
Tolerability of CAB LA+RPV LA through Week 24, Week 48, and Week 96 for 
Cohort 2A (oral followed by injectable); through Week 20, Week 44, and Week 92 
for Cohort 2B (injectable only) 
• Tolerability measures will include measures of side effects, pain during and after 
injections, injection site reactions, and perceptions of injections from 
comprehensive surveys of adolescents 
 
Acceptability of CAB LA+ RPV LA through Week 24, Week 48, and Week 96 for 
Cohort 2A (oral followed by injectable); through Week 20, Week 44, and Week 92 
for Cohort 2B (injectable only) 
• Acceptability measures will include assessments of motivation for changing 
regimens, satisfaction with treatment, preferences for injectable versus oral 
regimen, quality of life, changes in attitudes towards the study products from 
comprehensive surveys of adolescents  
9.2.3.2 
Safety through Week 96 weeks for CAB LA+ RPV LA for Cohort 2A (oral 
followed by injectable); through Week 92 for Cohort 2B (injectable only) 
• Safety Outcome: All adverse events, regardless of grade 
• Number of participants who: 
o Had Grade 3 or higher adverse events 
o Had Grade 3 or higher adverse events assessed as related to study 
product/s 
o Had serious adverse events meeting ICH criteria assessed as related to 
study product/s 
o Permanently discontinued study product due to adverse events assessed as 
related to study product/s   
o Died due to adverse events assessed as related to study product/s 


 
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9.2.3.3 
Virologic activity of CAB LA+RPV LA through Week 96 for Cohort 2A (oral 
followed by injectable); through Week 92 for Cohort 2B (injectable only)  
• Outcome: Plasma HIV-1 RNA  
• Number of participants with HIV-1 RNA ≥200 copies/mL, missing HIV-1 RNA, 
study treatment discontinuations  
 
Immunologic activity of CAB LA+RPV LA through Week 96 for Cohort 2A (oral 
followed by injectable); through Week 92 for Cohort 2B (injectable only) 
• Outcome: CD4 count and percentage 
9.2.3.4 
Participants’ and parents/caregivers’ overall perceptions of their/their child’s 
experience with CAB LA and/or RPV LA for Cohorts 1 and 2 as elicited through 
in-depth interviews centered around an ecological model of health behavior 
9.2.3.5 
Tolerability through 48 weeks following permanent discontinuation of CAB LA or 
RPV LA for Cohort 1 and CAB LA+RPV LA for Cohort 2 
• Tolerability measures will include measures of side effects, pain during and after 
injections, injection site reactions, and perceptions of injections from 
comprehensive surveys of adolescents 
 
Acceptability through 48 weeks following permanent discontinuation of CAB LA 
or RPV LA for Cohort 1 and CAB LA+RPV LA for Cohort 2 
• Acceptability measures will include assessments of motivation for changing 
regimens, satisfaction with treatment, preferences for injectable versus oral 
regimen, quality of life, changes in attitudes towards the study products from 
comprehensive surveys of adolescents  
9.2.3.6 
Long-term safety through 48 weeks following permanent discontinuation of CAB 
LA or RPV LA for Cohort 1 and CAB LA+RPV LA for Cohort 2 
• 
Safety Outcome: All adverse events, regardless of grade 
• 
Number of participants who: 
o Had Grade 3 or higher adverse events 
o Had Grade 3 or higher adverse events assessed as related to study 
product/s 
o Had serious adverse events meeting ICH criteria assessed as related to 
study product/s 
o Died due to adverse events assessed as related to study product/s 
9.2.3.7 
HIV-1 genotype and phenotype resistance to CAB and/or RPV in participants 
experiencing confirmed virologic failure (defined in Section 9.6.3) in both Cohort 1 
and Cohort 2 
 
9.3 
Randomization and Stratification 
 
There will be no randomization for Cohorts 1 and 2. Participants for Cohort 1 will be placed into 
CAB or RPV arms based on suppressive oral cART at entry: participants on PI-based or NNRTI-
based cART will be assigned to Cohort 1C, while participants on INSTI-based cART will be 
assigned to Cohort 1R. In Cohort 2, participants will either receive oral CAB+RPV for 4 weeks 
followed by CAB LA +RPV LA Q8W (Cohort 2A) or directly receive CAB LA+ RPV LA Q8W 
(Cohort 2B) per participant’s preference.  
 
9.4 
Sample Size and Accrual 
 


 
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The sample size is the minimum number of participants, driven primarily by safety 
considerations, which is likely to be needed to determine the dosage across the possible weight, 
age and sex at birth distributions. Monte Carlo simulations based on existing PK models in adults 
with extrapolation to the study population characteristics were performed to estimate the 
variability for selected primary and secondary parameters and confidence intervals.  
 
(i) 
To ensure a Cohort 1 sample size able to provide precise estimates of apparent clearance 
(CL/F) consistent with the FDA guidelines for pediatric trials. Monte Carlo (MC) 
simulations incorporated adult CAB and RPV population PK model and the expected 
adolescent IMPAACT 2017 participant characteristics.  One hundred virtual PK trials 
were generated with 20 CAB and 15 RPV simulated participants for each study. Each 
simulated trial was analyzed independently for median PK parameter estimates (including 
CL/F) specific for that trial, resulting in 100 median values for each PK parameter. 
Confidence intervals of the individual median PK parameters (from each study) were 
generated from these 100 values. The 90% CI of the medians from the 100 simulated trial 
CAB CL/F estimates ranged from 0.84 -1.17 of the overall adolescent median CL/F value 
and no study estimated deviated from the overall median by > 25%. The corresponding 
90% CI for CAB median V/F estimates were 0.92-1.09 of the overall median V/F. For 
RPV the 90% CI for RPV CL/F was 0.86-1.15 of the overall adolescent median value. 
 
(ii) 
To ensure a sample size able to provide precise estimates of oral CAB AUC (Cohort 1C); 
CAB LA and RPV LA concentration at 28 days (C28D) (Cohort 1C and 1R). Simulated 
PK trials were also used to construct confidence intervals for these exposure parameters. 
For CAB, the AUC 90% CI ranged from 0.86-1.19 of the overall value and the C28D 
90% CI ranged from 0.80-1.29 of the overall value. For RPV LA the C28D 90% CI 
ranged from 0.80-1.29. While a few individual simulated participants had concentrations 
outside of target, all 100 of the virtual trials had median exposure parameters within the 
target range.  
 
Table 10 presents exact 95% confidence intervals around various potential rates of Grade 3+ AEs 
which might be observed in a total sample of 100 participants who might contribute data to the 
safety analysis, a minimum sample of 15 participants from Cohort 1C, a minimum of 15 
participants from Cohort 1R, a potential sample of 30 or 35 participants which represents the 
combined arms of Cohort 1, and a potential sample of 70 participants who enrolled directly into 
Cohort 2A or 2B and who will be regarded as the primary sample for the Cohort 2 safety 
assessment. This table indicates that confidence intervals will be quite wide around the sample 
size of 15 participants but would be considerably more precise around the target samples of 70 
primary or 100 overall Cohort 2 participants. 
 


 
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Table 10. Percent of Participants Experiencing ≥ Grade 3 Adverse Events (or ≥ Grade 3 
Adverse Events Attributed to the Study Medications) with Exact 95% Confidence 
Intervals 
N* 
n (%) With ≥ Grade 3 Adverse Events 
95% C.I. 
15 
0 (0%) 
0.00, 0.22 
20 
0 (0%) 
0.00, 0.17 
30 
0 (0%) 
0.00, 0.12 
35 
0 (0%) 
0.00, 0.10 
70 
0 (0%) 
0.00, 0.05 
100 
0 (0%) 
0.00, 0.04 
 
 
 
15 
3 (20%) 
0.04, 0.48 
20 
4 (20%) 
0.06, 0.44 
30 
6 (20%) 
0.08, 0.39 
35 
7 (20%) 
0.08, 0.37 
70 
14 (20%) 
0.11, 0.31 
100 
20 (20%) 
0.13, 0.29 
* Note: N refers to total sample size of possible sub-group analysis but note that dosing decisions 
will make use of all available data. 
 
9.5 
Monitoring 
 
Implementation of this study will be monitored at multiple levels, consistent with standard 
procedures described in the IMPAACT Network Manual of Procedures. A study monitoring plan 
that details monitoring roles and responsibilities and data to be reviewed at each level will be 
prepared before the study opens to accrual. Sections 12 and 13 provide more information 
concerning on-site monitoring and quality management at the site level. Further information on 
monitoring of study progress, quality of study conduct, and participant safety across sites is 
provided below. 
 
9.5.1 
Monitoring by the Protocol Team 
 
9.5.1.1 Study Progress and Quality of Study Conduct 
 
The Protocol Team is responsible for continuous monitoring of study progress, including timely 
achievement of key milestones, and the quality of study conduct.  
 
The team will closely monitor participant accrual and retention based on reports that will be 
generated at least monthly by the SDMC. The team has developed a study accrual plan that 
includes site-specific and total enrollment projections over the course of the accrual period, and 
actual accrual will be monitored relative to these projections. The team will monitor the timing of 
site-specific study activation, which will determine when each site will begin accruing 
participants, and accrual performance following activation. For any site that is delayed in 
completing the study activation process, or that falls short of its accrual projections, the team will 
communicate with the site to identify the barriers it has encountered and the operational strategies 
and action plans to address these.  
 
The Protocol Team will monitor participant retention in a manner similar to participant accrual. 
On behalf of the Protocol Team, the CMC will monitor other key indicators of the quality of 


 
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study conduct (e.g., adherence to study product regimen, data quality, and data and specimen 
completeness), based on reports generated by the SDMC, and will take action with study sites as 
needed to ensure high quality study conduct throughout the period of study implementation.  
 
9.5.1.2 Participant Safety 
 
On behalf of the Protocol Team, the CMC will closely monitor participant safety through routine 
review of safety reports generated by the SDMC. These reports will provide tabulations of 
adverse events specified for entry into eCRFs, as described in Section 7.2. The CMC will review 
these reports via conference call or other means at least monthly. At the time of each review, the 
DAIDS Medical Officer will also review any EAEs (defined in Section 7.3) reported to the 
DAIDS Safety Office that are not yet reflected in the data reports. The CMC will continually 
evaluate the pattern and frequency of reported events and will identify any individual issues or 
trends of concern.  
 
The CMC will assess the relationship of adverse events listed in toxicity summary reports and 
these assessments will be recorded by the SDMC. Except in the two specific scenarios listed in 
this section and in Section 9.5.2, the CMC’s assessments will not be used for study-related 
decision-making. 
 
The CMC will also monitor whether any of the safety-related triggers specified in Section 9.5.2 
are met. If so, the CMC will rapidly review the triggering events and notify the SMC that an ad 
hoc review is required. The CMC will likewise request SMC review of any other safety concerns 
that may be identified throughout the course of the study.  
 
9.5.1.3 Dose Finding/Confirmation 
 
During the dose finding/confirmation stages of this study (Cohort 1), the CMC will also review 
the pharmacokinetic data, with the aim of determining the appropriate dose of each product for 
Cohort 2, while protecting participant safety. The CMC will review PK and safety data reports at 
least monthly and take action as needed according to the guidelines in Section 10.3 (PK) and 
Section 9.5.1.2, Participant Safety, above. In addition, the CMC and relevant members of the 
protocol team in conjunction with the SMC will discuss any dose adjustment changes based on 
the PK (of cohort level data) and safety reviews. 
 
In the case of any pause to address safety concerns, participant accrual may be resumed if 
recommended by the CMC and SMC. 
 
For the purpose of dose-finding, dose-evaluable participants will be defined as participants 
having been treated exclusively on the dose being evaluated for a given cohort, and having either 
(1) completed all treatment regimen and completed Week 16 visit or (2) having experienced any 
of the following:  
• 
death that is attributable to the study product/s, OR 
• 
study product-related Grade 3+ events (excluding injection-site AEs) OR 
• 
permanently discontinued from treatment due to study product-related toxicities (regardless 
of grade) during the dose-finding period. 
 


 
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Dose Finding/Confirmation Algorithm 
 
Cohort 1 
 
The study will implement a dose-finding/confirmation algorithm separately for oral CAB/CAB 
LA and RPV LA based on PK and safety data through Week 16. The PK elements from this 
algorithm are based on CAB and RPV exposures seen in adult studies that maintain 
concentrations above the protein adjusted (PA) 90% inhibitory concentration (IC90). Cohorts 1C 
and 1R will each enroll an initial group of 7 dose-evaluable participants and their PK and safety 
data will be evaluated as follows: 
• 
If these 7 dose-evaluable participants meet the PK guidelines (see Section 10) and there are 
no safety concerns (see Safety Guidelines for the First 7 Participants Started at a Given Dose 
Level in Each Group in Cohort 1 below), then the oral/LA IM doses for CAB and LA IM 
doses for RPV in Cohort 2 will be established and Cohort 2 will be open to accrue for Cohort 
1 participants, following an interim analysis (see Section 9.5.2, Monitoring by the SMC).  
• 
If either group fails the safety or PK criteria and an alternative dose is determined by the 
study team to be needed to safely achieve necessary study product concentrations, another 
N=7 dose-evaluable participants will be enrolled into that group and administered a modified 
dose which will be evaluated as described above. 
• 
If there is more variability than expected in the PK results in each or both groups of Cohort 1, 
such that a confident determination regarding achievement of the PK targets cannot be made, 
an additional interim evaluation of the PK results will be done after additional 4 participants 
have been enrolled into the appropriate group/s of Cohort 1 to clarify the PK results as 
needed.  In this scenario, Cohort 2 accrual for Cohort 1 participants will be delayed until an 
interim analysis which includes these extra participants has been performed and Cohort 2 
dosing established by the study team.   
• 
Cohort 1 study enrollment and study procedures will not be interrupted for the preliminary 
PK and safety assessments to be performed on the first 7 dose-evaluable participants enrolled 
into each group. (Note: interim analysis #1 was conducted under protocol Version 2.0; see 
Section 1.3) 
• 
Once approximately 15-20 Cohort 1C participants and approximately 15 Cohort 1R 
participants who could contribute to the dose-finding algorithm have enrolled, and 80% of 
these participants have completed the Step 2 Week 8 visit, an interim analysis of all available 
safety and PK data will be conducted to determine if Cohort 2 accrual can be opened to 
study-naïve participants. Once all Cohort 1C and 1R participants complete Week 16 visit, the 
final analysis of all safety and PK data for Cohort 1 will be conducted to confirm the oral and 
LA IM doses for Cohort 2.  
 
Cohort 2 
 
Cohort 2 will begin to enroll, starting with the participants who passed Cohort 1, once the dosing 
of the oral/IM CAB and oral/IM RPV been established, based on data of the first 7 dose-
evaluable participants from Cohorts 1C and 1R, as described above. Once approximately 15-20 
participants in Cohort 1C and approximately 15 participants in Cohort 1R who could contribute to 
the dose-finding algorithm are enrolled with 80% of participants in each arm passing the Week 8 
visit, another interim analysis of the safety and PK data will be conducted and Cohort 2 will open 
to accrual for study-naïve participants if approved by SMC. 
 
Sparse PK sampling will be collected from Cohort 2 participants to further describe the oral/IM 
CAB and RPV exposure.  


 
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Safety Guidelines for the Evaluation of Cohort 1 Starting Doses 
 
The study site’s attribution of any serious adverse event to study product will be used for the 
purposes of employing the start, stop, and pause rules. However, when assessments will affect 
conduct of the study or dose-finding decisions, the CMC will review the AE and the site’s 
attribution. In an event of disagreement in assessments, the protocol team will try to reach a 
consensus with the site with respect to attribution. If this should prove impossible, the SMC will 
be consulted and will make the final judgment concerning the relationship between study 
product/s and the adverse event. Attribution of AE to study product will use the following 
terminology: ‘Not related’ and “Related”. 
 
Table 11 and Table 12 use a multinomial response model to assess the probability of failing the 
safety criteria under each of the hypothetical situations in those tables. The calculations are 
performed as follows: Each of the total number of participants represents a trial, which may have 
1 of 3 mutually exclusive outcomes: (1) a fatal or life threatening adverse event  assessed as 
related to study treatment; (2) a Grade 3+ adverse event (excluding injection site AEs), not 
satisfying the criteria set forth in #1, immediately above, but judged to be related to study 
treatment, or an adverse event assessed as related to study treatment resulting in termination of 
study treatment; and (3) a relatively benign outcome, satisfying neither the criteria in #1 nor #2, 
immediately above.  
 
Each table has its sets of results under which the set of trials would pass the safety criteria. The 
probability of passing the safety criteria represents the sum of the probabilities of these sets of 
results, and “1 minus the probability of passing the safety criteria” represents the probability of 
failing them. The “True Toxicity Rates” presented in the tables, along with the true rate of having 
neither of the types of toxicity represented by the true toxicity rates (which is 1 - the sum of the 
true toxicity rates), provide the probabilities for the outcomes which are used in the multinomial 
calculations for each of the hypothetical situations. 
 
Safety Guidelines for the First 7 Dose-evaluable Participants Started at a Given Dose Level in 
Each Group in Cohort 1  
 
 
For each group in Cohort 1, the frequency of adverse reactions to the starting dose of the study 
medication will be evaluated on the first 7 dose-evaluable participants, and will include all their 
safety data through the Week 16 visit. Safety data will be monitored on frequent conference calls 
to assess safety across both oral dosing and injections. Moreover, a CMC review of safety will be 
triggered during which accrual into Cohort 1C or 1R will be paused, if the following safety issues 
are encountered:   
 
If any of the first 7 dose-evaluable participants should experience death or a life-threatening event 
that is attributable to the study product/s, or 3 or more participants have experienced study 
product-related Grade 3+ events (excluding injection-site AEs) or have been permanently 
discontinued from treatment due to study product-related toxicities (regardless of grade), accrual 
will be stopped into this dose group. In addition, if patterns of concern are noted, a safety review 
by the CMC will be conducted.  
 
If these safety issues have been encountered, all of the relevant safety and pharmacokinetic data 
will be reviewed. If the CMC determines that it is safe to proceed, it will recommend any changes 
in the dosing and/or monitoring procedures which have been judged to be necessary. The SMC 
will then review all of the relevant safety and pharmacokinetic data, along with the 


 
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recommendations of the CMC, and will determine whether and under what conditions further 
dose finding activities for this group may proceed. Note that there may be a point, prior to 
accruing and evaluating the 7 participants, where it becomes inevitable that the dose under 
consideration will fail the safety criteria. In this event, the reviews described above will be 
performed immediately and no further accrual will occur until the CMC and SMC determine the 
conditions under which further treatment may proceed. 
 
The protocol will only proceed if this review has led to a CMC recommendation that it is safe to 
do so, and the SMC agrees. The safety review may lead to a recommendation that the dose be de-
escalated. Before implementing such a recommendation, the CMC will review the PK data to 
determine whether a lower dose is likely to achieve adequate study product exposure. 
 
If none of the first 7 dose-evaluable participants has experienced death or life-threatening event 
that is attributable to the study products, and fewer than 3 of these 7 dose-evaluable participants 
have experienced study product-related Grade 3+ event (excluding injection-site AEs) or have 
been permanently discontinued for study product-related toxicities (regardless of grade) then this 
group has passed the initial safety guidelines. The safety and PK results of the overall group of 
approximately 15-20 (Cohort 1C) or approximately 15 (Cohort 1R) participants will be evaluated 
when all participants in these groups have reached Week 16. 
 
Given the small sample sizes within each cohort, the information available for preliminary safety 
decisions will be imperfect. Two types of sampling errors are possible:  
1) In a group where the true rate of toxicity is too high to warrant increased exposure to the 
current starting dose of the medication, the sample data may pass the safety guidelines;  
2) In a group where the true rate of toxicity is low enough that further exposure to the current 
starting dose is warranted, the sample data may fail the guidelines.   
 
The extent to which the safety guidelines protect against the errors described above can be 
assessed by examining various hypothetical rates of "true toxicity" which could occur, if the 
study medication were used extensively among the participant population at the dose level under 
question. The hypothetical situations presented in Table 11 range from conditions under which a 
given dose level would cause a high incidence of study product-related severe and life-
threatening AEs to conditions under which severe adverse events would be relatively rare and 
would not be life threatening. For each of these hypothetical situations it is assumed that a sample 
of 7 participants is drawn from the participant population and that the safety guidelines, 
summarized above, are followed.  
 
As an example of how to read Table 11, the second row shows that there is a 87% chance of 
failing the safety guidelines at doses in which the true rate of study product-related life-
threatening AEs is 5% and the true rate of study product-related non-life-threatening adverse 
events is 50%. 


 
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Table 11. Probability of Failing Dose Guidelines Under Potential Rates of True Toxicity 
True Toxicity Rates 
Probability of 
Failing Safety 
Guidelines 
Non-life-threatening study product-
related Grade 3+ AEs, or AEs 
assessed as product related resulting 
to permanent treatment 
discontinuation 
Study product related life-
threatening AEs or death 
0.50 
0.00 
0.77 
0.50 
0.05 
0.87 
0.50 
0.25 
0.99 
0.25 
0.00 
0.24 
0.25 
0.05 
0.49 
0.25 
0.25 
0.92 
0.05 
0.00 
0.004 
0.05 
0.05 
0.30 
0.05 
0.25 
0.87 
0.00 
0.05 
0.30 
0.00 
0.25 
0.87 
 
Under the conditions specified in row 2 of the table, assuming that it would be undesirable to treat 
additional participants at a dose that had these true rates of adverse events, the 13% chance of 
NOT failing the safety guidelines would represent the probability of error. As a further example, 
the table also shows that there is 0.4% chance of failing, when the true rate of study product-
related non-life-threatening AE is only 5% and the true rate of study product-related life-
threatening AE is zero. Assuming that the potential benefits associated with exposing additional 
participants to this dose of the study product would outweigh the risks associated with this 
relatively low rate of toxicity, failing the safety guidelines under these conditions would be an 
error. 
 
If the safety criteria discussed above are met by the initial 7 dose-evaluable participants treated 
with each of the study products, and the PK estimates are judged to be sufficiently precise and 


 
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indicate adequate exposure to each of these medications, then participants who have participated 
in Cohort 1 will be allowed to progress to Cohort 2 upon completion of their Week 16 visit.  
 
Safety Guidelines for the Total Group of Approximately 15-20 (Cohort 1-C) or Approximately 
15 (Cohort 1-R) Potentially Dose-evaluable/ Dose-evaluable Participants Started at a Given 
Dose Level in Cohort 1  
 
The second safety evaluation of a given starting dose of the study medication administered to 
each Cohort 1 group will happen once approximately 15-20 participants in Cohort 1C and 
approximately 15 participants in Cohort 1R who could contribute to the dose-finding algorithm 
are enrolled with 80% of participants in each arm passing the Week 8 visit. The safety evaluation 
will make use of available safety data from all enrolled participants except those who have been 
determined to be not dose-evaluable at that time. The final safety evaluation of a given starting 
dose of the study medication administered to each Cohort 1 group will make use of data from all 
dose-evaluable participants in that group who started at that dose.  In both evaluations, if any of 
these participants has experienced death or a life-threatening event that is attributable to the study 
product/s, or more than 25% of the participants have experienced study product-related Grade 3+ 
events (excluding injection-site AEs) or have been permanently discontinued from treatment due 
to study product-related toxicities (regardless of grade), this starting dose will fail the safety 
guidelines for the group under investigation. If none of these participants has experienced a study 
product-related death or life-threatening AE, and no more than 25% have experienced study 
product-related Grade 3+events or have been permanently discontinued for study product-related 
toxicities (regardless of grade), then this starting dose will pass the safety guidelines for the group 
under investigation. Some participants may have Cohort 1 data well beyond Week 16, and the 
CMC will examine events occurring during this extended time period to determine whether there 
are serious or life-threatening events which may be study product related and may require SMC 
review before determining whether and under what conditions further treatment with this dose of 
the medication may proceed.  
 
As in Table 11, the hypothetical rates of "true toxicity" which could occur if the study medication 
were used extensively among the participant population at the dose level are again presented in 
Table 12, this time assuming that a sample of 15 or 20 participants is drawn from the participant 
population and the safety guidelines allow no drug-related death or life-threatening events or no 
more than a 25% rate of drug-related Grade 3+ events. 


 
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Table 12. Probability of Failing Dose Guidelines Under Potential Rates of True Toxicity 
True Toxicity Rates 
Probability of Failing Safety 
Guidelines 
N=20/  
N=15   
Non-life-threatening study product 
related Grade 3+ AEs, or AEs 
assessed as product related resulting 
to permanent treatment 
discontinuation 
Study product-related 
life-threatening AEs or 
death 
0.50 
0.00 
           0.98 / 0.98 
0.50 
0.05 
          1.00 / 0.99 
0.50 
0.25 
          1.00 / 1.00 
0.25 
0.00 
          0.38 / 0.54 
0.25 
0.05 
          0.80 / 0.81 
0.25 
0.25 
         1.00 / 1.00 
0.05 
0.00 
          0.00 / 0.01 
0.05 
0.05 
          0.64 / 0.54 
0.05 
0.25 
         1.00 / 0.99 
0.00 
0.05 
         0.64 / 0.54 
0.00 
0.25 
         1.00 / 0.99 
 
9.5.2 
Monitoring by the SMC  
 
An independent IMPAACT SMC will review this study regularly, following policies described in 
the IMPAACT Network Manual of Procedures.  
 
SMC reviews will occur at least annually and may also occur on a more frequent or ad hoc basis 
if any issues or concerns arise, or if requested by the CMC. Reviews will focus on participant 
accrual, retention, study conduct, safety, and PK. In addition, analyses of the safety and PK data 
will take place: 1) interim analysis #1 prior to opening Cohort 2 for Cohort 1 participants, 2) 
interim analysis #2 prior to opening Cohort 2 for accrual of study-naïve participants, and 3) the 
final Cohort 1 analysis after all Cohort 1 participants have completed Week 16 visit. Additional 
SMC reviews focused on safety may also occur as indicated below (Participant Safety). Based on 
any of its reviews, the SMC may recommend that the study proceed as currently designed, 


 
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proceed with design modifications, or be discontinued. The SMC may also provide operational 
recommendations to help address any study implementation challenges identified during their 
reviews.  
 
Study Progress and Quality of Study Conduct 
 
The SMC will monitor study progress and the quality of study conduct through review of the 
same types of data reports as the Protocol Team and CMC.  
 
Participant Safety 
 
The SMC will monitor participant safety through review of the same types of safety data reports 
as the CMC, which will be described in a separate Study Monitoring Plan. For ad hoc or triggered 
safety reviews, more limited data may be provided, focusing on the events that triggered the 
reviews. 
 
Triggered SMC reviews will occur in the following scenarios: 
 
(1) In the event of any adverse event that is life-threatening or results in death, the CMC will 
review the event as soon as possible (ideally within three business days of site awareness) and 
assess its relationship to study product: 
• 
If either the site investigator or the CMC assesses the event as related to study product/s, 
participant accrual will immediately be paused. An ad hoc SMC review will be convened 
as soon as possible to discuss how the study should proceed. 
• 
If the site investigator and the CMC assess the event as not related to study product, 
participant accrual will continue. The SMC will be informed of any of these events along 
with the CMC’s assessment and decision-making. 
(2) In the event of any unresolvable disagreement within the CMC on an issue that would impact 
decision making, or in the event of an unresolvable disagreement between the CMC and a site 
regarding the site’s attribution of any adverse event to study product(s) that will affect 
conduct of the study or dose-finding decisions, or if the CMC requests SMC review of any 
other event or trend of concern, an SMC review of the relevant data will be convened. The 
CMC may choose to pause participant accrual and/or administration of study product(s), 
pending the outcome of the SMC review.  
(3) If, for each cohort (1R, 1C, 2), more than 25% of the planned total sample for that cohort 
experiences study product-related Grade 3+ events (excluding injection-site AEs) or have 
been permanently discontinued from treatment due to study product-related toxicities 
(regardless of grade), an ad hoc SMC review will be convened as soon as possible. The SMC 
will review all the relevant safety and pharmacokinetic data, along with the recommendations 
of the CMC, and will determine whether and under what conditions further accrual and/or 
opening of Cohort 2 may proceed.  
 
9.6 
Analyses 
 
9.6.1 
Analyses of the Dose-Finding Data 
 
The analysis of dose finding data will consist of descriptive statistics summarizing the safety and 
PK data from the dose finding phase in Cohort 1 of the study. The safety data of dose-evaluable 
participants in Cohort 1 will be used and will be broken down by group (Cohort 1R and Cohort 
1C) and will present the results of the safety evaluations applied to each starting dose tested 


 
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within each group, including information indicating which starting doses have passed or failed the 
safety guidelines. For each starting dose within each group, every adverse event of Grade 3 or 
higher will be listed, along with participant demographics, the dose prescribed to the participant 
at the time of the event and the site’s assessment of the probability that this event was due to the 
study treatment. 
 
9.6.2 
Primary Safety Analyses  
 
The primary safety analyses will focus on the Week 4 (CAB), Week 16 (CAB LA or RPV LA) 
periods for Cohort 1, Week 24 (Cohort 2A-oral CAB and oral RPV followed by CAB LA+RPV 
LA), and Week 20 (Cohort 2B – directly receive CAB LA+RPV LA), where the primary safety 
analysis will include only evaluable participants. An additional requirement for inclusion in the 
primary analyses for Cohort 2 is that the participants be directly accrued to this cohort and be 
exclusively treated with the combination of the two study products without a prior period of 
exposure to one or the other; this will be approximately 70 participants.   
 
Two primary safety analyses will be performed: (1) after the last participant in Cohort 1 has 
completed the Week 16 visit, and (2) after the last participant in Cohort 2A has completed 24 
weeks on therapy or the last participant in Cohort 2B has completed 20 weeks on therapy 
(whichever is later). 
 
Each participant’s safety data will be summarized as:    
(1) the worst grade of AEs, and  
(2)  the worst grade of AEs judged to be related to study treatment.  
 
Proportions will present participants experiencing:  
(1) ≥ Grade 3 AEs,   
(2) ≥ Grade 3 events which have been judged to be related to study product/s,  
(3) serious adverse events assessed as related to study products,   
(4) permanent discontinuation of study product due to adverse events assessed as related to 
study product/s, and  
(5) deaths due to product-related adverse events. 
 
Overall proportions of participants meeting any of these criteria will be presented, in addition to 
specific proportions meeting each individual criterion. 
 
Listings of all ≥ Grade 3 events regardless of treatment attribution, ≥ Grade 3 events and serious 
adverse events assessed as related to study product/s, as well as AEs which resulted in permanent 
discontinuation of study product/s or deaths will be provided, broken down by System Organ 
Class and Preferred Term. 
 
The proportions of participants meeting each of the endpoints which would trigger an SMC 
review will be presented descriptively. 
 
All proportions will be presented together with their exact 95% confidence intervals (Clopper-
Pearson). 
 
The safety data will also be presented separately for Cohort 2A, Cohort 2B, and for Cohort 2A 
and 2B combined. 
 
Details concerning the analyses will be included in a separate statistical analysis plan. 


 
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For regulatory submission purposes, all the above analyses will be performed for all Cohort 1 and 
Cohort 2 evaluable participants and all-treated participants, where all-treated is defined as 
participant who received at least one dose of the study drug. For Cohort 2, frequency distributions 
of the safety outcomes will be presented in aggregate and will be broken down by prior 
participation in Cohort 1 vs. exclusive participation in Cohort 2. In addition, the safety data will 
be presented separately for those who were in Q4W and Q8W LA IM dosing. 
  
9.6.3 
Secondary Analyses  
 
9.6.3.1 Maintenance of Viral Suppression 
 
Virologic outcomes, based on HIV-1 RNA (copies/mL), will be assessed through Week 16 for 
Cohort 1 participants.  The proportion of participants maintaining suppression (<50 copies/mL) 
will be presented, along with the exact 95% confidence intervals (Clopper-Pearson). 
 
9.6.3.2 Acceptability and Tolerability 
 
Acceptability and tolerability measures on CAB LA or RPV LA reported by the Cohort 1 
participants through Week 16 will be summarized.  
9.6.3.3 Safety  
 
Week 24 (Cohort 2A)/Week 20 (Cohort 2B) analyses described above for the primary analysis 
will be repeated as secondary analyses through Week 48 (Cohort 2A)/Week 44 (Cohort 2B) for 
the same participants mentioned under the primary analysis. 
 
In addition to the primary analyses restricting the sample to appropriate participants as described 
above, further analyses which include safety data from all treated participants through all 
mentioned periods will be performed. These secondary safety analyses will cover all safety data 
collected from first participant exposure to the end of the study. The Cohort 2 secondary analyses 
will include approximately 30-35 participants whose treatment started in Cohort 1 at the final 
recommended dose and who progressed to Cohort 2 after completing participation in Cohort 1 
(see Section 9.1 for a discussion of about the potential for selection bias in this group, and this 
section on how this bias will be addressed). All Cohort 2 secondary analyses will be presented 
separately for Cohort 2A, 2B, and in aggregate. 
 
Descriptive and exposure-related analyses will present safety data from participants who were 
treated on doses other than the final recommended dose for their cohorts. This will include data 
representing the final dose for each cohort, as well as data gathered during the dose finding stage, 
which may represent exposure to doses which have failed. For each starting dose, every AE of ≥ 
Grade 3 will be listed, along with participant demographics, the dose prescribed to the participant 
at the time of the event and the protocol team’s assessment of the probability that this event was 
due to the study products. 
 
9.6.3.4 Virologic activity 
 
Virologic outcomes, based on HIV-1 RNA (copies/mL), will be assessed at Weeks 24 (Cohort 
2A)/Week 20 (Cohort 2B), Weeks 48 (Cohort 2A)/Week 44 (Cohort 2B) for Cohort 2 evaluable 
participants. At both of these time points the virologic outcome will be calculated according to 


 
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the FDA’s snapshot algorithm with three main categories (i.e., HIV-1 RNA <50 c/mL, HIV-1 
RNA ≥50 c/mL, and no virologic data). The detailed algorithm for defining virologic response 
will be described in the statistical analysis plan. The snapshot outcome will be presented at the 
above Weeks. The exact 95% confidence intervals (Clopper-Pearson) for the proportion of 
participants with HIV-1 RNA <50 c/mL will be calculated. The similar summary and analysis 
will also be performed using the cutoff of HIV-1 RNA 200 c/mL. In addition to the snapshot 
analysis, the proportions of participants meeting the criteria for confirmed virologic failure 
through the above Weeks will also be presented.  
 
In addition, the above analyses results will also be presented for all treated Cohort 2 participants. 
 
The efficacy analysis will be presented for Cohort 2A and 2B respectively, and for Cohort 
2A+2B combined. 
 
Table 13 presents exact 95% confidence intervals (Clopper-Pearson) around various potential 
rates of virologic success which might be observed in a total sample of 100 participants or in 
subsamples of various sizes (N=15, 20, 35, 70).  
 
Table 13. Percent of Participants with HIV-1 RNA<50 c/mL per Snapshot algorithm with 
Exact 95% Confidence Intervals 
N 
% Undetectable RNA 
95% C.I. 
15 
40% 
0.16, 0.68 
20 
40% 
0.15, 0.59 
35 
40% 
0.24, 0.58 
70 
40% 
0.28, 0.52 
100 
40% 
0.30, 0.50 
15 
80% 
0.52, 0.96 
20 
80% 
0.56, 0.94 
35 
80% 
0.63, 0.92 
70 
80% 
0.69, 0.89 
100 
80% 
0.71, 0.87 
15 
90% 
0.68, 1.00 
20 
90% 
0.68, 0.99 
35 
90% 
0.77, 0.98 
70 
90% 
0.80, 0.96 
100 
90% 
0.82, 0.95 
 
9.6.4 
Other Analyses 
 
9.6.4.1 Acceptability and Tolerability 
 
The acceptability and tolerability measures on CAB LA + RPV LA through Week 24 (Cohort 
2A/Week 20 (Cohort 2B), through Week 48 (Cohort 2A)/Week 44 (Cohort 2B), and through 
Week 96 (Cohort 2A)/Week 92 (Cohort 2B) will be summarized. Additionally, these participants’ 
acceptability and tolerability measures through 48 weeks following permanent discontinuation of 
CAB LA or RPV LA (Cohort 1), through 48 weeks following permanent discontinuation of CAB 
LA + RPV LA (Cohort 2) will be summarized.  
 


 
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See Section 11.6 for the planned analyses regarding the adolescent and parent/caregiver 
interviews and relating to the outcomes listed in Section 9.2. 
 
9.6.4.2  Safety 
 
The Week 24 (Cohort 2A)/Week 20 (Cohort 2B) analyses described above for the primary 
analysis will be repeated as secondary analyses through Week 96 (Cohort 2A)/Week 92 (Cohort 
2B), and through 48 weeks following permanent discontinuation of and CAB LA + RPV LA for 
the same participants mentioned under the primary analysis. Refer to Section 3.3. 
 
In addition to the primary analyses restricting the sample to appropriate participants as described 
above, further analyses which include safety data from all treated participants through all 
mentioned periods will be performed. These safety analyses will cover all safety data collected 
from first participant exposure to the end of the study. Descriptive and exposure-related analyses 
will present safety data from participants whose doses have undergone cohort-based adjustment 
or who were treated on doses other than the final recommended dose for their cohorts. This will 
include data representing the final dose for each cohort, as well as data gathered during the dose 
finding stage, which may represent exposure to doses which have failed. 
 
All these Cohort 2 analyses will be done separately for Cohorts 2A, 2B, and in aggregate. 
 
For each starting dose, every AE of ≥ Grade 3 will be listed, along with participant demographics, 
the dose prescribed to the participant at the time of the event and the site’s assessment of the 
probability that this event was due to the study products. 
 
9.6.4.3  Virologic Activity 
 
The Week 24(Cohort 2A)/Week 20 (Cohort 2B) and Week 48 (Cohort 2A)/Week 44 (Cohort 2B) 
analyses described in Section 9.6.3.3 
Safetyfor the secondary analysis on virologic activity will 
be repeated as other analysis through Week 96 (Cohort 2A)/Week 92 (Cohort 2B) for the same 
participants mentioned under said secondary analysis.  
 
9.6.4.4  Immunologic Activity 
 
Absolute values and change from baseline in CD4+ lymphocyte count and percentage will be 
summarized over time for Cohort 2 participants.  
 
Median and the associated interquartile range for changes in CD4+ count and percentage from 
baseline to Weeks 24/20, 48/44, 72/68 and 96/92 will be presented for Cohorts 2A/2B and in 
aggregate. Missing CD4+ values for participants who discontinued study drug prior to the time 
point of interest due to safety or virologic failure will be replaced with their baseline CD4+ 
values. 
 
9.6.4.5  Genotype and Phenotype Resistance  
 
The incidence of HIV drug resistance for Cohorts 1 and 2 participants will be presented 
descriptively at the point of failure for those who meet the criteria for confirmed virologic failure 
(CVF). Participants will be evaluated for HIV genotypic and phenotypic drug resistance for CAB 
and/or RPV at the time of CVF. Plasma collected at the Confirmation of Virologic Failure visit, 
the visit in which the participant had an initial elevated viral load test result, whole blood 
collected at the Entry (baseline) visit, and any other study visits as requested by the CMC for 


 
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genotypic and phenotypic resistance testing, will be shipped per Section 6.16 and the LPC for 
testing. See Section 6.16 and the LPC for more details. 
 
9.6.4.6 Additional considerations 
 
Additionally, special statistical and data analysis considerations may be warranted in the event 
that the COVID-19 or related epidemics or natural disasters may affect the study and data 
integrity. To the extent possible, these will be described in the main study analysis plan; 
alternatively, a separate analysis plan focusing on modified data handling rules (e.g., changes to 
analysis populations, visit windows, and endpoints) and analyses (e.g., sensitivity analyses to 
assess impact of and account for missing data) may be prepared, taking in to account applicable 
regulatory guidance and industry best practices for handling such situations. (26-28) 
 
Further data cuts and analyses may be conducted as necessary to support regulatory submissions 
and publications. The details for such analyses will be described in the statistical analysis plan, 
which will be finalized prior to database lock. 
 
 
10 
CLINICAL PHARMACOLOGY PLAN 
 
10.1 
Clinical Pharmacology Objectives 
 
10.1.1 Cohort 1 
 
Under protocol Version 2.0 (see Section 1.3), injectable CAB and RPV were evaluated with a 
Q4W injection dosing regimen i.e. oral CAB 30mg once daily followed by CAB LA 600mg then 
400mg every 4 weeks (Cohort 1C) or oral RPV 25mg once daily followed by RPV LA 900mg 
then 600mg every 4 weeks (Cohort 1R) in adolescents weighing at least 35kg living with HIV 
who are virologically suppressed.  Recent results from clinical studies (FLAIR, ATLAS, ATLAS-
2M) in adults now justify use of CAB LA and RPV LA with every 8-week administration: IM 
CAB LA 600 mg at Week 4b and Week 8 and every 8 weeks thereafter and IM RPV LA 900 mg 
at Week 4b and Week 8 and every 8 weeks thereafter. 
 
Since daily oral RPV 25mg is already approved in this population, the approved oral dose will be 
used for both Cohort 1R and Cohort 2A, and only limited intensive RPV PK will be collected in 
Step 1 (oral lead-in phase) of Cohort 1R. In Cohort 1C and 1R, study product will be added onto 
the participants’ existing ARV therapy and participants will be assigned into Cohort 1C versus 1R 
based on the agents used in their suppressive ARV regimen (avoiding study product interactions 
between the ARVs). Multiple PK samples will be collected throughout the oral and LA dose 
intervals to allow determination of PK parameters for CAB or RPV, as applicable, using 
appropriate analyses.  
 
The PK results from all evaluable Cohorts 1C and 1R participants will be used to confirm the use 
of adult doses for the oral (CAB only) and LA (CAB and RPV) products in adolescents, to be 
used in combination in Cohort 2: oral CAB + oral RPV in Cohort 2A, Step 3, and CAB LA+RPV 
LA in Cohort 2, Step 4 and Step 5. The exposures observed with the proposed CAB and RPV 
doses evaluated in adolescent participants living with HIV in the study will be characterized and 
compared to exposures observed in adult pivotal efficacy trials to aid dosing recommendation in 
this population. 
 


 
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Primary Pharmacology Objectives within Cohort 1 
 
• 
To confirm the doses for oral CAB followed by injectable CAB LA in adolescents living with 
HIV who are virologically suppressed by evaluating: 
o Safety and multiple dose PK of oral CAB through Week 4 
o Safety and multiple dose PK of CAB LA through Week 16 
 
• 
To confirm doses for injectable RPV LA in adolescents living with HIV who are 
virologically suppressed by evaluating safety and multiple dose PK of RPV LA through 
Week 16 
 
Other Pharmacology Objectives within Cohort 1 
 
• 
To characterize washout PK through 48 weeks following the final Cohort 1 dose of CAB LA 
or RPV LA (except when participants rollover into Cohort 2) 
 
10.1.2 Cohort 2 
 
Cohort 2 will use CAB and RPV in combination. Cohort 2A will first use oral and then as an IM 
injectable with the LA formulations, as a complete ARV regimen, in adolescents living with HIV 
who are virologically suppressed and weighing at least 35kg. Cohort 2B will only use CAB and 
RPV as an IM injectable with the LA formulations, as a complete ARV regimen, in adolescents 
living with HIV who are virologically suppressed and weighing at least 35kg.The Cohort 2 
dosage regimen will be the confirmed dosages based on data observed in Cohorts 1C and 1R, 
with the exception of oral RPV for which the dose of daily 25 mg has already been previously 
approved.   
 
The overall PK goal for Cohort 2 is to characterize the plasma concentrations following more 
prolonged LA dosing in Cohort 2 confirming their ability to achieve concentrations comparable 
to those observed in adults. Only sparse PK samples will be collected during Cohort 2 which may 
limit the PK analysis to descriptive summaries of study product concentrations and future 
population pharmacokinetic analyses. 
 
Secondary Pharmacology Objectives within Cohort 2 
 
• 
To evaluate repeat-dose pharmacokinetics of CAB LA + RPV LA in adolescents living with 
HIV who are virologically suppressed through: 
o Week 24 and through Week 48 (Cohort 2A: oral followed by injectable); 
o Week 20 and through Week 44 (Cohort 2B: injectable only). 
 
Other Pharmacology Objectives within Cohort 2 
 
 
• 
To evaluate the safety, antiviral and immunologic activity, and characterize PK of CAB LA + 
RPV LA in adolescents living with HIV who are virologically suppressed through:  
o Week 96 (Cohort 2A: oral followed by injectable); 
o Week 92 (Cohort 2B: injectable only). 
 
• 
To characterize long-term safety and PK through 48 weeks following permanent 
discontinuation of CAB LA + RPV LA 


 
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10.2 
Primary and Secondary Data: Cohorts 1 and 2 
 
Demographic data used in the PK analysis will include age, sex at birth, race, ethnicity, height, 
weight, weight Z score, weight group (35-<50kg vs >50kg), BMI, and BSA.  Available laboratory 
data will include serum creatinine, albumin, AST, ALT, bilirubin, and hemoglobin. Complete 
dosing information will also be utilized including dose dates, times, dose amounts, food intake 
(Step 1 and 3 only), dose administration, location of injections, and sample collection dates and 
times.  
 
Plasma concentrations will be measured: 
• 
Cohort 1C (CAB) 
o Step 1 (oral dosing):  Wk. 2: Pre-dose, 1, 2, 3, 4, and 8h post dose (6 samples)  
o Step 2 (LA dosing):  Wk. 4b: Pre-dose and 2h post dose, Wk. 5: Day 3-7 post-dose, Wk. 
8: pre-dose, Wk. 9: Day 3-7 post-dose, Wk. 12: Day 28 post dose, Wk. 16: Day 56 post-
dose.  
• 
Cohort 1R (RPV) 
o Step 1 (oral dosing):  Wk. 2:  Pre-dose, 4, and 8h post dose (3 samples)  
o Step 2 (LA dosing):  Wk. 4b: Pre-dose and 2h post dose, Wk. 5: Day 3-7 post-dose, Wk. 
8: pre-dose, Wk. 9: Day 3-7 post-dose, Wk. 12: Day 28 post dose, Wk. 16: Day 56 post-
dose. 
• 
Cohort 2 (CAB and RPV) 
o Step 3 (Cohort 2A oral dosing):  Wk. 2:  Pre-dose and 3h post dose (2 samples) 
o Step 4 (Cohort 2A LA dosing):  Wk. 4b: Pre-dose and 2h post dose, Wk. 5 and Wk. 25: 
Day 3-7 post-dose, pre-dose prior to every injection at Wk. 8, Wk. 16, Wk. 24, Wk. 32, 
Wk. 40, Wk. 48, Wk. 64, Wk. 80, Wk. 88, Wk. 96. 
o Step 5 (Cohort 2B LA dosing): Entry: 2h post dose, Wk. 1 and Wk. 21: Day 3-7 post-
dose, pre-dose prior to every injection at Wk. 4, Wk. 12, Wk. 20, Wk. 28, Wk. 36, Wk. 
44, Wk. 60, Wk. 76, Wk. 84, Wk. 92. 
• 
LSFU 
o Samples collected 8, 24, 36 and 48 weeks after the final injection (random PK samples). 
 
Assay Site: Plasma pharmacokinetic samples collected will be sent to the IMPAACT 
Pharmacology Laboratory listed in the LPC for both CAB and RPV containing specimens. 
Sample collection, processing, storage and shipping details are provided in the LPC. Of note RPV 
samples need to be protected from light as detailed in the LPC. 
 
Methods to be used: All assay methods will be standardized with a filed Methods Report, under 
Good Laboratory Practice (GLP) conditions and cross-validated with primary assay providers 
used for CAB and RPV. The assays will be performed using high-performance liquid 
chromatography and tandem mass spectrometry (HPLC/MS/MS). 
 
Reporting of Assay Data:  Cohort 1 samples will undergo ongoing analysis and reporting with 
scheduled interim PK analyses to assess if the initial dosing is achieving the PK targets. Assaying 
of Cohort 2A PK samples through the Wk. 24 visit, and then through the Wk. 48 visit, may be 
performed in batches and reported. Assaying of Cohort 2B PK samples through the Wk. 20 visit, 
and then through the Wk. 44 visit, may be performed in batches and reported. Remaining Cohort 
2 PK samples may be assayed in batches and reported at completion of the study, along with PK 
samples collected during LSFU for the final PK analyses. PK samples collected from Cohort 2 
after Wk. 48 and collected from any Confirmation of Virologic Failure visit, will be assayed as 


 
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requested by the team. Additional sample PK analysis may be performed prior to the completion 
of the study based on the study team’s review of the initial interim analyses or at the request of 
the CMC or SMC. 
 
10.3 
Endpoints and Outcome Measures 
 
10.3.1 Primary Endpoints and Outcome Measures 
10.3.1.1 
Pharmacokinetic output measures as data permit 
• 
Cohort 1C – Step 1 PO dosing: Wk. 2 AUC, CL/F, Cmax, Tmax, and pre-dose 
concentrations (C0).  
• 
Cohort 1C – Step 2 LA dosing:  Wk. 16 concentrations (C16WK), Cmax, Tmax 
(Dose 1) and C0 prior to IM doses.   
• 
Cohort 1R – Step 2 LA dosing:  Wk. 16 concentrations (C16WK), Cmax, Tmax 
(Dose 1) and C0 prior to IM doses.   
10.3.2 Secondary Endpoints and Outcome Measures 
10.3.2.1 
Pharmacokinetic outcome measures as data permit 
• 
Cohort 2A (oral followed by injectable):  CAB and RPV pre-dose 
concentrations following PO administration at Step 3 Wk. 2. 
• 
Cohort 2A (oral followed by injectable):  CAB and RPV concentrations 
following IM administration at Step 4 from Wk. 8 (after the first LA 
injections) to Wk. 24 and accumulation ratio (Wk. 24 Pre-dose Conc: Wk. 
8 Pre-dose concentration). 
• 
Cohort 2B (injectable only):  CAB and RPV concentrations following IM 
administration at Step 5 from Wk. 4 (after the first LA injections) to Wk. 
20 and accumulation ratio (Wk. 20 Pre-dose Conc: Wk. 4 Pre-dose 
concentration). 
• 
Cohort 2A (oral followed by injectable):  CAB and RPV concentrations 
following IM administration at Step 4 from Wk. 8 (after the first LA 
injections) to Wk. 48 and accumulation ratio (Wk. 48 Pre-dose Conc: Wk. 
8 Pre-dose concentration). 
• 
Cohort 2B (injectable only):  CAB and RPV concentrations following IM 
administration at Step 5 from Wk. 4 (after the first LA injections) to Wk. 
44 and accumulation ratio (Wk. 44 Pre-dose Conc: Wk. 4 Pre-dose 
concentration). 
• 
Cohort 2A (oral followed by injectable):  CAB and RPV concentrations 
following IM administration at Step 4 from Wk. 16 (after the first LA 
injections) to Wk. 24 and accumulation ratio (Wk. 24 Pre-dose Conc: Wk. 
16 Pre-dose concentration). 
• 
Cohort 2B (injectable only):  CAB and RPV concentrations following IM 
administration at Step 5 from Wk. 12 (after the first LA injections) to Wk. 
20 and accumulation ratio (Wk. 20 Pre-dose Conc: Wk. 12 Pre-dose 
concentration). 
• 
Cohort 2A (oral followed by injectable):  CAB and RPV concentrations 
following IM administration at Step 4 from Wk. 16 (after the first LA 
injections) to Wk. 48 and accumulation ratio (Wk. 48 Pre-dose Conc: Wk. 
16 Pre-dose concentration). 
• 
Cohort 2B (injectable only):  CAB and RPV concentrations following IM 
administration at Step 5 from Wk. 12 (after the first LA injections) to Wk. 
44 and accumulation ratio (Wk. 44 Pre-dose Conc: Wk. 12 Pre-dose 
concentration). 


 
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10.3.3 Other Endpoints and Outcome Measures  
10.3.3.1 
CAB and RPV Pharmacokinetic outcome measures as data permit 
• 
Cohort 2A (oral followed by injectable):  CAB and RPV concentrations 
following IM administration at Step 4 from Wk. 48 to Wk. 96 and 
accumulation ratio (Wk. 96 Pre-dose Concentration: Wk. 48 Pre-dose 
Concentrations). 
• 
Cohort 2B (injectable only): CAB and RPV concentrations following IM 
administration at Step 5 from Wk. 44 to Wk. 92 and accumulation ratio 
(Wk. 92 Pre-dose Concentration: Wk. 44 Pre-dose Concentrations). 
• 
Cohort 1: CAB or RPV concentrations 8 to 48 weeks following final IM 
dose. 
• 
Cohort 2A&B:  CAB and RPV concentrations 8 to 48 weeks following 
final IM dose.   
 
10.4 
Study Design, Data Analysis, and Modeling 
 
Pharmacokinetic blood samples will be collected as noted in Section 6.16 and Appendix I. The 
samples will be 2 mL whole blood for Cohort 1 (and for Cohort 1 participants during the LSFU 
visit schedule) and 4 mL whole blood for Cohort 2 (and for Cohort 2 participants during the 
LSFU visit schedule). Cohort 2 plasma samples, which should be protected from light, will be 
split into individual aliquots for CAB and RPV each containing 0.4-1.2 mL plasma; same will be 
done for Cohort 2 participants during the LSFU visit schedule. RPV samples should be protected 
from light at all times from collection through storage and during sample analysis. Plasma 
concentrations will be summarized by Cohort, analyte, and nominal time. PK analysis will be 
performed by appropriate methodology e.g., noncompartmental methods and/or population 
methods.  
 
CAB:  The observed concentrations and parameter estimates will be compared to those seen in 
adults (Sections 1.3.9.1 and 1.3.9.2).  
 
Specifically, following oral CAB 30mg once daily in adolescents  35kg Cmax and C are 
expected to be at steady state. Owing to the lower body weight of adolescents, their exposures are 
predicted to be 60-70% higher than the exposures seen with the 30mg daily oral dose in adults but 
comparable to the 60 mg dose in adults. These differences are considered to be not clinically 
relevant and higher CAB exposures have been observed without any safety findings in adults at 
supratherapeutic doses (150 mg administered orally every 12h x 3 doses). 
 
Little accumulation between LA doses is expected following the CAB LA Q8W regimen (Section 
5.1).  In the adult clinical study (207966) with the same regimen, the geometric mean (5th and 
95th percentiles) of the trough concentration following the initiation injection was 1.50 mcg/mL 
(0.65 mcg/mL – 2.90 mcg/mL), similar to that following the 6th LA IM injection (44 weeks after 
the initiation injection) of 1.61 mcg/mL (0.80 mcg/mL – 2.99 mcg/mL). Based on the POP PK 
model and simulations of the Q8W dosing in adolescents, the CAB concentrations are expected to 
be slightly higher but comparable to the levels observed in adults given the lower body weight in 
adolescents as compared to adults. These CAB levels are several folds higher than the PA-IC90 
(CAB PA-IC90=0.166 mcg/mL). 
 


 
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RPV:  The observed concentrations and parameter estimates following IM administration will be 
compared to those seen in adults (Section 1.3.9.4). With the every 2 months dosing regimen in the 
adult clinical study 207966 (ATLAS-2M, RPV oral 25mg for 4 weeks followed by IM RPV 
900 mg at Week 4 and Week 8 and every 8 weeks thereafter), the median (5th and 95th 
percentiles) trough concentration was 49.1 ng/mL (20.9 ng/mL – 116 ng/mL) at Week 8 (4 weeks 
following the first initiation injection), and was 64.7 ng/mL (33.0 ng/mL – 120ng/mL) following 
the 6th LA IM injection (44 weeks after the initiation injection). Greater than 80% of the RPV 
steady-state concentrations are reached within 48 weeks, with limited further accumulation 
thereafter.  
 
10.4.1 Interim Pharmacokinetic Analyses  
 
A non-compartmental pharmacokinetic analysis (NCA) will be performed on the plasma CAB or 
RPV concentration-time data generated for each individual in Cohort 1C and 1R. Calculated 
pharmacokinetic parameters will include, as permitted by data:  
• 
area-under-the-curve during the dosing interval (AUC0-),  
• 
maximum concentration (Cmax),  
• 
time to Cmax (Tmax),  
• 
trough concentration (C), 
• 
apparent clearance (CL/F),  
• 
terminal rate constant (z), and  
• 
the terminal half-life (T1/2).  
 
The accumulation for C28D from Dose 1 to the last dose following LA administration will also be 
determined. Cmax and Tmax will be taken directly from the observed concentration-time data. Data 
permitting, the terminal slope, z, will be determined from log- linear portion of the curve and the 
terminal half-life (T1/2) calculated as 0.693/z. AUC0- will be determined using the linear 
trapezoidal method and C0 will be used as an estimate of C24h (for oral), when needed, assuming 
steady-state conditions. In absence of adequate PK data to perform an NCA, other appropriate 
analyses may be undertaken to support dose recommendations. 
 
Pharmacokinetic analyses will be performed as data from each Cohort become available.  
Individual participant’s PK data results will be included if they are available for analysis.  
   
10.4.2 Population Pharmacokinetic Analysis  
 
POP PK analyses may be performed using the IMPAACT 2017 PK data alone or in combination 
with existing adult PK data using appropriate methodology. There are no population PK analysis 
outputs required for the dose selection in Cohort 1 nor do any Cohort 1 or 2 PK objectives require 
POP PK analysis for generation. Thus, POP PK analysis will be considered outside of the scope 
of this protocol and will be reported separately. However, other PK analyses of collected data, 
including POP PK evaluations, may be performed to assist the study team with assessment of 
safety or dosing. 
 


 
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10.5 
Expected Outcome 
 
Based on simulations presented in Section 1.3.9, oral and LA regimens in this adolescent 
participant population are expected to achieve concentrations within an acceptable range of those 
observed clinically in adults. If results deviate from expected predictions, dose modifications will 
be considered.    
 
PK Acceptance Criteria 
Oral CAB (Cohort 1C, Step 1) 
 
The CAB PK acceptable criteria following oral administration in Cohort 1C Step 1 is: 
• 
A median Wk. 2 AUC0- between 46 and 277 mcg*h/mL (approximately 33-200% of the 
geometric mean in adults which is 134 mcg*h/mL).  
• 
Median Trough (C) concentrations >0.45 mcg /mL  
• 
Median Cmax ≤ 22.5 mcg/mL that was observed in the TQT study in adults without any 
impact on QT interval.  
 
The study team will review all of the PK parameters following oral CAB, safety and tolerability 
data to determine if a dose modification is warranted. In general, slightly higher exposures may 
be expected in adolescents when administered the same dose as adults due to lower body weight.    
 
Dose Modification (Cohort 1C, Step 1) 
 
No individual dose modification for the use of short-term oral lead-in will be explored in Cohort 
1C. In the event of failure with respect to safety concerns and/or PK criteria that are deemed 
potentially avoidable by a lower exposure to CAB, as judged by the protocol team, dose 
adjustment will be considered for a future Cohort 1C, subject to availability of a suitable 
formulation if deemed appropriate. Any participant that fails Cohort 1C due to safety concerns 
will not receive CAB LA in Cohort 1C Step 2. 
 
CAB LA (Cohort 1C, Step 2) 
 
For the participants that received CAB LA with Q4W dosing under protocol version 2.0, the 
Week 16 Ct data were within the median target range applicable for that dosing regimen (see 
Section 1.3.2) at the time of safety review (January 2020).  The study exposure will also be 
assessed against the 5th percentile CAB concentration (0.45 mcg/mL) observed in the pivotal 
successful efficacy trials in adults, ATLAS and FLAIR, and similar to ATLAS-2M and oral 
CAB.  
 
The CAB PK acceptable criteria following LA administration in Cohort 1C Step 2 is: 
• 
A median Wk. 16 Ct between 0.71-6.7 mcg/mL  
• 
A calculated 5th percentile Wk. 16 Ct ≥0.45 mcg/mL 
 
If the PK results fail to meet the above Wk. 16 Ct acceptability criteria, the IMPAACT 2017 
study team will review all available PK data to determine if any changes are deemed necessary in 
the proposed dosing regimen. 
  
RPV LA (Cohort 1R, Step 2) 
 


 
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For the participants that received RPV LA with Q4W dosing under protocol version 2.0, the 
Week 16 Ct data were within the median target range applicable for that dosing regimen (see 
Section 1.3.2) at the time of safety review (January 2020).  The study exposure will also be 
assessed against the 5th percentile RPV concentration (17.3 ng/mL) observed in the pivotal 
successful efficacy trials in adults, ATLAS and FLAIR, and similar to ATLAS-2M and oral RPV.  
 
The RPV PK acceptable criteria following LA administration in Cohort 1R Step 2 is: 
• 
A median Wk. 16 Ct between 25-100 ng/mL  
• 
A calculated 5th percentile Wk. 16 Ct ≥17.3 ng/mL 
 
If the PK results fail to meet the above Wk. 16 Ct acceptability criteria, the IMPAACT 2017 
study team will review all available PK data to determine if any changes are deemed necessary in 
the proposed dosing regimen. 
 
 
11 
QUALITATIVE PHONE INTERVIEWS (U.S. Sites Only) 
 
A single in-depth qualitative phone interview will be conducted with a sub-set of adolescent 
participants enrolled at U.S. study sites and as selected by the protocol team, to identify 
acceptability and tolerability concerns unique to the participant population, and to evaluate 
adolescent participants’ experience of CAB LA and/or RPV LA. This section provides details on 
the qualitative phone interviews, including selection of participants, coordinating the phone 
interviews, conducting the interviews, and data analysis. 
 
See Appendix IV for details regarding qualitative phone interviews with the parents/caregivers of 
adolescent participants. 
 
11.1 
Sample Size and Selection Process 
 
Adolescent participants will be selected to take part in a single in-depth qualitative interview to 
achieve up to 30 completed phone interviews in each Cohort (for a maximum of 60 completed 
phone interviews in Cohort 1 and Cohort 2 combined). The sample size is based on the likely 
number of interviews needed to achieve thematic saturation. For each Cohort, selection for the 
interviews will continue until there is either saturation of themes, or the maximum sample size is 
reached, whichever occurs first. See Section 11.6 regarding thematic saturation and qualitative 
interview data analyses. 
 
Self-reported demographics from Screening and Entry visits will be used to inform selection with 
the goal of balancing participant sex at birth and age (both older and younger adolescents) in the 
completed interviews. This will ensure that perspectives from participants assigned both male and 
female at birth, as well as older and younger participants, are reflected in the final analysis. 
Additionally, participants who permanently discontinue injectable study product will be 
purposefully selected to ensure reasons for discontinuing the injections are also reflected in the 
final analysis. Participants will be selected across multiple U.S. sites but restricted to those 
willing and able to conduct the interview by phone in English. 
 
Participants will be selected on an on-going basis as they approach the respective interview 
procedure window for their Cohort, and some participants may be selected after they have entered 
the interview procedure window. The selection process will continue until thematic saturation or 
the sample size is reached for each Cohort; see Section 11.2 below for the interview procedure 
windows for each Cohort. The interviews must be completed within the specified interview 


 
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window to allow for comparison between participants. Participants enrolling to the study early 
will thus be selected for interviews first, as they will be the first to enter the specified interview 
windows. 
 
11.2 
Qualitative Phone Interview Procedural Window 
 
The qualitative phone interviews will be conducted with selected participants within the 
following timeframes:  
• 
For selected Cohort 1 participants: Between the Week 4b and Week 12 visits (inclusive), 
or during LSFU visits.  
• 
For selected Cohort 2A participants: Between the Week 24 and Week 96 visits 
(inclusive), or during LSFU visits.  
• 
For selected Cohort 2B participants: Between the Week 20 and Week 92 visits 
(inclusive), or during LSFU visits. 
 
11.3 
Consenting Considerations and Scheduling Qualitative Phone Interviews 
 
For all adolescent participants, consent (or assent, as applicable) for the possibility of being 
selected for a phone interview will be obtained from the adolescent and their parent/guardian as 
part of the informed consent process (or informed assent process, as applicable) for the 
IMPAACT 2017 study. The protocol interview team will notify site staff when participants are 
selected for an interview; see Section 11.1 above for details on the selection process.  
 
Upon notification of selection by the protocol interview team, site staff will approach selected 
participants (either in person or by phone) to confirm willingness to take part in the phone 
interview. Willingness to take part in the phone interview does not affect overall study 
participation or other scheduled study visit procedures. 
 
Upon confirmation of the selected participant being willing to take part in the phone interview, 
site staff will work with the protocol interview team and the selected participant to schedule the 
phone interview. Operational considerations and guidance, including coordinating the interview, 
are provided in the IMPAACT 2017 MOP.  
 
11.4 
Conducting Qualitative Phone Interviews 
 
Once the phone interview is scheduled, site staff will provide the selected participant with 
detailed instructions and guidance on accessing the phone interview platform. Phone interviews 
may be completed either in the study clinic during a scheduled study visit, or from a phone 
outside the study clinic at a time that is convenient for the participant and within the interview 
procedural window. All phone interviews will be conducted by a protocol interview team member 
external to participating clinical research sites, following an interview guide, and will be audio 
recorded and transcribed.  
 
Sites must source document notification by the protocol interview team of participant selection, 
and all attempts to contact the participant. Sites must source document and enter into eCRFs 
willingness to take part in the phone interview, whether they are able to conduct the interview in 
English, and the date the phone interview occurred. Operational and logistical details regarding 
communication with the protocol interview team members and site staff are provided in the 
IMPAACT 2017 MOP. 
 


 
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11.5 
Disclosure of Harm 
 
As described above, the purpose of conducting in-depth qualitative phone interviews with 
participants is to identify acceptability and tolerability concerns unique to the participant 
population, and to evaluate adolescent participant’s experience of CAB LA and/or RPV LA. 
Conducting the interviews is not expected to increase the likelihood or risk of self-harm or harm 
to others.    
 
During the consent (or assent, as applicable) process, participants will be informed that the 
information that they provide in the interview will be kept confidential, with the exception of 
disclosures of significant risk for harm, including being abused or experiencing violence, 
suicidality or homicidality. 
 
If at any time during a qualitative phone interview, a participant divulges that s/he is at risk for 
harm, including but not limited to being abused or experiencing violence, if harm is suspected or 
likely, or if the participant states s/he is suicidal or homicidal, the following will occur to ensure 
his or her safety: 
• 
The protocol interview team member conducting the interview will immediately contact 
the site IoR or designee and share any time-sensitive, potentially life-threatening 
information received from the study participant as part of the phone interview 
discussions. 
• 
The IoR or designee contacted with this information will follow local policies for 
management of such situations including engaging immediate/first responders as 
applicable. 
• 
The IoR or designee will also follow local reporting policies and legal statutes, including 
reporting to child protection or other appropriate agencies, as well as arranging referrals 
to appropriate support, counseling or treatment resources. 
 
After the safety of the participant is addressed according to the steps above, the IoR or designee 
will notify the CMC and document the event, as applicable per Section 7. 
 
To facilitate rapid communications, the IoR or designee is expected to provide up-to-date contact 
information to the protocol interview team while phone interviews are being scheduled and 
conducted with participants from the site.  
 
11.6 
Qualitative Phone Interview Data Analyses 
  
This section provides an overview of the qualitative data analysis process, which will be a 
descriptive analysis without formal inference, with a more detailed description presented in the 
qualitative analysis plan. See Section 12 for details regarding data management responsibilities 
and source data of the in-depth qualitative phone interviews, audio files, and transcriptions. 
 
Analysis will begin during data collection to allow for an iterative process through which 
questions and probes can be refined to enhance the depth of understanding elicited, so that topics 
for further exploration can be noted and incorporated into ongoing interviews. Contemporaneous 
analysis will also be used for determination of the achievement of thematic saturation. Thematic 
saturation is determined on the basis of analysis of the completed scripts by multiple investigators 
who agree that novel information has ceased to arise as new interviews are completed. The 
qualitative data analysis will utilize a thematic approach whereby the protocol interview team will 


 
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search for patterns in data and will conceptualize ideas that help explain the presence of those 
patterns (29). Analysis of textual data will consist of 5 main steps:  
1) Reading for content: Analysis will begin with reading and rereading transcripts until content 
becomes intimately familiar (30). As data are reviewed, emergent themes will be noted;  
2) Coding: A list of codes will be created based on both pre-specified and identified themes. 
Codes will then be assigned to specific sections of text so that the text can be easily and 
meaningfully searched (31). Code definitions will be documented in a code book and will 
include information about the code’s central meaning and may also provide examples of text 
considered within and outside the code’s parameters (30). To ensure inter-coder reliability, all 
transcripts will be double-coded (i.e. by two separate coders who will compare and reconcile 
coding results);  
3) Displaying: Once transcripts have been coded, principle sub-themes will be identified within 
each code that reflect finer distinctions in the data;  
4) Data Reduction: Matrices and tables that categorize and display data will be used to help the 
analysts understand the dimensions by which the data are categorized and facilitate 
comparisons (31);  
5) Interpretation: Themes will be identified and explained. Relationships between themes and 
speakers (e.g. adolescents/parents, assigned male/female at birth, older/younger adolescents) 
will be mapped to highlight similarities and differences of perspective. 
 
 
12 
DATA HANDLING AND RECORD KEEPING 
 
12.1 
Data Management Responsibilities 
 
As described in Section 4.7, data on screening and enrollment in this study will be collected using 
the DMC SES.  
 
Study sites must maintain adequate and accurate research records containing all information 
pertinent to the study for all screened and enrolled adolescent participants, and all enrolled 
parents/caregivers, including paper-based CRFs (if used), eCRFs, and supporting source data. In 
maintaining these records, sites must comply with the standards of source documentation 
specified in the DAIDS Site Clinical Operations and Research Essentials (SCORE) Manual, 
which is available at: https://www.niaid.nih.gov/research/daids-clinical-site-implementation-
operations. 
 
eCRFs and an eCRF completion guide will be made available to study sites by the DMC. Study 
site staff will enter required data into eCRFs, with system checks applied and data queries 
generated immediately upon saving the entered data. Data must be entered within timeframes 
specified by the DMC; queries must also be resolved in a timely manner. Selected laboratory data 
will be transferred electronically to the DMC through the LDMS.  
 
The Protocol Team and/or study oversight bodies (e.g., SMC or DSMB) may determine that 
additional source data associated with procedures or evaluations performed per protocol should 
be entered into eCRFs so that the data can be used for analysis or to otherwise assist with 
interpretation of study findings. In such cases, sites will be officially instructed to enter the 
additional data into eCRFs from available source documentation.  
 
Further information on eCRFs and IMPAACT data management procedures will be provided by 
the DMC. A User Manual for the Subject Enrollment System is available on the DMC portal at: 
 https://www.frontierscience.org 


 
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For US sites: The protocol interview team at the Children’s Hospital of Philadelphia (CHOP) will 
collect and manage qualitative phone interview data for the study. In-depth phone interview 
guides will be developed by the protocol interview team at CHOP and will receive IRB/EC 
review and approval. The protocol interview team at CHOP will conduct the phone interviews 
with participants (and parents/caregivers) using a secure teleconference platform. The phone 
interviews will be digitally-audio recorded, downloaded to a secure server, and subsequently 
transcribed by an external transcription service. The audio recordings and transcripts will be 
securely electronically transferred to the protocol interview team at CHOP. Transcripts will then 
be processed by the protocol interview team at CHOP for quality assurance, including ensuring 
that all personal identifiers have been removed. After completion of quality assurance processing, 
de-identified transcripts will be labeled as final source data of the phone interview. The audio 
recordings and transcripts generated by the external transcription service will be deleted from 
their secure server, as well as from any back-up servers. The audio recordings and finalized 
transcripts will be kept on a password-protected secure server at CHOP. At no time will study 
sites have access to the audio files or the transcripts. 
 
For US sites: The finalized transcriptions of interviews will be uploaded and managed by the 
protocol interview team at CHOP using a qualitative software package (e.g. NVivo). The DMC 
will serve as a repository for the following data, which will be securely transferred by the 
protocol interview team at CHOP:  finalized transcripts, codebook, and output data.  
 
12.2 
Essential and Source Documents and Access to Source Data 
 
Study sites must comply with requirements for essential documents and source documentation 
specified in the DAIDS SCORE Manual. This includes establishing SOPs for maintaining 
essential and source documents in compliance with these policies. Site SOPs should be updated 
and/or supplemented as needed to describe roles, responsibilities, and procedures for this study, 
and site SOPs should be followed throughout the study.  
 
For U.S. sites: In-depth qualitative phone interviews will be digitally audio-recorded and 
transcribed. See Section 12.1 above regarding data management and processing of the audio files 
and transcripts. 
 
Per the DAIDS policy on Storage and Retention of Clinical Research Records, study records must 
be stored in a manner that ensures privacy, confidentiality, security, and accessibility during the 
conduct of the study and after the study is completed. Records must be retained for a minimum of 
three years after the completion of the study. Per 21 CFR 312.62, records must be maintained for 
two years after the date a marketing application is approved for one or more of the study products 
for the indication for which it is evaluated in this study; or, if no application is filed, or if the 
application is not approved for this indication, records must be retained two years after the study 
is discontinued and the FDA is notified. 
 
All study records must be accessible for inspection, monitoring, and/or auditing during and after 
the conduct of the study by authorized representatives of the study sponsors and their contracted 
monitors, IMPAACT, ViiV Healthcare, Janssen Pharmaceuticals, the US Food and Drug 
Administration, site drug regulatory authorities, site IRBs/ECs, the sIRB (for US sites), OHRP, 
and other US, local, and international regulatory entities. Records must be kept on-site throughout 
the period of study implementation; thereafter, instructions for off-site storage may be provided 
by NIAID. No study records may be removed to an off-site location or destroyed prior to 
receiving approval from NIAID.  


 
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12.3 
Quality Control and Quality Assurance 
 
Study sites must ensure that essential documents and participant research records are subject to 
continuous quality control and quality assurance procedures consistent with the DAIDS SCORE 
Manual. 
 
 
13 
CLINICAL SITE MONITORING 
 
Site monitors under contract to NIAID or NICHD will visit study sites to inspect study facilities 
and review participant study records including consent and/or assent forms, paper-based CRFs (if 
used), eCRFs, medical records, laboratory records, and pharmacy records, to ensure protection of 
study participants, compliance with the IRB/EC approved protocol, and accuracy and 
completeness of records. The monitors will also review essential document files to ensure 
compliance with all applicable regulatory requirements. Site investigators will make study 
facilities and documents available for inspection by the monitors.  
 
Monitoring visits may be conducted on-site or remotely. Remote visits may include remote 
source document verification using methods specified for this purpose by NIAID or NICHD. 
Remote monitoring visits may be performed in place of, or in addition to, onsite visits to ensure 
the safety of study participants and data integrity(32). Site investigators will make available study 
documents for site monitors to review utilizing a secure platform that is 21 CFR Part 11 and 
HIPAA compliant. Potential platform options include: Veeva SiteVault, Medidata Rave Imaging 
Solution, site-controlled SharePoint or cloud-based portal, and direct access to electronic medical 
records. Other secure platforms that are 21 CFR Part 11 and HIPAA compliant may be utilized, 
as allowed by DAIDS Office of Clinical Site Oversight (OCSO) or NICHD. 
 
 
14 
HUMAN SUBJECTS PROTECTIONS 
 
14.1 
Institutional Review Board/Ethics Committee Review and Approval  
 
Prior to study initiation, site investigators must obtain IRB/EC review and approval of this 
protocol and site-specific informed consent and assent forms in accordance with 45 CFR 46; 
subsequent to initial review and approval, IRBs/ECs must review the study at least annually. Site 
investigators must promptly report to the IRBs/ECs any changes in the study and must comply 
with the requirements of 45 CFR 46.108(a)(4) and 21 CFR 56.108(b) for promptly reporting the 
following: unanticipated problems involving risks to participants or others; serious or continuing 
noncompliance with applicable regulations or the requirements or determinations of their 
IRBs/ECs; and any suspension or termination of IRB approval. 
 
All IRB/EC policies and procedures must be followed and complete documentation of all 
correspondence to and from the IRBs/ECs must be maintained in site essential document files. 
Sites must submit documentation of both initial review and approval, and continuing review to 
the DAIDS Protocol Registration Office (PRO) in accordance with the DAIDS Protocol 
Registration Manual (see also Section 15.2). 
 


 
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14.2 
Vulnerable Participants 
 
It is NIH policy to ensure that children be included in clinical research when appropriate (33, 34). 
This study responds to that mandate and will provide clinical research data to inform oral CAB, 
CAB LA, RPV LA, as well as oral CAB + oral RPV, and CAB LA + RPV LA safety and dosing 
in children and adolescents. Nonetheless, the children and adolescents who take part in this study 
are considered vulnerable participants per the US Code of Federal Regulations, and IRBs/ECs 
must consider the potential risks and benefits to child and adolescent participants as described in 
45 CFR 46 Subpart D (for children). 
 
With respect to 45 CFR 46 Subpart D, IRBs/ECs must determine the level of risk to children in 
the categories specified in 45 CFR 46.404-407. Documentation of this determination is required 
to complete the DAIDS protocol registration process described in Section 15.2, and the risk 
category assigned by the IRB/EC further determines the parental informed consent requirements 
for the study at each site. Per 45 CFR 46.408 (b), the IRB/EC may find that the consent of one 
parent is sufficient for research to be conducted under 46.404 or 46.405. If the IRB/EC finds that 
the research is covered by 46.406 or 46.407, both parents must give their consent, unless one 
parent is deceased, unknown, incompetent, or not reasonably available or when only one parent 
has legal responsibility for the care and custody of the child (as determined locally). IRBs/ECs 
must document their risk determination, and study sites should adapt the signature pages of their 
site-specific ICFs as needed to accommodate the parental consent requirements associated with 
the IRB/EC determination. 
 
Study sites must comply with the requirements for enrolling minors in clinical research specified 
in the DAIDS SCORE Manual. In addition, to the US regulations cited above, sites must also 
comply with all applicable local and national and international guidelines and regulations. In 
cases where multiple different sets of requirements apply, the most stringent requirements must 
be followed. 
 
14.3 
Informed Consent 
 
This section provides details regarding informed consent and assent requirements and procedures 
for adolescents. Refer to Section 4.7 and the IMPAACT 2017 MOP for further information on 
informed consent and assent procedures for this study. 
 
As indicated in Section 4.1.2, site investigators and their designees will be required to determine 
participant age and ability to provide independent informed consent for study participation 
consistent with IRB/EC policies and procedures. Each site must establish SOPs, roles, and 
responsibilities for completing these determinations, and study staff involved in completing these 
determinations must have documented training in the relevant policies and procedures prior to 
study initiation.  
 
Written informed consent and written assent will be obtained for study participation as follows: 
 
• 
If the potential participant is not of legal age to provide independent informed consent as 
determined by site SOPs:  Parent, legal guardian, or other legally authorized representative 
must provide written informed consent for study participation and the potential participant 
must provide written assent for study participation.  
 


 
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Note:  Refer to Section 14.2 for considerations related to parental consenting requirements; 
IRB/EC risk determinations will guide whether the consent of one or both parents may be 
required for this study. All IRB/EC requirements must be followed.  
 
• 
If the potential participant is of legal age and able to provide independent informed consent 
as determined by site SOPs:  The potential participant must provide written informed consent 
for study participation. 
 
Written informed consent and assent (as applicable) for participation will be obtained before any 
study-specific procedures are performed. The informed consent process will include information 
exchange, detailed discussion, and assessment of understanding of all required elements of 
informed consent, including the potential risks, benefits, and alternatives to study participation. 
The process will describe what is known about the safety and tolerability of the study products 
and participants and parents/guardians will be extensively counseled on the importance of 
adherence to the study product regimen, as well as to cART regimen (for Cohort 1 and LSFU). 
The informed assent process will include a similar process, with the amount of information and 
level of detail provided as part of assent processes tailored to the age of the potential participant, 
guided by IRB/EC policies and procedures.  
 
As part of the informed consent and assent process, consenters will be asked whether they agree 
to storage and future research testing of biological specimens remaining after all protocol-
specified testing has been performed. This storage and future use is optional and may be declined 
with no impact on other aspects of study participation. Likewise, genetic testing of residual 
specimens is optional and may be declined.  
 
Appendix II provides sample informed consent forms, including a section of the form for 
indicating consent to storage and future research testing. Appendix III provides sample informed 
assent forms for adolescents who are unable to provide consent (i.e., require parent or legal 
guardian consent for study participation), including a section of the form for indicating assent to 
storage and future research testing. For the Cohort 2 assent forms, a section is also included to 
indicate the participant’s choice of either Cohort 2A or Cohort 2B. All sample informed consent 
and assent forms provided in AppendicesAppendix II and Appendix III may be modified by sites 
to meet IRB/EC requirements. Study sites are permitted to develop separate assent and consent 
forms for this study, if required by site or IRB/EC policies and procedures; for example, sites may 
develop one assent form for children 12 years of age at lower reading and comprehension levels 
than another assent form for children 13 to less than 18 years of age. 
 
If the participant, parent, or guardian (as applicable) is unable to read, the process for consenting 
illiterate participants, as defined or approved by the local IRB/EC, should be followed. Sites must 
also establish and maintain written procedures describing standards for obtaining informed assent, 
reflective of applicable IRB/EC guidance. 
 
As indicated above, parental consenting requirements at each site will depend on the IRB/EC risk 
determination described in Section 14.2; all IRB/EC requirements will be followed. Participants 
enrolling in the study as minors will generally require consent from a parent or guardian.  
 
In general, each participant is expected to take part in the informed consent process with their 
parent or legal guardian, and both the assent of the participant and the consent of the parent or 
legal guardian will be required for all consent decisions. For example, if the participant does not 
provide assent, or the parent or legal guardian does not provide consent, the participant will not 
be enrolled in the study. The same approach will be taken for consent for storage and future 


 
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research testing of biological specimens. However, should the participant be unaware of his/her 
HIV status, the informed consent process may be conducted with the parent or legal guardian 
separately and without the presence of the participant, per IRB/EC policies. In these 
circumstances, the assent process must be conducted with both the parent or legal guardian and 
the participant present. Per IRB/EC policies, sites may modify the consent and/or assent (as 
applicable) forms and processes to remove mentioning of HIV for participants who do not know 
their status.  
 
Should the consenting parent (or guardian) of a participant die or no longer be available for any 
reason, sites should follow the guidelines and procedures in Section 8.8, in addition to those 
described by their IRBs/ECs. Study sites may continue to provide care for the participant as 
needed and appropriate (outside of the study), consistent with local standard of care. If a guardian 
cannot be identified, or if the guardian does not consent to continued study participation, the 
participant must be withdrawn from the study. In accordance with the DAIDS requirements for 
enrolling minors in clinical research (as specified in the DAIDS SCORE Manual), all sites must 
establish and maintain written procedures describing the standards that will be followed to 
identify who may serve as guardian for an enrolled child or adolescent, reflective of applicable 
IRB/EC guidance for conduct of human subjects research within the context of available local 
law, regulation, or government policy.  
 
Participants may also reach the legal age of consent during follow-up. In this case, written 
informed consent for continued participation and specimen storage and future use (Appendix II-
A, Appendix II-B, or Appendix II-C, as applicable) will be obtained from participants once they 
reach legal age at their next study visit. If participants do not consent for continued study 
participation, they should be discontinued from the study; similarly, if they do not consent for 
specimen storage and future use, all specimens will be destroyed after all protocol-related testing 
is complete. 
 
See Appendix IV for informed consent considerations for parent/caregivers who may enroll to the 
study to participate in a single in-depth qualitative phone interview.  
 
14.4 
Potential Benefits 
 
There may be no direct benefit to participants who take part in this study although there is a 
potential benefit for improved understanding of, and engagement in, HIV care. Information 
learned in this study may be of benefit to participants and others in the future, particularly 
information that may lead to more treatment options for children and adolescents living with 
HIV. As mentioned in Section 1.4 there is also the potential risk-benefit of early access to Cohort 
2 and its related benefits with the opportunity to stop oral cART and switch to an entirely long-
acting injectable regimen. Lastly, participants may also appreciate the opportunity for themselves 
to contribute to HIV-related research. 
 
14.5 
Potential Risks  
 
The potential risks of participation in this study include risks associated with study procedures 
and risks associated with receipt of CAB and RPV.  
 
Most study procedures are routine medical procedures that are associated with minimal to no risk 
in participants. Blood collection may cause pain, bruising, swelling, or fainting. There is a very 
small chance of infection where the needle is inserted, though the injections may cause pain, 
swelling, reddening of the skin, and nodule formations where the needle is inserted. 


 
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Although there is already a great deal of robust safety, PK and efficacy data in adults, these drugs 
have not yet been studied in adolescents. There may also be additional risks associated with use 
of these study products in adolescence. Refer to Section 1.2.3 for a complete description of the 
potential risks associated with the use of these drugs.  
 
A preliminary analysis of an ongoing birth outcome surveillance study in Botswana involving 
women exposed to DTG a different molecule in the same integrase class of medications as CAB, 
identified five cases (as of March 2019) of neural tube defects in 1,683 infants born to mothers 
who were exposed to DTG-containing regimens from the time of conception. In the same study, 
one infant born to a woman who started DTG during pregnancy had a neural tube defect, out of 
3,840 women. More recent data from this same study suggest an even lower incidence of neural 
tube defects amongst women taking dolutegravir-containing regimens from the time of 
conception.  A causal relationship of these events to the use of DTG has not been established. The 
incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live 
births. As neural tube defects occur within the first 4 weeks of fetal development (at which time 
the neural tubes are sealed) this potential risk would concern women exposed to DTG at the time 
of conception and in early pregnancy. Cabotegravir is not dolutegravir. While these medications 
share a common molecular backbone, and have a similar mechanism of activity, they are separate 
chemical compounds and have differences in antiviral activity, pharmacokinetics, metabolism and 
drug-drug interactions. It is not known if the safety signal identified with dolutegravir will be 
observed with cabotegravir. Cabotegravir was evaluated in a complete package of reproductive 
toxicology studies, including embryofetal development studies, and no safety findings suggestive 
of teratogenesis or neural tube defects were identified in the 17 December 2019 version of the 
Investigator’s Brochure. Every effort will be made in this study to avoid the occurrence of 
pregnancies among participants. 
 
The CAB LA and RPV LA injections are long-acting and may be present in the participant’s 
blood one year, and for some participants more than one year, after a single injection. The amount 
of drug will decrease overtime and will eventually disappear. 
 
For virologically suppressed, ART-experienced participants enrolling into Cohort 2, and dropping 
their background cART, there is the potential risk that the study products may not be as effective 
in maintaining viral suppression as participants’ current regimen. 
 
Despite all efforts to maintain confidentiality, involvement in the study could become known to 
others, possibly leading to unfair treatment, discrimination, or other social impacts (e.g., because 
participants could become known as having HIV). For example, participants could be treated 
unfairly or discriminated against or could have problems being accepted by their families and/or 
communities. Refer to Section 14.7 for further information on privacy and confidentiality.  
 
14.6 Reimbursement/Compensation 
 
Pending IRB/EC approval, participants will be reimbursed for costs associated with completing 
study visits (e.g., transport costs). Reimbursement amounts will be specified in site-specific ICFs 
or other materials if applicable per IRC/EC policies and procedures.  
 


 
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14.7 
Privacy and Confidentiality 
 
All study procedures will be conducted in private and every effort will be made to protect 
participant privacy and confidentiality to the extent possible. Participant information will not be 
released without written permission from the parent/guardian, as well as the adolescent, to do so 
except as necessary for review, monitoring, and/or auditing as described in Section 12.2. 
 
All study-related information will be stored securely. Participant research records will be stored 
in locked areas with access limited to study staff. All laboratory specimens, CRFs, and other 
documents that may be transmitted off-site (e.g., EAE report forms) will be identified by PID 
only. Likewise, communications between study staff and protocol team members regarding 
individual participants will identify participants by PID only. Audio files and transcripts will be 
kept on a secure and password protected server with the protocol interview team, and will be 
identified by PID only when transmitted to contracting services (e.g., a transcription service 
provider).  
 
Study sites are encouraged but not required by DAIDS to store study records that bear participant 
names or other personal identifiers separately from records identified by PID. All local databases 
must be secured with password protected access systems. Lists, logbooks, appointment books, 
and any other documents that link PID numbers to personal identifying information should be 
stored in a separate, locked location in an area with limited access.  
 
In addition to the above, a Certificate of Confidentiality has been obtained for this study from the 
US Department of Health and Human Services. This certificate protects study staff from being 
compelled to disclose study-related information by any US Federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings. It thus serves to protect the identity and privacy 
of study participants. Because the certificate cannot be enforced outside of the US, however, it 
applies only to US sites and participants. 
 
14.8 
Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases including HIV 
identified among study participants to health authorities. Participants will be made aware of all 
applicable reporting requirements as part of the study informed consent process. 
 
14.9 
Management of Incidental Findings 
 
Site clinicians will inform parents (or other authorized guardians if applicable) of all clinically 
meaningful physical exam findings and laboratory test results, including results of HIV tests (if 
applicable), and hematology and chemistry tests. Pregnancy test results will be disclosed to 
participants and their parent/guardians consistent with local standards of care; local standard 
procedures will be noted in site-specific informed consent and assent forms. When applicable, 
site clinicians will provide referrals to non-study sources of medical care for further evaluation 
and/or treatment of these findings. 
 


 
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14.10 Management of New Information Pertinent to Study Participation 
 
Participants, and their parent (or other authorized guardians if applicable) will be provided any 
new information learned over the course of the study that may affect their willingness to allow 
their adolescent to continue receiving study product and/or remain in follow-up in the study.  
 
14.11 Post-Trial Access to Study Product 
 
Participants will be transitioned into care and treatment outside of the study at the end of their 
study participation. If CAB LA + RPV LA is not locally available for a participant in Cohort 2 
completing the study, then the pharmaceutical company or their partners will provide access to 
CAB LA + RPV LA following the participant’s completion of the study through a mechanism 
outside of the IMPAACT 2017 protocol until one or both of the following events occur:  
• 
CAB LA + RPV LA is available from another source (e.g., government programs, aid 
programs, assistance programs, etc.); OR 
• 
If development of CAB LA + RPV LA is terminated. 
 
 
15 
ADMINISTRATIVE PROCEDURES 
 
15.1 
Regulatory Oversight 
 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), 
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), 
and National Institute of Mental Health (NIMH), which are part of the United States National 
Institutes of Health (NIH). Study products are provided by ViiV Healthcare; however, this 
organization is not involved in sponsorship or regulatory oversight of this study.  
 
The Division of AIDS (DAIDS) within the NIAID is responsible for regulatory oversight of this 
study. DAIDS will distribute safety-related information pertaining to the study products prior to 
and during the conduct of the study, in accordance with its sponsor obligations.  
 
NIAID and NICHD provide funding to the clinical research sites at which this study will be 
conducted. Each institute contracts with an independent clinical site monitoring group to perform 
clinical site monitoring as described in Section 13. As part of these visits, monitors will inspect 
study-related documentation to ensure compliance with all applicable US, local, and international 
regulatory requirements. 
 
15.2 
Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol ICFs approved, as appropriate, by applicable IRBs/ECs, 
and any other applicable regulatory entity. Upon receiving final approval, sites will submit all 
required protocol registration documents to the DAIDS PRO at the RSC. The DAIDS PRO will 
review the submitted protocol registration packet to ensure that all of the required documents 
have been received.  
 


 
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Site-specific ICFs will be reviewed and approved by the DAIDS PRO and sites will receive an 
Initial Registration Notification from the DAIDS PRO that indicates successful completion of the 
protocol registration process. A copy of the Initial Registration Notification should be retained in 
the site's regulatory files. 
 
For any future protocol amendments, upon receiving final IRB/EC and any other applicable 
regulatory entity approvals, as well as meeting any additional study specific requirements as 
determined by the protocol team, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the RSC. The DAIDS 
PRO will review the submitted protocol registration packet to ensure that all the required 
documents have been received. Site-specific ICFs will NOT be reviewed and approved by the 
DAIDS PRO and sites will receive an Amendment Registration Notification when the DAIDS 
PRO receives a complete registration packet. A copy of the amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific documents required 
for initial and amendment registrations, refer to the current version of the DAIDS Protocol 
Registration Manual, which is available on the RSC website: https://rsc.niaid.nih.gov/clinical-
research-sites/daids-protocol-registration-policy-and-procedures-manual 
 
15.3 
Study Implementation 
 
This study will be conducted in accordance with the protocol, international good clinical practice 
guidelines, and all applicable US, local, and international regulations. Study implementation will 
also be guided by the IMPAACT MOP, study-specific MOP, LPC, and other study 
implementation materials, which will be available on the IMPAACT web site:  
www.impaactnetwork.org. 
 
Study implementation at each site will also be guided by site-specific SOPs. The DAIDS SCORE 
Manual specifies the minimum set of SOPs that must be established at sites conducting DAIDS 
funded and/or sponsored clinical trials. These SOPs should be updated and/or supplemented as 
needed to describe roles, responsibilities, and procedures for this study.  
 
15.4 
Protocol Deviation Reporting 
 
Per the requirements for source documentation specified in the DAIDS SCORE Manual, all 
protocol deviations must be documented in participant research records. Reasons for the 
deviations and corrective and preventive actions taken in response to the deviations should also 
be documented.  
 
Deviations should be reported to applicable IRBs/ECs and other applicable review bodies in 
accordance with the policies and procedures of these review bodies. Serious deviations that are 
associated with increased risk to one or more study participants and/or significant impacts on the 
integrity of study data must also be reported within IMPAACT, following procedures specified in 
the IMPAACT Network Manual of Procedures. 
 
 
15.5 
ClinicalTrials.gov 
 


 
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The NIH Policy on Dissemination of NIH-funded Clinical Trial Information establishes the 
expectation that clinical trials funded in whole or in part by the NIH will be registered and have 
summary results information submitted to ClinicalTrials.gov for public posting. The Protocol 
Team will comply with this policy as well as the requirements of 42 CFR 11. 
 
 
16 
PUBLICATIONS 
 
All presentations and publications of data collected in this study are governed by IMPAACT 
policies, which are available in the IMPAACT Network Manual of Procedures.   
 
 
17 
REFERENCES 
 
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3. 
Santer M, Ring N, Yardley L, Geraghty AW, Wyke S. Treatment non-adherence in pediatric 
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Zanoni BC, Mayer KH. The adolescent and young adult HIV cascade of care in the United States: 
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Achhra AC, Mwasakifwa G, Amin J, Boyd MA. Efficacy and safety of contemporary dual-drug 
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7. 
Boffito M, Jackson A, Owen A, Becker S. New approaches to antiretroviral drug delivery: 
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Landovitz RJ, Kofron R, McCauley M. The promise and pitfalls of long acting injectable agents 
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9. 
Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, Eron JJ, Yazdanpanah Y, Podzamczer D, et al. 
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2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 
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10. 
Orkin C, Arasteh K, Górgolas Hernández-Mora M, Pokrovsky V, Overton ET, Girard PM, et al. 
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11. 
Swindells S, Andrade-Villanueva JF, Richmond GJ, Rizzardini G, Baumgarten A, Masiá M, et al. 
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12. 
Overton ET, Richmond GJ, Rizzardini G, Jaeger H, Orrell C, Nagimova F, et al. Cabotegravir + 
rilpivirine every 2 months is noninferior to monthly: ATLAS-2M study. In: Conference on 
Retroviruses and Opportunistic Infections; 8-11 March 2020; Boston, MA. Available from: 
https://www.croiconference.org/abstract/cabotegravir-rilpivirine-every-2-months-is-noninferior-
to-monthly-atlas-2m-study/. 


 
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13. 
ViiV Heathcare. Investigator's brochure for GSK1265744 (cabotegravir), edition 11. 22 Feb 
2021. 
14. 
New study suggests risk of birth defects in babies born to women on HIV medicine dolutegravir 
[press release]. 2018. 
15. 
Janssen. Edurant® (rilpivirine) tablets for oral use [package insert, revised 05/2019]. Titusville, 
NJ, USA: Janssen Products, LP; 2019. 
16. 
Janssen Research & Development. Investigator's brochure for TMC278 (rilpivirine, oral and 
parenteral), edition 14. 8 Jul 2021. 
17. 
Lombaard J, Bunupuradah T, Flynn PM, Ramapuram J, Ssali F, Crauwels H, et al. Rilpivirine as 
a treatment for HIV-infected antiretroviral-naive adolescents: Week 48 safety, efficacy, virology 
and pharmacokinetics. Pediatr Infect Dis J. 2016;35(11):1215-21. 
18. 
Eron J, Margolis, D., Gonzalez-Garcia, J., Stellbrink, H-J., Yazdanpanah, Y., Podzamczer, D.,  
Lutz, T., Angel, JB., Richmond, GJ., Clotet, B., Gutierrez, F., Sloan, L., Sutton, KC.,  Dorey, D., 
Smith, KY., Williams, PE., Spreen, WR., editor Safety and efficacy of long-acting CAB and RPV 
as two drug im maintenance therapy: LATTE-2 week 96 results. 9th IAS Conference on HIV 
Science; 2017; Paris, France. 
19. 
Orkin C, Oka S, Philibert P, Brinson C, Bassa A, Gusev D, et al. Long-acting cabotegravir plus 
rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, open-
label, phase 3 FLAIR study. Lancet HIV. 2021;8(4):e185-e96. 
20. 
Orkin C, Bernal Morell E, Tan DHS, Katner H, Stellbrink H-J, Belonosova E, et al. Initiation of 
long-acting cabotegravir plus rilpivirine as direct-to-injection or with an oral lead-in in adults 
with HIV-1 infection: Week 124 results of the open-label phase 3 FLAIR study. The Lancet HIV. 
2021;8(11):e668-e78. 
21. 
Jaeger H, Overton ET, Richmond G, Rizzardini G, Andrade-Villanueva JF, Mngqibisa R, et al. 
Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection 
(ATLAS-2M), 96-week results: A randomised, multicentre, open-label, phase 3b, non-inferiority 
study. The Lancet HIV. 2021;8(11):e679-e89. 
22. 
Moore C, Capparelli E, Calabrese K, Best B, Ward S, McCoig C, et al., editors. Safety and PK of 
long-acting cabotegravir and rilpivirine in adolescents. CROI 2022. 2022 Conference on 
Retroviruses and Opportunistic Infections 2022. 
23. 
ViiV Healthcare G. Cabenuva® (cabotegravir extended-release injectable suspension; rilpivirine 
extended-release injectable suspension), [package insert, revised 03/2022]. GlaxoSmithKline; 
2022. 
24. 
Momper JD, Mulugeta Y, Green DJ, Karesh A, Krudys KM, Sachs HC, et al. Adolescent dosing 
and labeling since the food and drug administration amendments act of 2007. JAMA pediatrics. 
2013;167(10):926-32. 
25. 
Orkin C, Oka S, Philibert P, Brinson C, Bassa A, Gusev D, et al. Long-acting cabotegravir + 
rilpivirine for HIV treatment: FLAIR week 96 results. In: Conference on Retroviruses and 
Opportunistic Infections; 8-11 March 2020; Boston, MA. Available from: 
https://www.croiconference.org/abstract/long-acting-cabotegravir-rilpivirine-for-hiv-treatment-
flair-week-96-results/. 
26. 
U.S. Department of Health and Human Services. FDA guidance on conduct of clinical trials of 
medical products during COVID-19 pandemic - guidance for industry, investigators, and 
institutional review boards. In: (FDA) FaDA, editor. 2020. 
27. 
European Medicines Agency (EMA). Guidance on the management of clinical trials during the 
COVID-19 (coronavirus) pandemic. 2020. 
28. 
European Medicines Agency (EMA). Points to consider on implications of coronavirus disease 
(COVID-19) on methodological aspects of ongoing clinical trials. 2020. 
29. 
Bernard HR, Wutich A, Ryan GW. Analyzing qualitative data: Systematic approaches: SAGE 
publications; 2016. 


 
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30. 
Ulin PR, Robinson ET, Tolley EE. Qualitative methods in public health. San Francisco, CA: 
JosseyBass. 2005. 
31. 
Miles MB, Huberman AM. Qualitative data analysis: An expanded sourcebook: SAGE; 1994. 
32. 
FDA guidance on conduct of clinical trials of medical products during the COVID-19 public 
health emergency: Guidance for industry, investigators, and institutional review boards. March 
2020. [updated January 27, 2021. Available from: https://www.fda.gov/media/136238/download.  
33. 
National Institutes of Health. Guidelines for the inclusion of women and minorities as subjects in 
clinical research. Federal register.; 1994 March 18. 
34. 
National Institutes of Health. NIH policy and guidelines on the inclusion of children as 
participants in research involving human subjects. 1998 March 6. 
 


 
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Appendix I: Schedule of Evaluations 
Appendix I-A: Schedule of Evaluations for Cohort 1 Adolescents (Cohort 1C and Cohort 1R)  
Cohort 1 (CT 1) 
Study Visit1 
CT 1 
Screen 
Step 1 (oral phase) 
Step 2 (injection phase) 
 
CT 1 
Entry 
  
CT 1 
Wk 2 
  
CT 1 
Wk 4a 
  
 CT 1  
Wk 4b  
(Step 2 Entry) 
CT 1 
Wk 5 
  
CT 1 
Wk 8 
  
CT 1 
Wk 9 
  
CT 1 
Wk 12 
  
CT 1 
Wk 16 
  
Confirmation of 
Virologic 
Failure 
Behavioral Evaluations 
Acceptability/Tolerability assessment2 
 
X  
* 
*  
X 
*  
X  
  
 
X  
  
Qualitative Interview3 
  
  
  
  
* 
* 
* 
* 
*  
  
  
Clinical Evaluations 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence assessment 
 
 
X 
X 
X 
 
 
 
 
 
 
Complete physical examination 
X 
 
 
X 
 
 
 
 
 
X 
 
Symptom-directed physical examination 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
Sexual Maturity Rating 
X 
 
 
 
 
 
 
 
 
X 
 
ECG4 
X 
 
 
 
 
 
 
X 
 
X 
 
Study Product 
Dispense oral study product (for up to 6 
wks) 
  
X 
* 
* 
  
  
  
  
  
  
  
Administer injection study product 
  
  
  
  
X 
  
X 
  
  
  
  
Laboratory Evaluations 
hCG (females only) 
X 
X 
X 
X 
X 
  
X 
  
  
X 
X 
Confirmation of HIV infection 
0-6 mL* 
 
  
  
  
  
  
  
  
  
  
Hematology 
2 mL 
2 mL 
2 mL 
2 mL 
  
2 mL 
2 mL 
  
  
2 mL 
  
Chemistries 
3 mL 
3 mL 
3 mL 
3 mL 
  
3 mL 
3 mL 
  
  
3 mL 
  
CD4 count and percentage 
 
3 mL 
 
 
 
 
 
 
 
3 mL 
 
HIV-1 RNA 
6 mL 
6 mL 
6 mL 
  
6 mL 
  
6 mL 
  
  
6 mL 
6 mL 
Whole blood for genotypic resistance 
testing5 
 
4 mL 
 
 
 
 
 
 
 
 
 
Plasma for genotypic and phenotypic 
resistance testing5 
 
 
6 mL 
  
6 mL 
  
6 mL 
  
  
6 mL 
6 mL 
Pharmacology Evaluations 
PK Sampling6 
  
  
6-12 mL 
  
4 mL 
2 mL 
2 mL 
2 mL  
2 mL 
2 mL 
2 mL  
Total maximum blood volume 
11-17 mL 
18 mL 
23-29 mL 
5 mL 
16 mL 
7 mL 
19 mL 
2 mL  
2 mL 
22 mL 
14 mL 
Notes:  X – required; * - if indicated 


 
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1) Target dates and visit windows may vary per visit. See Section 6.3 for Cohort 1 study visits, procedures, and target dates associated with each visit. See Section 6.1 for 
further details regarding target dates, target visit windows, and allowable visit windows. See Section 0 and Appendix I-D for details on conducting an Early Termination 
visit. 
2) Acceptability/tolerability assessment questionnaires will be administered at the following Cohort 1 study visits (required): Step 1 Entry, Week 4b, Week 8, and Week 16. 
Additionally, acceptability/tolerability assessment questionnaires will be administered at indicated visits should premature permanent study product discontinuation be 
initiated (noted in the table as if indicated). See Section 6.15 and the IMPAACT 2017 MOP for further details on the specific questionnaires and timing of administration. 
3) Only a sub-set of participants will be selected for the qualitative phone interview. For selected Cohort 1 participants, the qualitative phone interview may be conducted 
between and including the Week 4b and Week 12 visits (noted in the table as if indicated). See Section 11 for qualitative interview window and details on participant 
selection. 
4) See Section 6.12 for details regarding performing an ECG/EKG. 
5) HIV genotypic and phenotypic resistance samples (collected at the Confirmation of Virologic Failure visit and other visits) will be processed, stored, and shipped for 
testing per Section 6.16.2 and the LPC. 
6) See Sections 6.3 and 6.6 for PK sample collection timepoints and windows. 
 
 
 


 
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Appendix I-B: Schedule of Evaluations for Cohort 2A Adolescents 
 
Cohort 2A (CT 2A) 
Study Visit1 
CT 2A 
Screen 
Step 3 (oral phase) 
Step 4 (injection phase) 
Confirmation 
of Virologic 
Failure 
CT 2A 
Entry 
CT 2A 
Wk 2 
CT 2A 
Wk 4a 
CT 2A  
Wk 4b 
(Step 4 
Entry) 
CT 
2A 
Wk 5 
CT 2A 
Wks 8 
and 16 
CT 2A 
Wk 24 
CT 2A 
Wk 25 
CT 2A 
Wks 32 
and 40 
CT 2A 
Wk 48 
CT 2A 
Wks 56, 
64, 72, 80, 
and 88 
CT 2A 
Wk 96 
Interim 
Injection 
Visit7 
Behavioral Evaluations 
Acceptability/ 
Tolerability 
assessment2 
 
X 
* 
* 
X 
* 
Wk 8 (X) 
Wk 16(*) 
X 
* 
* 
X 
* 
X 
 
 
Qualitative 
Interview3 
 
 
 
 
 
 
 
* 
* 
* 
* 
* 
* 
 
 
Clinical Evaluations 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence 
assessment 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Symptom-directed 
physical 
examination 
 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Sexual Maturity 
Rating 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
ECG4 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study Product 
Dispense oral study 
products (for up to 
6 wks) 
 
X 
* 
* 
 
 
 
 
 
 
 
 
 
 
 
Administer 
injection study 
products 
 
 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
Laboratory Evaluations 
hCG (females 
only) 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Confirmation of 
HIV infection 
0-6 mL* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
2 mL 
2 mL 
2 mL 
2 mL 
 
2 mL 
2 mL 
2 mL 
 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
 


 
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Chemistries  
3 mL 
3 mL 
3 mL 
3 mL 
 
3 mL 
3 mL 
3 mL 
 
3 mL 
3 mL 
3 mL 
3 mL 
3 mL 
 
CD4 count and 
percentage 
 
3 mL 
 
 
 
 
 
3 mL 
 
 
3 mL 
Only Wk 72 
(3 mL) 
3 mL 
 
 
HIV-1 RNA 
6 mL 
6 mL 
6 mL 
 
6 mL 
 
6 mL 
6 mL 
 
6 mL 
6 mL 
Only Wks 
64 and 80 
(6 mL) 
6 mL 
6 mL 
6 mL 
Whole blood for 
genotypic 
resistance testing5 
 
4 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma for 
genotypic and 
phenotypic 
resistance testing5 
 
 
6 mL 
 
6 mL 
 
6 mL 
6 mL 
 
6 mL 
6 mL 
Only Wks 
64 and 80 
(6 mL) 
6 mL 
6 mL 
6 mL 
Pharmacology Evaluations 
PK Sampling6 
 
 
8 mL 
 
 8 mL 
4 mL 
4 mL 
4 mL 
4 mL 
4 mL 
4 mL 
Only Wks 
64, 80, and 
88  
(4 mL) 
4 mL 
4 mL 
4 mL 
Total maximum 
blood volume 
11-17 mL 
18 mL 
 25 mL 
5 mL 
 20 mL 
9 mL 
21 mL 
24 mL 
4 mL 
21 mL 
24 mL 
5-21 mL 
24 mL 
21 mL 
16 mL 
Notes:  X – required; * - if indicated 
1) Target dates and visit windows may vary per visit. See Section 6.4 for Cohort 2 study visits, procedures, and target dates associated with each visit. See Section 6.1 for 
further details regarding target dates, target visit windows, and allowable visit windows. See Section 0 and Appendix I-D for details on conducting an Early Termination 
visit. 
2) Acceptability/tolerability assessment questionnaires will be administered at the following Cohort 2A study visits (required): Step 3 Entry, Week 4b, 8, 24, 48, and Week 
96. Additionally, acceptability/tolerability assessment questionnaires will be administered at indicated visits should premature permanent study product discontinuation be 
initiated (noted in the table as if indicated). See Section 6.15 and the IMPAACT 2017 MOP for further details on the specific questionnaires and timing of administration  
3) Only a sub-set of participants will be selected for the qualitative phone interview. For selected Cohort 2A participants, the qualitative phone interview may be conducted 
between and including the Week 24 and Week 96 visits (noted in the table as if indicated). See Section 11 for qualitative interview window and details on participant 
selection. 
4)  See Section 6.12 for details regarding performing an ECG/EKG. 
5) HIV genotypic and phenotypic resistance samples (collected at the Confirmation of Virologic Failure visit and other visits) will be processed, stored, and shipped for 
testing per Section 6.16.2 and the LPC. 
6) See Sections 6.4 and 6.6 for PK sample collection timepoints and windows. 
7) See Section 6.4.14 for interim injection visit scheduling considerations and required procedures for Cohort 2 participants. 
 
 
 
 


 
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Appendix I-C: Schedule of Evaluations for Cohort 2B Adolescents 
 
Cohort 2B (CT 2B) 
Study Visit1 
CT 2B 
Screen 
Step 5 (injection phase) 
Confirmation of 
Virologic 
Failure 
CT 2B  
Entry 
(Step 5 
Entry) 
CT 2B 
Wk 1 
CT 2B 
Wks 4 
and 12 
CT 2B 
Wk 20 
CT 2B 
 Wk 21 
CT 2B 
Wks 28 
and 36 
CT 2B 
Wk 44 
CT 2B 
Wks 52, 60, 
68, 76, and 
84 
CT 2B 
Wk 92 
Interim 
Injection 
Visit7 
Behavioral Evaluations 
Acceptability/ 
Tolerability 
assessment2 
 
X 
* 
Wk 4 (X) 
Wk 12(*) 
X 
* 
* 
X 
* 
X 
 
 
Qualitative Interview3 
 
 
 
 
* 
* 
* 
* 
* 
* 
 
 
Clinical Evaluations 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical 
examination 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Symptom-directed 
physical examination 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Sexual Maturity Rating 
X 
 
 
 
X 
 
 
 
 
X 
 
 
ECG4 
X 
X 
 
 
 
 
 
 
 
 
 
 
Study Product 
Administer injection 
study products 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
Laboratory Evaluations 
hCG (females only) 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Confirmation of HIV 
infection 
0-6 mL* 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
 
2 mL 
2 mL 
2 mL 
2 mL 
2 mL 
 
Chemistries  
3 mL 
3 mL 
3 mL 
3 mL 
3 mL 
 
3 mL 
3 mL 
3 mL 
3 mL 
3 mL 
 
CD4 count and 
percentage 
 
3 mL 
 
 
3 mL 
 
 
3 mL 
Only Wk 68 
(3 mL) 
3 mL 
 
 
HIV-1 RNA 
6 mL 
6 mL 
 
6 mL 
6 mL 
 
6 mL 
6 mL 
Only Wks 60 
and 76 (6 
mL) 
6 mL 
6 mL 
6 mL 


 
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Whole blood for 
genotypic resistance 
testing5 
 
4 mL 
 
 
 
 
 
 
 
 
 
 
Plasma for genotypic 
and phenotypic 
resistance testing5 
 
 
 
6 mL 
6 mL 
 
6 mL 
6 mL 
Only Wks 60 
and 76 (6 
mL) 
6 mL 
6 mL 
6 mL 
Pharmacology Evaluations 
PK Sampling6 
 
 4 mL 
4 mL 
4 mL 
4 mL 
4 mL 
4 mL 
4 mL 
Only Wks 60, 
76, and 84  
(4 mL) 
4 mL 
4 mL 
4 mL 
Total maximum blood 
volume 
11-17 mL 
 22 mL 
9 mL 
21 mL 
24 mL 
4 mL 
21 mL 
24 mL 
5-21 mL 
24 mL 
21 mL 
16 mL 
Notes:  X – required; * - if indicated 
1) Target dates and visit windows may vary per visit. See Section 6.4 for Cohort 2 study visits, procedures, and target dates associated with each visit. See Section 6.1 for 
further details regarding target dates, target visit windows, and allowable visit windows. See Section 0 and Appendix I-D for details on conducting an Early Termination 
visit. 
2) Acceptability/tolerability assessment questionnaires will be administered at the following Cohort 2B study visits (required): Step 5 Entry, 4, 20, 44, and Week 92. 
Additionally, acceptability/tolerability assessment questionnaires will be administered at indicated visits should premature permanent study product discontinuation be 
initiated (noted in the table as if indicated). See Section 6.15 and the IMPAACT 2017 MOP for further details on the specific questionnaires and timing of administration  
3) Only a sub-set of participants will be selected for the qualitative phone interview. For selected Cohort 2B participants, the qualitative phone interview may be conducted 
between and including the Week 20 and Week 92 visits (noted in the table as if indicated). See Section 11 for qualitative interview window and details on participant 
selection. 
4) See Section 6.12 for details regarding performing an ECG/EKG. 
5) HIV genotypic and phenotypic resistance samples (collected at the Confirmation of Virologic Failure visit and other visits) will be processed, stored, and shipped for 
testing per Section 6.16.2 and the LPC. 
6) See Sections 6.4 and 6.6 for PK sample collection timepoints and windows. 
7) See Section 6.4.14 for interim injection visit scheduling considerations and required procedures for Cohort 2 participants. 
 
 
 


 
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Appendix I-D: Schedule of Evaluations for Long-Term Safety and Washout PK Follow-
Up (LSFU) Adolescents 
Study Visit1 
LSFU Week 
82 
LSFU Week 
24 
LSFU Week 
36 
LSFU Week 48/  
Early Termination3 
 
Confirmation of 
Virologic Failure 
Behavioral Evaluations 
Acceptability/ Tolerability 
assessment 
X 
 
 
X 
 
Qualitative Interview4 
* 
* 
* 
* 
 
Clinical Evaluations 
Medical history 
X 
X 
X 
X 
X 
Complete physical examination 
X 
 
 
X 
 
Symptom-directed physical 
examination 
 
X 
X 
 
X 
Sexual Maturity Rating 
 
 
 
X 
 
Laboratory Evaluations 
hCG (females only)5 
X 
X 
X 
X 
X 
Hematology  
2 mL 
2 mL 
2 mL 
2 mL 
 
Chemistries 
3 mL 
3 mL 
3 mL 
3 mL 
 
HIV-1 RNA 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
Plasma for genotypic and 
phenotypic resistance testing6 
6 mL 
6 mL 
6 mL 
6 mL (LSFU Week 48 
only) 
6 mL 
Whole blood for genotypic 
resistance testing3, 6 
 
 
 
4 mL (Early 
Termination visit only) 
 
Pharmacology 
PK Sampling7 
2-4 mL 
2-4 mL 
2-4 mL 
0-4 mL3,7 
2-4 mL7 
Total maximum blood volume 
19-21 mL 
19-21 mL 
19-21 mL 
15-21 mL 
14-16 mL 
Notes:  X – required 
1) Target dates and visit windows may vary per visit. See Section 6.5 for LSFU study visits, procedures, and target 
dates, and target visit windows associated with each visit.  
2) Participants completing the Cohort 1 Step 2 Week 16 visit will not complete the LSFU Week 8 visit.  
3) See Sections 0 and 6.7 for more details on conducting Early Termination visits. Participants completing an Early 
Termination visit will have whole blood collected for genotypic and phenotypic resistance testing. Cohort 1 Step 1 
and Cohort 2 Step 3 participants completing an Early Termination visit will not have a PK evaluation performed and 
a PK sample will not be collected. 
4) Only a sub-set of participants will be selected for the qualitative phone interview. For selected Cohort 1 or Cohort 2 
participants being followed per the LSFU schedule, the qualitative phone interview may be conducted between and 
including the LSFU Week 8 and LSFU Week 48 visits (noted in the table as if indicated). See Section 11 for 
qualitative interview window and details on participant selection. 
5) Pregnancy testing will not be required for participants who are currently pregnant. 
6) HIV genotypic and phenotypic resistance samples (collected at the Confirmation of Virologic Failure visit and other 
visits) will be processed, stored, and shipped for testing per Section 6.16.2 and the LPC. 
7) See Sections 6.5 and 6.6 for PK sample collection timepoints and windows. Cohort 1 Step 2 participants being 
followed per the LSFU visit schedule will have 2 mL collected for each PK sampling timepoint, whereas Cohort 2 
Step 4 and Step 5 participants being followed per the LSFU visit schedule will have 4 mL collection for each PK 
sampling timepoint.  
 


 
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Appendix II: Sample Informed Consent Forms 
  
Appendix II-A:  Sample Informed Consent Form for Participation in Cohort 1 
 
for adolescents who can provide independent informed consent for study participation and parents/legal guardians 
of adolescents 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 4.0, dated 27 May 2022 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
If you are the parent or legal guardian of a child who may take part in this study, your permission and the 
permission of your child will be needed.  When “you” appears in this form, it refers to your child except where it 
says otherwise. 
 
Introduction 
 
You are being asked to take part in the research study named above. 
 
This form gives information about the study. Please read it, or have it read to you, and ask any questions you may 
have. We will take as much time as needed for you to fully understand the study. We will ask you questions to see 
if we have explained the study clearly. 
 
Here is a summary of important information about the study: 
 
• 
The study is testing two anti-HIV medicines (ARVs), Cabotegravir (CAB) and Rilpivirine (RPV), taken as 
pills and given as long-acting shots in adolescents 12 to less than 18 years of age.  
• 
 Some of the study drugs are already approved in some countries for use in adolescents or adults, but more 
data is needed for use in adolescents.  
• 
There are two parts to this study, Cohort 1 and Cohort 2. This form is about Cohort 1. Adolescents who 
participate in Cohort 1 may qualify for Cohort 2 of the study after completing Cohort 1. 
• 
Participants in Cohort 1 will be in this part of the study for at least 4 months and up to 16 months. 
• 
Adolescents in Cohort 1 will continue taking their usual ARVs while also taking the study medicine. After 
entering the study, adolescents will take daily CAB or RPV pills for 4 to 6 weeks while taking their usual 
ARVs. Adolescents will then switch to getting CAB or RPV shots 4 weeks apart (for a total of 2 shots) while 
continuing to take their usual ARVs.  
• 
After the last shot, adolescents will be followed for up to 1 year for long-term safety follow-up. During this 
time, adolescents will not take any study medicine (shots or pills) but will continue taking their usual ARVs.   
• 
While in the study, adolescents will have clinic visits with physical examinations and blood draws for 
laboratory tests. Some visits will include a review of adolescents’ medical records and ECG tests to look at 
the adolescent’s heart. Participants assigned female at birth will also be tested for pregnancy.  
• 
If interested, participants in the U.S. may be eligible to do one in-depth phone interview where they will talk 
about their experience getting their ARV’s as shots. 


 
IMPAACT 2017, FINAL Version 4.0 
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• 
There are some possible risks for adolescents in the study. One possible risk is that the pills or shots being 
tested could cause side effects.  The most severe side effects include allergic reaction, liver problems, and 
mental health problems.  These side effects are uncommon. 
• 
There are some possible benefits for adolescents in the study. One possible benefit is a better understanding 
of your health and HIV care.  Another possible benefit is early access to the Cohort 2 part of the study, if you 
qualify.  
• 
Your decision on your participation in the study will have no effect on the medical care you receive at this 
clinic. Your access to services, and the benefits and rights you normally have, will not be affected. You may 
choose to leave the study at any time.  
 
More information is given in this form about the study, its risks and benefits. You should feel that you understand 
the study before deciding whether to participate. If you decide to participate, you will be asked to sign or make 
your mark on this form. You will be offered a copy to keep. 
 
About the study 
 
This study is being done by the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
(IMPAACT) and [insert site name]. The person in charge of the study at [insert site name] is [insert name of 
IoR].  
 
The study is being done to test two anti-HIV medicines (antiretrovirals or ARVs) in adolescents 12 to less than 18 
years old who have HIV. The study ARVs are called cabotegravir (CAB) and rilpivirine (RPV). HIV is the virus 
that can lead to AIDS.  
 
The study will include up to 155 adolescents from the United States, Botswana, South Africa, Thailand and 
Uganda. There will be two groups of adolescents, called Cohort 1 and Cohort 2. This form is about Cohort 1. 
Participants in Cohort 1 will be in the study for at least 16 weeks (4 months) and then up to an additional 48 
weeks (12 months) as part of long-term follow-up, for a total of 64 weeks (16 months).  
 
The United States National Institutes of Health and the companies that make CAB and RPV, ViiV Healthcare and 
Janssen Pharmaceuticals, are paying for this study.  
 
1. The study is testing CAB and RPV in adolescents. 
 
People living with HIV usually take a combination of ARVs daily to stay healthy. There are not as many ARVs 
available for adolescents as for adults because many ARVs have not yet been tested in adolescents. ARVs can be 
made in different forms, such as liquids, pills, and injections (shots). The study will test CAB and RPV when 
taken as pills and when given as shots in adolescents. The pills are taken every day. The shots can be given every 
4 weeks or every 8 weeks. The shots are being developed because it can be difficult to take pills every day, and 
some people may prefer to have the shots rather than taking pills.  
 
RPV pills (25 mg), RPV shots (600mg and 900mg), CAB pills (30mg), and CAB shots (400mg and 600mg) are 
now approved by the U.S. Food and Drug Administration (FDA) for adults and adolescents living with HIV. The 
approvals are based on this study and studies in adults which showed that CAB and RPV were safe and well 
tolerated. The adult studies also showed that the shots worked well to control HIV.  The study drugs are approved 
by the European Medicines Agency (EMA) for adults. Only the RPV pills (25mg taken once daily) are approved 
by the EMA for adolescents. 
 
This will be the first study of RPV shots, CAB pills and CAB shots in adolescents. The testing in adults has 
shown that the study pills and study shots work as well as other ARVs that are approved. So far, the testing in this 
study has shown that the study pills and study shots also work well for adolescents. However, because these 


 
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ARVs are still being tested, there may be some effects that we do not know about yet. More information is needed 
from this study so that the study drugs can be approved for adolescents in more countries.  
 
This study will test the effects of these ARVs in adolescents. The study will look at whether these ARVs:  
• 
Are being given at the correct dose for adolescents  
• 
Are safe and well-tolerated in adolescents 
• 
Can control HIV in adolescents as well as other ARVs 
 
The study will also look at how willing adolescents are to take these ARVs.  
 
Cohort 1 of this study will be done first to test CAB and RPV pills when taken for about 1 month followed by 
CAB and RPV shots. Adolescents in Cohort 1 will take either CAB pills followed by CAB shots or RPV pills 
followed by RPV shots. They will keep taking their usual ARVs (see #4 below for more information). 
 
Some adolescents who took part in Cohort 1 of this study received the study pills for about 1 month followed by 3 
study shots given over 2 months. The RPV shots given at that time were 900mg for the first and second shots and 
then 600mg for the third RPV shot. The CAB shots given at that time were 600mg for the first and second shots 
and then 400mg for the third CAB shot.  
 
Some adolescents who took part in Cohort 1, the study pills were taken for about 1 month and followed by 2 
study shots given 1 month apart. These adolescents only received 2 study shots in Cohort 1. Both RPV study shots 
were 900mg, while both CAB study shots were 600mg. This is because the testing in adults has shown that fewer 
study shots can be given with these amounts. 
 
If the results from Cohort 1 show that CAB pills, CAB shots and RPV shots are safe and that the dose is correct, 
Cohort 2 will start. Cohort 2 will test whether CAB and RPV pills taken together, followed by CAB and RPV 
shots taken together are safe and can control HIV when adolescents stop taking their previous ARVs. Some 
adolescents from Cohort 1 may be eligible to also take part in Cohort 2.  
 
More information about the study, Cohort 1, and CAB and RPV is given in the rest of this form. 
 
2. Only adolescents who are eligible can participate in the study. 
 
If you decide to join the study, we will first do some tests to find out if you are eligible. More information about 
the tests is given in #5 (see below). If you are eligible, you will be entered in the study. If you are not eligible, you 
cannot be entered in the study.  
 
3. It is your decision whether or not you join the study. 
 
Deciding to join the study is voluntary (your choice). You may choose to join or not join. If you choose to join, 
you can change your mind and leave the study. Your choices will have no effect on the medical care you would 
normally receive. Your access to services, and the benefits and rights you normally have, will not be affected.  
 
Take your time and consider your decision carefully. If you wish, you can talk to other people about the study. 
You can bring other people here to learn about the study with you. 
 
No matter what you decide about the study, it is important for you to keeping taking ARVs. This is the best known 
way for you to stay healthy. 
 
 
4. There are three phases in Cohort 1.  


 
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For participants in Cohort 1, there are three phases of the study. All participants will take part in Cohort 1-Phase 
1. Only those who are eligible will take part in Cohort 1-Phase 2. Participants who take part in Cohort 1-Phase 2 
will also take part in Cohort 1-Phase 3, called the long-term safety follow-up phase. 
 
In Cohort 1-Phase 1, you will keep taking your usual ARVs. You will also take either the CAB or the RPV pills. 
The type of usual ARVs you take will determine whether you will take CAB or RPV in this study. The pills must 
be swallowed whole. They cannot be broken or crushed. They should be taken with a meal. This phase lasts for 
about 4-6 weeks. After the study entry visit (see #8 below), you will have 2 more visits during Phase 1. At these 
visits, we will check to see how you are doing while taking the pills (see #9 for more information). We will also 
check to see if you are eligible for Cohort 1-Phase 2. 
 
If you are eligible for Cohort 1-Phase 2, you will keep taking your usual ARVs. You will stop taking the CAB 
or RPV pills and start getting either the CAB or the RPV shots. The study ARV you get in the shot will be the 
same study ARV you were taking by pill. The shots are long-acting, meaning the medicine stays in the body for a 
long time. This phase lasts about 12 weeks. You will have 6 visits during this time, and you will get shots at two 
of these visits. Each shot is about 3mL (about 1 teaspoon). The shots are given in the buttocks (bottom “cheeks”). 
At each of these two visits, you will be given one shot of CAB or one shot of RPV. At all of the Phase 2 visits, we 
will check on how you are doing while getting the shots (see #11 for more information). 
 
After Cohort 1-Phase 2, you will stop taking the study drugs and take part in the long-term safety follow-up phase 
of the study. This phase lasts about 48 weeks. We will check on how you are doing and the amount of study drugs 
in your blood after stopping the study drugs. You will keep taking your usual ARVs. There will be 3 or 4 visits 
during long-term follow-up (see #16 for more information). 
 
Finding out if you are eligible for Cohort 1 
 
5. We will ask questions, examine you, and discuss the study requirements with you. 
 
To find out if you are eligible for the study, we will: 
 
• 
Review your medical records. 
• 
Ask questions about you, your health, and the medications you take.  
• 
Talk with you about birth control (ways to prevent pregnancy).  
• 
Talk with you about the study requirements and if you are able to meet these requirements. 
• 
Do a physical exam. This will include looking at your genitals to see your stage of development. For 
participants assigned female at birth, this will also include looking at your breasts. 
• 
Do an electrocardiogram (ECG). This is to test how well your heart is working.  
• 
Draw between 11-17mL (about 2-3 teaspoons) of blood for tests. The tests will: 
o Check your blood cells. 
o Check how well your liver and kidneys are working. 
o Confirm that you have HIV. There are certain HIV tests that are required for this study. If the required 
tests are not in the medical records, we will do the tests that are needed. 
o Check the amount of HIV in your blood. This is called the HIV viral load.  
 
These procedures will take about 4 hours [here and throughout this form, sites may modify the expected visit 
duration as needed]. 
 
 


 
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6. For participants assigned female at birth, we will also test for pregnancy. 
 
Participants in this study cannot be pregnant. Participants should not join this study if they are pregnant or intend 
to become pregnant within 30 days after stopping the study ARV pills or within 48 weeks after stopping the study 
shots. Because the effects of the study ARVs on unborn babies are unknown, you should not become pregnant 
while in this study. For all participants assigned female at birth in the study, we will collect urine or blood to test 
for pregnancy. 
 
There are certain effective methods of birth control that participants who are able to become pregnant must use 
while in this study. These effective methods must be continued for 30 days after stopping the study ARV pills, or 
for at least 48 weeks after stopping the study ARV shots. Participants who are able to become pregnant, must 
agree to use these methods in order to take part in the study. We will help make sure you can get effective 
methods by providing them here in the clinic or offering a referral. At study visits when you will receive study 
medicines (either the pill or shot), we will need to confirm that you are using effective birth control before giving 
you the study medicines. 
 
Participants who become pregnant during the study will stop taking the study medicines and enter the long-term 
safety follow-up phase of the study (see #16 below). You must continue taking your usual ARVs. We will 
contact you to find out the outcome of the pregnancy even if the outcome occurs after leaving the study. 
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure of 
pregnancy results to parents or guardians: As soon as the pregnancy test result is available, we will go over it 
with you in private, without your parents/guardians present. You must give us permission before we can share 
these results with your parents/guardians. If the test shows that you are pregnant, we will give you information on 
where medical care and other services can be received.] 
 
If you are pregnant, your doctor may report your pregnancy to the Antiretroviral Pregnancy Registry. The 
Antiretroviral Pregnancy Registry assists participants and doctors in gauging potential benefits and risks of 
treatment; however, the registry does not collect any identifying information about you, such as your name, 
initials, contact information, or date of birth.  
 
7. We will tell you if you are eligible. 
 
We will give you the results of all procedures and explain the results to you. We will tell you about getting care, 
treatment and any other services you may need. While waiting for the results, it is important for you to keep 
taking your usual ARVs. 
 
If you are not eligible for the study for any reason, we will tell you this. You will not be entered in the study. You 
can and should continue to receive medical care and treatment outside of the study. We will tell you more about 
getting this care and treatment and any other services you may need.  
 
If you do not enter the study, we will still use some information collected about you (for example age, sex, and 
race). We will use this information to look at patterns or common reasons for not entering the study. 
 
If you are eligible for the study, you will be entered into the study.  
 
Entering the study 
 
8. If you are eligible, you will enter the study. 
 
On the day you enter the study we will:   


 
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• 
Review your medical records.  
• 
Talk with you about your ARV use 
• 
Talk with you about preventing pregnancy 
• 
Ask you questions about what you think about CAB or RPV 
• 
Do a physical exam.  
• 
Draw about 18mL (about 4 teaspoons) of blood for tests. The tests will: 
o Check your blood cells. 
o Check how well your liver and kidneys are working. 
o Check how much the virus has affected your ability to fight the virus. This is called CD4 cell count.  
o The tests will check your HIV viral load.  
o Some blood will be saved for later testing for resistance to ARVs. This test shows whether different 
ARVs may work against the HIV in your blood. 
• 
For participants assigned female at birth, we will collect urine or blood for a pregnancy test.  
• 
Ask if you are willing to complete an in-depth phone interview. [US sites only.] 
 
At this visit, you will start taking CAB or RPV pills. We will give you the pills and explain how to take them. 
You will take your first dose at the visit. You will continue taking your usual ARVs. This visit will take about 4 
hours.  
 
Being in the study 
 
9. After entering the study, you will have two more visits in Cohort 1-Phase 1 (Weeks 2 and 4a).  
 
The first visit in Cohort 1-Phase 1 will be the study entry visit and is described in #8 above.  After that visit, you 
will have 2 more visits in Cohort 1-Phase 1.  These visits will be scheduled 2 weeks apart. [Sites to modify] Each 
visit will take about 1-3 hours. At each of these visits, we will:  
 
• 
Review your medical records.  
• 
Talk with you about your ARV use 
• 
Do a physical exam. 
• 
For participants assigned female at birth, we will also collect urine or blood to test for pregnancy.  
• 
Talk with you about preventing pregnancy.  
• 
Remind you to bring the oral CAB or oral RPV to the study clinic. 
 
At two of these visits (Week 2 and Week 4a), we will draw about 5mL (about 1 teaspoon) of blood for tests. 
These tests will check your blood cells and how well your liver and kidneys are working.  
 
At the second visit (Week 2), we will also draw about 12mL (about 2-3 teaspoons) blood for tests. This test will 
check your HIV viral load. Some blood will be saved for later resistance testing.  
 
At the second visit (Week 2), we will also do an intensive pharmacokinetic (PK) test. This is a test to look at the 
amount of CAB or RPV in your blood. At this visit, we will ask you when you took CAB or RPV in the past three 
days. [Sites: modify language as appropriate to align the three prior doses with the timing (morning or evening) 
of the Week 4b pre-dose PK sample collection.] For three days before this visit, you must be sure to take CAB or 
RPV on time and in the morning. This is very important. We will help you remember this before the visit. 
 
If you are taking oral CAB, we will need to draw your blood six times during the visit, one time before and five 
times after taking CAB. We will also remind you not to take CAB before coming to this visit. When you come to 
the visit, we will draw your blood, then you will take CAB, and then we will draw your blood 5 more times, about 


 
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1, 2, 3, 4, and 8 hours later. Each time we will draw 2mL (less than 1 teaspoon), for a total of 12mL (about 3 
teaspoons).  
 
If you are taking oral RPV, we will need to draw your blood three times during the visit, before and after taking 
RPV. We will remind you not to take RPV before coming to this visit. When you come to the visit, we will draw 
your blood, then you will take RPV, and then we will draw your blood 2 more times, about 4, and 8 hours later. 
Each time we will draw 2mL (less than 1 teaspoon), for a total of 6mL (about 1 teaspoon). 
 
[Sites: modify language as appropriate to indicate procedures for the intensive PK collection. For the intensive 
PK tests, a small plastic tube will be placed in your arm to draw blood samples. This tube is attached to a plastic 
needle so that we can draw blood several times. We will not need to stick you with a needle each time. The plastic 
tube may stay in place for the blood draws.]  
 
[Sites: modify language as appropriate to indicate procedures for intensive PK visit and overnight stays – You 
may need to stay at the clinic or hospital for up to 8 hours. If the study clinic is able, you may be allowed to stay 
at the clinic the night before and during your first PK visit.] 
 
[Sites to modify] On rare occasions, we may offer some of the visit activities off-site, or by phone. The study staff 
will discuss the location and best time to visit you so that the visit is at a convenient time and the visit is done at a 
place you feel comfortable and confidentiality can be maintained. 
 
10. If you are eligible, you will enter Cohort 1-Phase 2 (Week 4b). 
 
At the Week 4b visit, we will determine if you are eligible for Cohort 1-Phase 2. At this visit, we will:  
• 
Review your medical records.  
• 
Talk with you about your ARV use. 
• 
Do a physical exam. 
• 
Ask you questions about your experience with the study drug.  
• 
Talk with you about preventing pregnancy.  
• 
Draw about 12mL (about 2-3 teaspoons) blood for tests. These tests will check your HIV viral load. Some 
blood will be saved for later resistance testing.  
• 
For participants assigned female at birth, we will also collect urine or blood to test for pregnancy. 
• 
Remind you to bring the oral CAB or oral RPV to the study clinic. 
• 
[Sites: modify language as appropriate to align the three prior doses with the timing (morning or evening) of 
the Week 4b pre-dose PK sample collection. Remind you to take your oral CAB or oral RPV in the morning 
for the three days before this visit.]  
 
If you are not eligible, you will stop taking oral CAB or oral RPV and will complete a final study visit about 4 
weeks after your last oral dose (see #15 for more information). 
 
If you are eligible for Cohort 1-Phase 2, you will continue taking your usual ARVs. You will take your last dose 
of oral CAB or oral RPV at the Week 4b visit. We will also give you the first shot of CAB or the first shot of RPV 
at the Week 4b visit. We will remind you not to take oral CAB or oral RPV before coming to this visit. You will 
take oral CAB or oral RPV at the study clinic before the first shot of CAB or the first shot of RPV.  
 
At this visit, we will also look closely at the amount of CAB or RPV in your blood. To do this, we will need to 
draw your blood two times during the visit, before taking oral CAB or RPV and after getting a shot of CAB or 
RPV. When you come to the visit, we will draw your blood, then you will take your oral CAB or RPV and get a 
shot of CAB or RPV, and then we will draw your blood again, about two hours later. Each time we will draw 
2mL (less than 1 teaspoon), for a total of 4mL (less than 1 teaspoon).  


 
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[Sites to include if combined Week 4a and Week 4b visits are planned.] This visit may be combined with the 
previous study visit (Week 4a). 
 
11. You will have 5 visits (Weeks 5-16) in Cohort 1-Phase 2.  
 
The first visit in Cohort 1-Phase 2 will be the Week 4b visit, which is described in #10 above. After that visit, you 
will have 5 more visits in this phase.  These visits will take place 1-4 weeks apart. [Sites to modify] Each visit will 
take about 1-3 hours.  
 
At each of these visits, we will:  
• 
Review your medical records.  
• 
Talk with you about preventing pregnancy. 
• 
Do a physical exam. At the Week 16 visit, this will include looking at your genitals to see your stage of 
development. For participants assigned female at birth, this will also include looking at your breasts 
• 
Draw about 2mL of blood (less than 1 teaspoon) to look at the amount of CAB or RPV in your blood. 
 
At 3 of these visits (Weeks 5, 8, and 16) we will also draw about 5mL of blood (about 1 teaspoon) to check your 
blood cells and how well your liver and kidneys are working.  
 
At 2 of these visits (Weeks 8 and 16) we will also draw about 12mL of blood (about 2-3 teaspoons) to check your 
HIV viral load. Some blood will be saved for later resistance testing.  
 
At 1 of these visits (Week 16), we will also draw about 3mL of blood (less than 1 teaspoon) for tests. These tests 
will check your blood cells and CD4 count. 
 
At 2 of these visits (Weeks 9 and 16) we will also do an ECG to look at your heart.  
 
At 1 of these visits (Week 8) we will also give you a shot of either CAB or RPV. 
 
At 2 of these visits (Weeks 8 and 16) we will also talk with you about your experience with study ARVs.  
 
For participants assigned female at birth, at 2 of these visits (Weeks 8 and 16) we will also collect urine or blood 
to test for pregnancy.  
 
12. In-depth phone interview [for U.S. sites only] 
 
We are very interested to understand what adolescents think about getting their ARV’s as shots. You may be 
asked if you would like to complete an in-depth phone interview. If you would like to take part in the interview, 
then you may be contacted to have the interview after getting the first shot of CAB or RPV. Not all participants 
will be contacted for the interview. You do not have to do the interview to take part in this study.  
 
If contacted, an interviewer will talk to you for about 1-2 hours and will ask how you feel about having shots of 
CAB or RPV. This information will help us understand if CAB shots and RPV shots have any side effects for 
adolescents. It will also help us understand how adolescents and families feel about the shots. The interview may 
take place at or in between the Week 4b, 5, 6, 8, and 12 study visits, or during the long-term follow-up safety 
phase. The interview will only take place once. The interview will be audio recorded and written down in a report. 
Your name will not be included in the report.  
 


 
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We may also ask your parent or caregiver to complete an in-depth interview. This interview would ask them how 
they felt about you having shots of CAB or RPV.  
 
13. We will tell you if you are eligible for Cohort 2. 
 
After your last visit in Cohort 1-Phase 2, we will tell you if are eligible for Cohort 2 or if you need additional tests 
to see if you qualify for Cohort 2.  
 
If you are not eligible for Cohort 2, or if Cohort 2 is not ready to take participants, you will stop getting shots of 
CAB or RPV and will enter Cohort 1-Phase 3, also called the long-term safety follow-up phase (see #16 below for 
more information). We will let you know when Cohort 2 is ready and if you need additional tests to see if you 
qualify for Cohort 2. 
 
If you are eligible for Cohort 2 and Cohort 2 is ready to take participants, you can enter into Cohort 2.  
 
14. Adolescents may have an extra visit if their HIV is not controlled. 
 
Participants will have viral load tests at almost all visits to check the amount of HIV in the blood. If tests show 
that the viral load is higher than expected (200 copies/mL or more) you will have repeat testing. This may occur 
as part of another study visit or may occur as an extra study visit.  
 
The extra visit will take about 1-2 hours. At this visit we will: 
• 
Review your medical records. 
• 
Do a physical exam.  
• 
Draw about 14mL (about 3 teaspoons) of blood for tests. The tests will: 
o Check your HIV viral load.  
o Check the amount of CAB or RPV in the blood.  
o We will save some blood for later resistance testing. 
• 
Talk with you about preventing pregnancy.  
• 
For participants assigned female at birth, we will also collect urine or blood to check for pregnancy.  
 
If the repeat test also shows an increased amount of HIV in your blood, you will stop taking the study product. If 
you were getting shots of CAB or RPV, you will enter long-term follow-up (more information in #16 below).   
 
15. If you are not eligible to receive shots of CAB or RPV you will stop the study early. 
 
If you are not eligible to get shots of CAB or RPV in Cohort 1-Phase 2, you will stop taking oral CAB or oral 
RPV and will complete a final study visit about 4 weeks after your last oral dose.  
During this visit, we will:  
• 
Review your medical records.  
• 
Do a physical exam. This will include looking at your genitals to see the stage of development. For 
participants assigned female at birth, this will also include looking at the breasts.  
• 
Draw blood for tests. This would be about 15-20mL of blood (about 3-4 teaspoons) for these tests. These tests 
will check:  
o Your blood cells.  
o How well your liver and kidneys are working. 
o Your HIV viral load.  
o Some blood will be saved for future resistance testing. 
• 
Talk with you about preventing pregnancy.  


 
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• 
For participants assigned female at birth, we will also collect urine or blood to check for pregnancy.  
• 
Ask you questions about what it is like taking CAB or RPV.  
• 
We will also talk with you about your ARV use.  
 
16. If you stop the shots of CAB or RPV early, or if you are not eligible to enroll in Cohort 2, or if Cohort 2 is not yet 
ready, you will enter Cohort 1-Phase 3 (long-term safety follow-up phase). 
 
You will enter Cohort 1-Phase 3 (long-term safety follow-up phase) after the last shot of study product, if you: 
• 
Stop the shots of CAB or RPV during Cohort 1-Phase 2 early, or 
• 
Are not eligible to enroll in Cohort 2, or 
• 
If Cohort 2 is not yet ready for participants 
 
If you become pregnant, you will enter this phase of the study after your positive confirmatory pregnancy test 
result, whether you are taking the pill or the shot.  
 
You will keep taking your usual ARVs. There will be 3 or 4 visits during the long-term safety follow-up phase. 
These visits will be scheduled 8, 24, 36 and 48 weeks after your last shot of CAB or RPV (or after a positive 
confirmatory pregnancy test result). [Sites to modify] Each of these visits will take about 1-3 hours. At these 
visits, we will:  
• 
Review your medical records.  
• 
Do a physical exam. At the final long-term follow-up visit, this will include examination of your genitals to 
see the stage of development. For participants assigned female at birth, this will also include looking at your 
breasts. 
• 
Talk with you about preventing pregnancy. 
• 
Draw blood for tests. This would be about 19mL of blood (about 4 teaspoons) for these tests. These tests will 
check:  
o Your blood cells.  
o How well your liver and kidneys are working. 
o Your HIV viral load.  
o The amount of CAB or RPV in the blood.  
o Some blood will also be saved for future resistance testing. 
• 
For participants assigned female at birth, we will also collect urine or blood to check for pregnancy.  
• 
At two of these visits (8 weeks and 48 weeks after your last shot of CAB or RPV) we will talk with you about 
your ARV use. 
• 
At two of the visits (8 weeks and 48 weeks after your last shot of CAB or RPV), we will also ask you 
questions about getting shots of CAB or RPV.  
 
For participants who complete the Week 16 visit in Cohort 1-Phase 2, the first long-term follow-up visit will be 
skipped entirely. The Week 16 visit and the first long-term follow-up visit are very similar and do not need to be 
conducted twice. 
 
17. Different tests will be done at different laboratories. 
 
We will do most of the tests of blood or urine here at our laboratory. We will give you the results of most of these 
tests at the next scheduled visit, or sooner, if necessary. We will explain the results and give you counseling and 
referrals as needed.  
 
We will also draw blood to check the amount of CAB or RPV in your blood. This is called a pharmacokinetic 
(PK) test. The PK test will be done at a laboratory in the United States. We will not usually give you the results of 
this PK test during the study.   


 
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If you need a test for resistance (see #14 above), that test will be done at a laboratory in the United States.  You 
will be given the results of this resistance test and referrals if needed.  
 
18. We may take you off of the study. 
 
We may take you off the study ARVs if: 
• 
You are not able to come to the study visits or we determine that you cannot meet the study requirements. 
• 
You are not able to take the study ARVs. 
• 
The study ARVs are not controlling the HIV in your blood. 
• 
Continuing the study ARVs may be harmful to you. 
• 
You request to stop the study ARVs. 
• 
You are not able to follow the birth control requirements of this study. 
• 
You become pregnant. 
 
If you stop the oral study ARVs early, we will ask you to come back to the clinic about four weeks after you stop 
the oral study ARVs (see #15 above). You will not have any other visits after this. 
 
If you stop the ARV shots early, we will ask you to come back to the clinic for four additional study visits for 
long-term safety follow-up (see #16 above). You will not have any other visits after these four visits. 
 
We may also take you off the study early if the study is stopped for any reason.  
 
The study cannot provide other types of ARVs, but we will give you information, counseling, and referrals to 
where you can get care and treatment needed. We will help make sure you can get ARVs from outside of the 
study. If the study stops early, every effort will be made to make certain that there is no interruption in your 
therapy.  
 
19. Please tell us if you want to leave the study. 
 
You are free to leave the study at any time for any reason. The care that you receive at this clinic will not be 
affected, but it is important for us to know about your decision.  
 
If you stop the study ARVs, we may ask you to return to the study clinic for additional study visits described in 
#15 and #16 above. If you stop the study early, we may ask you to return to the study clinic for one final study 
visit, like the last study visit described in #16 above. 
 
We will answer any questions you may have and give you information on how to contact us in the future, if you 
wish. 
 
Risks of the study 
 
Taking part in this study may involve some risks and discomfort. The risks are different for each phase of the 
study. Cohort 1-Phase 1 risks include: risks from blood draws, risk from the study pills (CAB or RPV), and risks 
to your privacy.  
 
Cohort 1-Phase 2 risks include: risks from blood draws, risks from receiving the injection, risks from the study 
pills (CAB or RPV) and the study shots (long-acting CAB or RPV) and risks to your privacy.  
 
Cohort 1-Phase 3 risks include: risks from blood draws, and risks to your privacy.  


 
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20. Risk from blood draws  
 
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted. Rarely, drawing blood 
can cause fainting or infection.  
 
21. Risk from receiving the injection  
 
People in other studies who have received the CAB and RPV shots said they had pain, skin irritation, skin 
redness, bumps, swelling, itching, bruising at the spot where they got the shot. Most reactions go away in a week 
or less but sometimes they can last longer. Most people usually do well with them and rarely need to stop the 
drug.  
 
The shots will be given in the muscles of your buttocks. The injection could be given too deeply or not deeply 
enough, missing the muscle and entering your skin, blood, or a nerve.  
 
The risks of this are not well understood but could make CAB or RPV levels too low or too high. If too low the 
drug may not work against your HIV. If RPV is too high, there could be a change in your heartbeat, which in 
severe cases can be life-threatening. In rare cases, symptoms such as feeling lightheaded, numbness or tingling, 
difficulty breathing, chest or stomach discomfort, sweating, rash, pain (e.g., back and chest), nausea and/or feeling 
anxious have occurred after an injection with RPV LA. In these cases, high blood levels of RPV have been 
observed, which may be due to an accidental injection of part of the medication into a blood vessel instead of the 
muscle. Not all participants in whom an accidental injection in a blood vessel was suspected reported such 
symptoms. Most of the symptoms resolved within minutes. Your doctor may need to administer treatment to help 
resolve these symptoms.  Everything possible will be done to decrease this risk, including watching you for 
problems during the study. If your doctor thinks that the injection was not given the right way, you might be 
asked to stay in the clinic up to 3 hours after the injection to watch how you are doing and extra tests may be 
needed to be sure you are safe. We will also draw blood (less than 1 teaspoon) about 2 hours after the study shot 
to look at the amount of study drugs in your blood. If you are worried about this risk, talk to your doctor. 
 
Receiving injections can cause some people to feel lightheaded or feel like they might pass out. Fainting can also 
occur. This reaction, called a ‘vasovagal reaction’, has been reported with other injectable medicines, and resolves 
quickly. 
 
22. There are risks from the study ARVs 
 
All ARVs can cause side effects. This includes the ARVs you are currently taking and the ARVs that are given in 
the study. Some side effects are minor; others can be severe. Some side effects are common; others are rare. Some 
people who take ARVs have some of the side effects. Other people have different side effects, or no side effects.  
 
The most common and most serious side effects of the study ARVs, CAB and RPV, are listed below. This is 
based on what we know now about CAB and RPV used in adults. There may be other side effects that we do not 
know about now. This may be especially true for adolescents, because this is the first study of CAB and RPV in 
adolescents.  
 
This form does not list all possible side effects of all ARVs. If you join the study, we will tell you more about the 
ARVs you will be taking. At each study visit, we will check on whether the ARVs may be causing side effects. 
We will also tell you what to do if you have side effects. If you have questions or concerns at any time, please tell 
us.  
 
 


 
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23. Some side effects from the CAB pills and the CAB  
 
Many people have received CAB pills or the CAB shot in other studies. The table below lists side effects from 
other studies of CAB with people who have HIV. It is not known if CAB, other drugs or the participant’s other 
health problems caused or affected these. Some of these are the same side effects as RPV (see #24 below).  
 
Common and Uncommon Side Effects of CAB 
Very Common Side Effects of 
CAB 
Common Side Effects of CAB 
Uncommon Side Effects of 
CAB 
• Headache 
• Pyrexia (fever), feeling hot, 
body temperature increase  
• Injection Site Reactions (pain 
and discomfort, a hardened 
mass or lump) 
 
• Rash 
• Vomiting (being sick) 
• Nausea (feeling sick to the stomach) 
• Abdominal pain, upper abdominal 
pain (stomach pain and discomfort)  
• Insomnia (problems sleeping)  
• Abnormal dreams/nightmares 
• Anxiety (feeling anxious) 
• Feeling lightheaded (dizziness) 
• Depression (feelings of deep sadness 
and unworthiness) 
• Flatulence (passing gas or wind) 
• Diarrhea or loose stools 
• Myalgia (muscle pain) 
• Fatigue (lack of energy) 
• Asthenia (feeling weak) 
• Malaise (feeling generally unwell) 
• Weight increase 
• Injection Site Reactions (swelling, 
redness, itching, bruising, warmth or 
discoloration) 
• Somnolence (sleepiness or 
Drowsiness) 
• Vasovagal reactions (light-
headedness or fainting, during 
or following an injection) 
• Hepatotoxicity (liver problems) 
• Transaminase increase (blood 
test may show increase in the 
level of liver enzymes) 
• Injection Site Reactions 
(cellulitis [heat, swelling or 
redness], abscess [collection of 
pus], numbness, minor 
bleeding, discoloration) 
 
The following effects have also been seen in some of the people who received CAB pills or the CAB shot in other 
studies: 
 
Abnormal liver tests: 
 
A small number of people across all studies (just over 1% of 1644 participants as of April 2017) had abnormal 
liver tests requiring them to stop CAB. Some abnormal liver tests were explained by other health conditions such 
as a new virus infection, like Hepatitis A, B or C. A small number of people did not have health conditions that 
could explain the abnormal test, so it is possible that a mild form of liver damage happened from taking CAB. 
The liver tests got better after stopping CAB, showing that any damage was temporary. 


 
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Blood tests to check the health of your liver will be done during the study. Your study doctor will tell you if you 
need to stop taking the study drugs or if other actions are needed. If you stop taking the study drug, you may be 
able to re-start the study drug or you may need to change your usual ARVs.  
 
 
Seizures/convulsions: 
 
Seizures have been seen (rarely) in people with and without HIV who have taken CAB. They are not thought to 
be caused by CAB, but the study staff will ask you about them.  
 
In other studies, two people without HIV had a history of seizures (epilepsy), and had a seizure about 3 months 
and 9 months after starting CAB. One other person with HIV but without a history of seizures, had seizures about 
one year after starting CAB. This participant had a long period of seizures without medical treatment and died. It 
is not known if CAB was part of the reason for seizures in these people. If you have a history of seizures, please 
let your study doctor know. 
 
24. Some side effects from the RPV pills and the RPV shot 
 
Oral RPV (Edurant) is a marketed drug which many people throughout the world have received to manage HIV. 
We know more about the side effects of Edurant than we do about CAB or RPV shots. The following side effects 
have been seen in studies in people with HIV taking RPV.  
 
Common and Uncommon Side Effects of RPV 
Common Side Effects of RPV 
Uncommon Side Effects of RPV 
• 
Dry mouth 
• 
Feeling less hungry (decreased appetite) 
• 
Sleep disorders 
• 
Immune reconstitution syndrome (this can be 
an overreaction of the body’s recovering 
defense system to a previously present 
infection, or problems in the immune system) 
• 
Depressed mood 
• 
Abdominal discomfort (belly ache) 
 
The following effects have also been seen in some people who received RPV in other studies: 
 
Abnormal blood tests: 
 
Other changes in blood tests have also been observed. People with Hepatitis B or C or who have possible liver 
damage before starting RPV may have worse liver tests while taking RPV. A few cases of liver problems were 
found in people taking RPV who did not already have any liver problems. 
 
Sometimes allergic reactions can affect body organs, like the liver, and cause liver problems which can lead to 
liver failure. Contact your study doctor right away if you have any of the following signs or symptoms of liver 
problems: 
• 
Yellowing of the skin or whites of the eyes 
• 
Dark or tea colored urine 
• 
Pale colored stools/bowel movements 
• 
Nausea/vomiting 
• 
Loss of appetite 


 
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• 
Pain, aching or tenderness on the right side below the ribs 
• 
Itchy skin  
 
Blood tests to check the health of your liver will be done regularly during the study. Your study doctor will tell 
you if you need to stop taking the study drugs or if other action is needed. If you stop taking the study drug, you 
may be able to re-start the study drug or you may need to change your usual ARVs.  
Skin Rash: 
 
Most rashes were mild or moderate, and happened within the first 4 weeks of taking RPV. Most of rashes got 
better after one week, and the people did not need to stop taking RPV. However, the study ARVs will need to be 
stopped for some types of moderate rash and all types of severe rash, which can be life-threatening. If this 
happens to you, you will need to come for extra study visits to monitor your health. Some people with rash may 
also have other signs and symptoms of allergic reaction. 
 
If you have any type of rash or other skin problems during the study you must tell your study doctor right away, 
and the doctor may tell you to stop taking CAB and/or RPV. 
 
25. There may be other possible risks from the study ARVs. 
 
The study ARV shots stay in your body for a long time 
 
The shots you get in this study are long acting, meaning they stay in your body for a long time. In most people the 
drugs will no longer be in the body one year after an injection, while in some people low levels of CAB and RPV 
may still be in the body after one year. If you develop a side effect to the study drug after the shot, there will be no 
way to remove the drug from your body. If you get a shot of CAB or RPV, we will monitor your health for 48 
weeks after your last shot. If you develop a symptom from these drugs while the drugs are still in your body, 
every effort will be made to treat the side effects. The amount of drug will decrease overtime and will eventually 
disappear. 
 
While the amount of study drugs in your body decrease slowly over time after you stop getting shots, the study 
drugs could stop working against your HIV. When stopping long acting HIV drugs, it will be very important to 
start taking other HIV medications, as your study doctor tells you, so your HIV medications do not stop working 
against your HIV. 
 
Risk of resistance 
 
All ARVs can cause some resistance if not taken correctly. Resistance means that the ARVs may not work against 
HIV if these ARVs are taken again in the future. To stop resistance, it is important that you take and/or receive the 
ARVs as instructed, and do not miss any doses. 
 
 
Effects on other ARVs 
 
We do not expect the study ARVs to change the way other ARVs work in the body. For example, if you were to 
join the study, we would expect the ARVs you are currently taking to keep working to control the amount of HIV 
in your body. We also do not expect the study ARVs to cause more or worse side effects from other ARVs. 
However, this study is being done to learn more about these kinds of possible effects. 
 
Mental illness or depression 
 


 
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Some people with HIV sometimes have feelings of depression or may feel sad or hopeless, feel anxious or 
restless, or may have thoughts of hurting or killing themselves (suicide). A small number of people being treated 
with drugs called integrase inhibitors [INIs] for HIV like CAB, have had suicidal thoughts and actions, 
particularly participants with a prior history of depression or mental health illness.  
 
Tell the study doctor if you have a history of mental health illness. If you have thoughts of hurting or killing 
yourself or have any other unusual or uncomfortable thoughts or feelings during this study, you should tell the 
study doctor or go to the nearest hospital right away.  
 
Possible effects on pregnancy or unborn babies 
 
HIV and ARVs may lead to some pregnancy complications, like early delivery or low weight of the baby at birth. 
We do not know if some ARVs are more likely to cause these effects than others. We do not yet know if CAB is 
safe in pregnancy. RPV does not appear to be a risk to pregnancy and the developing baby based on the 
information we know now, but additional data are still being collected. 
 
There are few data from humans on the effects of CAB in pregnancy. Most of the information we have comes 
from animal studies. In studies done in pregnant rats and their newborns, using very high amounts of CAB, there 
were more baby rats that died when they were born or right after they were born. This did not happen to the baby 
rats when the mother got lower amounts of the drug, or no drug. The amount of CAB that we are giving in this 
study is expected to be more than 7-times lower than the amount given to the pregnant rats. Birth defects have not 
been found in any animal studies of CAB so far. We do not know whether what happened to the baby rats has any 
impact on what will happen in pregnant humans taking this drug. 
 
Early results from one large study in Botswana showed that the ARV called dolutegravir (DTG) may increase the 
risk of serious birth defects of the brain or spine in the new baby. The increased risk was seen among babies 
whose mothers were taking DTG when they became pregnant. These birth defects happen during the first few 
weeks of pregnancy, before mothers may know they are pregnant. These birth defects have not been seen among 
babies whose mothers started taking DTG later in pregnancy.  
 
CAB is not the same drug as DTG. We do know that CAB and DTG belong to the same class of medications and 
work in a similar way to treat HIV infection. We do not know if CAB can cause brain or spine defects in babies.  
 
Participants who are able to become pregnant must agree to use certain effective methods of birth control to be in 
this study (see #6 above). If you become pregnant during the study, please let us know right away. 
 
Immune reconstitution syndrome 
 
In some people with advanced HIV, signs and symptoms from other infections or certain diseases (for example a 
liver condition called autoimmune hepatitis) may occur soon after starting combination ARVs but can also occur 
later. Some of these symptoms may be life threatening. If you start having new symptoms, or if you notice that 
any existing symptoms are getting worse after starting the ARVs, tell your doctor immediately. 
 
Abnormal placement of body fat and wasting 
 
The use of potent antiretroviral drug combinations may be associated with an abnormal placement of body fat and 
wasting. Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 
• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement 


 
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26. There could be risks of disclosure of your information. 
 
We will make every effort to keep your information private and confidential. Study records and specimens will be 
kept in secure, locked locations. All specimens and most records will be labeled only with a code number. 
However, your name will be written on some records.  
 
Despite our best efforts to keep your information private, it is possible that the information could be obtained by 
someone who should not have it. If this were to happen, you could be treated badly or unfairly. You could feel 
stress or embarrassment.  
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality that protects us from being 
forced to release information that may identify you, such as by the courts or police. The certificate cannot be used 
in all situations, but it can be used to resist demands for information that would identify you. The certificate does 
not protect against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your participation in the study to 
others, if you wish. 
 
Information collected for this study may be used for other research in the future. For example, researchers may 
use information from this study to try to answer different questions about children or adolescents with HIV. Any 
future research done with the information from this study must be approved by the IMPAACT Network. If any 
future research is done, information about you may be used, but your name will not be shared. 
 
Benefits of the study 
 
27. There may be a direct benefit to you from being in the study. 
 
By joining the study, you will be part of the search for ARVs that may be better for adolescents. We do not know 
if being in the study will benefit you in any way. There may be a direct benefit to you by taking part in this study, 
but no guarantee can be made. For example, you may gain a better understanding of your health and HIV care.  
Another possible benefit is early access to the Cohort 2 part of the study, if you qualify. There may also be benefit 
if the results from this study lead to a safe and effective dose of the study drugs for adolescents. It is also possible 
that you may receive no direct benefit from this study. Information learned from this study may help other 
adolescents who have HIV. 
 
You will have regular visits here and frequent checks on your health, including tests for amount of HIV in your 
blood, called viral load. It is possible that the study ARVs will slow your HIV infection. Information learned from 
this study may help other adolescents with HIV. 
 
Other information about the study 
 
28. There are no costs from being in the study. 
 
There are no costs to you for study visits, CAB, RPV or procedures.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits. For each visit, you will be given (specify amount).] 
 


 
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29. Study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include:  
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your name or identify you personally.  
 
A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify you. At most, the website will include a summary of the results. You can 
search this website at any time. 
 
Your study information may be given to other authorities if required by law. [Sites add more specific detail here 
as needed; example follows:] For example, we are required to report any significant risk of harm to you or others.  
 
30. If you get sick or injured, contact us immediately. 
 
Your health is important to us. We will make every effort to protect your well-being and minimize risks. It is 
possible, however, that you could have an illness or injury that is study-related. This means that the illness or 
injury occurred as a direct result of the study procedures.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage available 
through clinical trial insurance obtained by the site should be included if applicable; the statement regarding no 
program for compensation through the NIH may not be removed.]  If a study-related illness or injury occurs, we 
will treat you or tell you where you can get treatment. The cost for this treatment may be charged to you or your 
insurance company. There is no program for compensation either through [site name or] the U.S. National 
Institutes of Health.  
 
Whom to contact 
 
31. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about your rights as research participants or concerns about how you are being treated 
in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 
 


 
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• 
If you have any health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you want to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
 
Signatures 
 
If you agree to participate in this study, please sign or make your mark below. 
Before deciding whether to participate in this study, make sure you have read this form, or had it read to you, and 
that all of your questions have been answered. You should feel that you understand the study, its risks and 
benefits, and what is expected of you if you decide to join.  
 
If you decide to join, we will tell you any new information from this study or other studies that may affect your 
willingness to stay in the study. You are welcome to ask questions or request more information at any time. If you 
want the results from this study, please tell the study staff. 
 
You do not give up any rights by signing this form. 
[Insert signature blocks as required by site IRB/EC policies.] 
 
Signature blocks for participants of legal age to provide independent informed consent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 


 
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Signature blocks for parent/legal guardian of adolescent: 
 
 
 
_______________________________  
___________________________________ 
Name of Parent/Legal Guardian (print)  
Signature of Parent/Legal Guardian and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 
 
 


 
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Appendix II-B:  Sample Informed Consent Form for Participation in Cohort 2A 
 
for adolescents who can provide independent informed consent for study participation and parents/legal guardians 
of adolescents 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 4.0, dated 27 May 2022 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
If you are the parent or legal guardian of a child who may take part in this study, your permission and the 
permission of your child will be needed.  When “you” appears in this form, it refers to your child except where it 
says otherwise. 
 
Introduction 
 
You are being asked to take part in the research study named above. 
 
This form gives information about the study. Please read it, or have it read to you, and ask any questions you may 
have. We will take as much time as needed for you to fully understand the study. We will ask you questions to see 
if we have explained the study clearly. 
 
Here is a summary of important information about the study: 
 
• 
The study is testing two anti-HIV medicines (ARVs), Cabotegravir (CAB) and Rilpivirine (RPV), taken as 
pills and given as long-acting shots in adolescents 12 to less than 18 years of age.  
• 
 Some of the study drugs are already approved in some countries for use in adolescents or adults, but more 
data is needed for use in adolescents.  
• 
There are two parts to this study, Cohort 1 and Cohort 2. The Cohort 2 part to this study also has two groups: 
Cohort 2A and Cohort 2B. This form is about Cohort 2A.  
• 
Adolescents in Cohort 2 will switch from their usual ARVs to the study medicine and will be in this part of 
the study for at least 2 years up to 3 years. 
• 
In Cohort 2, you will have the option to either take the study pills and then get the study shots (this is called 
Cohort 2A) or skip the study pills and only get the study shots (this is called Cohort 2B).   
• 
After entering the study, adolescents in Cohort 2A will stop taking their usual ARVs and start taking daily 
CAB and RPV pills for 4 to 6 weeks. Adolescents will then switch to CAB and RPV shots every 8 weeks for 
about 2 years.  
• 
Adolescents in Cohort 2B will stop taking their usual ARVs and start CAB and RPV shots every 8 weeks for 
about 2 years. 
• 
We will discuss Cohort 2A and Cohort 2B with you and together make a decision that is best for you. 
• 
After the 2 years of getting the CAB and RPV shots, all Cohort 2 adolescents might be able to continue 
getting the same CAB and RPV shots outside of the study. We will explain the options to you and help 
ensure your access to ARVs outside the study. 


 
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• 
Adolescents who stop taking the CAB and RPV shots may be followed for up to 1 year for long-term safety 
follow-up. During this time, adolescents will not take any study medicine (shots or pills) but will take ARVs.   
• 
While in the study, adolescents will have clinic visits with physical examinations and blood draws for 
laboratory tests. Some visits will include a review of adolescents’ medical records and ECG tests to look at 
the adolescent’s heart. Participants assigned female at birth will also be tested for pregnancy.  
• 
If interested, participants in the U.S. may be eligible to do one in-depth phone interview where they will talk 
about their experience getting their ARVs as shots.  
• 
There are some possible risks for adolescents in the study. One possible risk is that the pills or shots being 
tested could cause side effects. The most severe side effects include allergic reaction, liver problems, and 
mental health problems.  These side effects are uncommon. 
• 
There are some possible benefits for adolescents in the study. One possible benefit is not taking daily pills 
while getting the CAB and RPV shots.  Another possible benefit is that the shots being tested will be better 
for your health and HIV care than the usual ARV pills.  
• 
Your decision on your participation in the study will have no effect on the medical care you receive at this 
clinic. Your access to services, and the benefits and rights you normally have, will not be affected. You may 
choose to leave the study at any time. 
 
More information is given in this form about the study, its risks and benefits. You should feel that you understand 
the study before deciding whether you will participate. If you decide to participate, you will be asked to sign or 
make your mark on this form. You will be offered a copy to keep. 
 
About the study 
 
This study is being done by the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
(IMPAACT) and [insert site name]. The person in charge of the study at [insert site name] is [insert name of 
IoR].  
 
The study is being done to test two anti-HIV medicines (antiretrovirals or ARVs) in adolescents 12 to less than 18 
years old who have HIV. The study ARVs are called cabotegravir (CAB) and rilpivirine (RPV). HIV is the virus 
that can lead to AIDS.  
 
The study will include up to 155 adolescents from the United States, Botswana, South Africa, Thailand and 
Uganda. There will be two groups of adolescents, called Cohort 1 and Cohort 2. This form is about Cohort 2. 
Participants in Cohort 2 will be in the study for 2 to 3 years. In Cohort 2, participants will get study product for 92 
or 96 weeks (about 2 years). After this time, participants will leave the study and may continue getting the study 
medicines outside of the study. If you stop getting the study shots early, you will enter long-term safety follow-up 
and continue having study visits for an additional 48 weeks (about 1 year). 
 
The United States National Institutes of Health and the companies that make CAB and RPV, ViiV Healthcare and 
Janssen Pharmaceuticals, are paying for this study.  
 
1. The study is testing CAB and RPV in adolescents. 
 
People living with HIV usually take a combination of ARVs daily to stay healthy. There are not as many ARVs 
available for adolescents as for adults because many ARVs have not yet been tested in adolescents. ARVs can be 
made in different forms, such as liquids, pills, and injections (shots). The study will test CAB and RPV when 
taken as pills and when given as shots in adolescents. The pills are taken every day. The shots can be given every 
4 weeks or every 8 weeks. The shots are being developed because it can be difficult to take pills every day, and 
some people may prefer to have the shots rather than taking pills.  
 


 
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RPV pills (25 mg), RPV shots (600mg and 900mg), CAB pills (30mg), and CAB shots (400mg and 600mg) are 
now approved by the U.S. Food and Drug Administration (FDA) for adults and adolescents living with HIV. The 
approvals are based on this study and studies in adults which showed that CAB and RPV were safe and well 
tolerated. The adult studies also showed that the shots worked well to control HIV.  The study drugs are approved 
by the European Medicines Agency (EMA) for adults. Only the RPV pills (25mg taken once daily) are approved 
by the EMA for adolescents. 
 
This will be the first study of RPV shots, CAB pills and CAB shots in adolescents. The testing in adults has 
shown that the study pills and study shots work as well as other ARVs that are approved. So far, the testing in this 
study has shown that the study pills and study shots also work well for adolescents. However, because these 
ARVs are still being tested, there may be some effects that we do not know about yet. More information is needed 
from this study so that the study drugs can be approved for adolescents in more countries.  
 
This study will test the effects of these ARVs in adolescents. The study will look at whether these ARVs:  
• 
Are being given at the correct dose for adolescents  
• 
Are safe and well-tolerated in adolescents 
• 
Can control HIV in adolescents as well as other ARVs 
 
The study will also look at how willing adolescents are to take these ARVs.  
 
Cohort 1 of this study was done first to test CAB and RPV pills when taken for about 1 month followed by 2 or 3 
CAB and RPV shots when taken 1 month apart. Cohort 2 is now being done to test CAB and RPV  when taken 
together. There are two groups within Cohort 2: 
• 
Adolescents in the Cohort 2A group will take CAB and RPV pills together for about 1 month, followed 
by getting the CAB and RPV shots together.  
• 
Adolescents in the Cohort 2B group will only get the CAB and RPV shots. This group will not take the 
CAB and RPV pills. 
 
Both CAB and RPV shots will be given together about every 8 weeks for up to two years. Each time the shots are 
given, the RPV shot will be 900mg and the CAB shot will be 600mg. Cohort 2 will look at whether these study 
ARVs are safe and can control HIV when adolescents stop taking their previous ARVs.  
 
We will discuss both Cohort 2A and Cohort 2B groups with you to make the decision of which group you will 
enter. If you decide to participate in the study, your signature or mark on this form will also document the 
decision of which Cohort 2 group. You can ask any questions about the groups at any time. You will not be able 
to switch to the other group after they have entered the study.  
 
More information about the study, the Cohort 2A group, and CAB and RPV is given in the rest of this form. 
 
2. Only adolescents who are eligible can participate in the study. 
 
If you decide to join the study, we will first do some tests to find out if you are eligible. More information about 
the tests is given in #5 (see below). If you are eligible, you will be entered in the study. If you are not eligible, you 
cannot be entered in the study.  
 
3. It is your decision whether or not you join the study. 
 
Deciding to join the study is voluntary (your choice). You may choose to join or not join. If you choose to join, 
you can change your mind and leave the study. Your choices will have no effect on the medical care you would 
normally receive. Your access to services, and the benefits and rights you normally have, will not be affected.  
 


 
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Take your time and consider your decision carefully. If you wish, you can talk to other people about the study. 
You can bring other people here to learn about the study with you. 
 
No matter what you decide about the study, it is important for you to keeping taking ARVs. This is the best known 
way for you to stay healthy. 
 
4. There are three phases in Cohort 2: the study pills, the study shots, and the long-term safety follow-up.  
 
For participants in Cohort 2, there are three phases of the study: 
• 
The CAB and RPV pills 
• 
The CAB and RPV shots 
• 
The long-term safety follow-up phase with no study medicines 
 
Not all participants will be in all three phases of the study. Participants in the Cohort 2A group will first take part 
in the CAB and RPV pills and then take part in the CAB and RPV shots phases of the study. In Cohort 2B, 
participants will also stop taking their usual ARVs but will skip the CAB and RPV pills phase and go straight to 
the CAB and RPV shots phase of the study.  
 
Any participant who takes part in the CAB and RPV shot phase but must stop the study shots early will take part 
in the long-term safety follow-up phase. 
 
In Cohort 2A, you will stop taking your usual ARVs and take CAB and RPV pills. The pills must be swallowed 
whole. They cannot be broken or crushed. They should be taken with a meal. This phase lasts for about 4-6 
weeks. After the study entry visit (see #8 below), you will have 2 more visits during this phase. At these visits, we 
will check to see how you are doing while taking the pills (see #9 for more information). We will also check to 
see if you are eligible to get the CAB and RPV shots. If you are eligible then, you will stop taking the CAB and 
the RPV pills and start getting CAB and RPV shots.  
 
For both Cohort 2A and Cohort 2B participants, the study shots phase lasts 2-3 years. You will have 15 visits over 
about two years. At 13 of these visits you will be given one shot of CAB and one shot of RPV. Each shot is about 
3mL (about 1 teaspoon). The shots are given in the buttocks (bottom “cheeks”). The shots may be given on the 
same side of the buttocks or on different sides. The shots are long-acting, meaning the medicine stays in your 
body for a long time. The first two visits with the CAB and RPV shots are 4 weeks apart. Then the CAB and RPV 
shots are given every 8 weeks. At all of these study visits, we will check on how you are doing while getting the 
shots (see #11 for more information). 
 
After the CAB and RPV shots, you might have the option to continue getting the long-acting injections outside of 
the study (see #19 for more information).  
 
If you no longer want to get the injections, or have to stop the study shots early, you will stop taking the study 
drugs and take part in the long-term safety follow-up phase of the study. This phase lasts about 48 weeks. We will 
check on how you are doing and the amount of study drugs in your blood after stopping the study drugs. You will 
also go back to taking your usual (pre-study) ARVs. There will be 4 visits during long-term follow up (see #15 for 
more information). 
 


 
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Finding out if you are eligible for Cohort 2 
 
5. We will ask questions, examine you, and discuss the study requirements with you. 
 
To find out if you are eligible for the study, we will: 
 
• 
Review your medical records. 
• 
Ask questions about you, your health, and the medications you take.  
• 
Talk with you about birth control (ways to prevent pregnancy). 
• 
Talk with you about the study requirements and if you are able to meet these requirements. 
• 
Talk with you about which group is best for you to join (Cohort 2A or Cohort 2B) 
• 
Do a physical exam. This will include looking at your genitals to see your stage of development. For 
participants assigned female at birth, this will also include looking at your breasts. 
• 
Do an electrocardiogram (ECG). This is to test how well your heart is working.  
• 
Draw about 11-17mL (about 2-3 teaspoons) of blood for tests. The tests will: 
o Check your blood cells. 
o Check how well your liver and kidneys are working. 
o Confirm that you have HIV. There are certain HIV tests that are required for this study. If the required 
tests are not in the medical records, we will do the tests that are needed. 
o Check the amount of HIV in your blood. This is called your HIV viral load.  
 
These procedures will take about 4 hours [here and throughout this form, sites may modify the expected visit 
duration as needed]. 
 
6. For participants assigned female at birth, we will also test for pregnancy. 
 
Participants in this study cannot be pregnant. Participants should not join this study if they are pregnant or intend 
to become pregnant within 30 days after stopping the study ARV pills or within 48 weeks after stopping the study 
shots. Because the effects of the study ARVs on unborn babies are unknown, you should not become pregnant 
while in this study. For all participants assigned female at birth in the study, we will collect urine or blood to test 
for pregnancy.  
 
There are certain effective methods of birth control that participants who are able to become pregnant must use 
while in this study. These effective methods must be continued for 30 days after stopping the study ARV pills, or 
for at least 48 weeks after stopping the study ARV shots. Participants who are able to become pregnant, must 
agree to use these methods in order to take part in the study. We will help make sure you can get effective 
methods by providing them here in the clinic or offering a referral. At study visits when you will receive study 
medicines (either the pill or shot), we will need to confirm that you are using effective birth control before giving 
you the study medicines. 
 
Participants who become pregnant during the study will stop taking the study medicines and enter the long-term 
safety follow-up phase of the study (see #15 below). They must continue taking their usual ARVs. We will 
also contact you to find out the outcome of the pregnancy even if the outcome occurs after leaving the study. 
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure of 
pregnancy results to parents or guardians: As soon as the pregnancy test result is available, we will go over it 
with you in private, without your parents/guardians present. You must give us permission before we can share 
these results with your parents/guardians. If the test shows that you are pregnant, we will give you information on 
where medical care and other services can be received.] 
 


 
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If you are pregnant, your doctor may report your pregnancy to the Antiretroviral Pregnancy Registry. The 
Antiretroviral Pregnancy Registry assists participants and doctors in gauging potential benefits and risks of 
treatment; however, the registry does not collect any identifying information about you, such as your name, 
initials, contact information, or date of birth.  
 
7. We will tell you if you are eligible. 
 
We will give you the results of all procedures and explain the results to you. We will tell you about getting care, 
treatment and any other services you may need. While waiting for the results, it is important for you to keep 
taking your usual ARVs. 
 
If you are not eligible for the study for any reason, we will tell you this. You will not be entered in the study. You 
can and should continue to receive medical care and treatment outside of the study. We will tell you more about 
getting this care and treatment and any other services you may need.  
 
If you do not enter the study, we will still use some information collected about you (for example age, sex, and 
race). We will use this information to look at patterns or common reasons for not entering the study. 
 
If you are eligible for the study, you will be entered into the study.  
 
Entering the study 
 
8. If you are eligible, you will enter the study 
 
On the day you enter the study we will:  
• 
Review your medical records.  
• 
Talk with you about your ARV use. 
• 
Talk with you about preventing pregnancy. 
• 
Talk with you about the study visit schedule and taking the study medicines correctly 
• 
Ask you questions about what you think about CAB and RPV 
• 
Do a physical exam.  
• 
Draw about 18mL (about 4 teaspoons) of blood for tests. The tests will: 
o Check your blood cells. 
o Check how well your liver and kidneys are working. 
o Check how much the virus has affected your ability to fight the virus. This is called CD4 cell count. 
o The tests will check your HIV viral load.  
o Some blood will be saved for later testing for resistance to ARVs. This test shows whether different 
ARVs may work against the HIV in your blood. 
• 
For participants assigned female at birth, we will collect urine or blood for a pregnancy test  
• 
Ask if you are willing to complete an in-depth phone interview. [US sites only.] 
 
 At this visit we will again talk with you about which group is best for you to join (Cohort 2A or Cohort 2B). You 
will not be able to switch to the other group after you have entered the study. 
 
If it is decided that you will enter Cohort 2A, then at this visit, you will stop taking your usual ARVs and start 
taking CAB and RPV pills. We will give you the pills and explain how to take them. You will take your first dose 
at the visit.  
 
This visit will take about 4 hours.  


 
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Being in the study 
 
9. After entering the study in the Cohort 2A group, you will have two more visits in the study pills phase (Weeks 2 
and 4a).  
 
The first visit in Cohort 2A will be the study entry visit and is described in #8 above.  After that visit, you will 
have 2 more visits in the study pill phase.  These visits will be scheduled 2 weeks apart. [Sites to modify] Each 
visit will take about 1-3 hours. At each of these visits, we will:  
 
• 
Review your medical records.  
• 
Talk with you about your ARV use 
• 
Do a physical exam. 
• 
Talk with you about preventing pregnancy.  
• 
For participants assigned female at birth, we will collect urine or blood to test for pregnancy.  
• 
Remind you to bring the oral CAB and oral RPV to the study clinic. 
 
At two of these visits (Week 2 and Week 4a), we will draw about 5mL (about 1 teaspoon) of blood for tests. 
These tests will check your blood cells and how well your liver and kidneys are working.  
 
At the second visit (Week 2), we will draw about 12mL (about 2-3 teaspoons) blood for tests. This test will check 
your HIV viral load. Some blood will be saved for later resistance testing.  
 
At the Week 2 visit we will also test the amount of CAB and RPV in your blood. This is called a pharmacokinetic 
(PK) test. At this visit, we will ask you when you took CAB or RPV in the past three days. [Sites: modify 
language as appropriate to align the three prior doses with the timing (morning or evening) of the Week 4b pre-
dose PK sample collection.] For three days before this visit, you must be sure to take CAB and RPV on time and 
in the morning. This is very important. We will help you remember this before the visit. 
 
We will need to draw your blood two times during the Week 2 visit, before and after taking CAB and RPV. We 
will remind you to not to take CAB or RPV before coming to this visit. When you come to the visit, we will draw 
your blood, then you will take CAB and RPV, and then we will draw your blood again, about three hours later. 
Each time we will draw 4mL (less than 1 teaspoon), for a total of 8mL (about 2 teaspoons).  
 
Study staff will let you know when these procedures will occur ahead of time.  
 
[Sites to modify] On rare occasions, we may offer some of the visit activities off-site, or by phone. The study staff 
will discuss the location and best time to visit you so that the visit is at a convenient time and the visit is done at a 
place you feel comfortable and confidentiality can be maintained. 
 
10. If you are eligible, you will enter the study shots phase (Week 4b). 
 
At the Week 4b visit, we will determine if you are eligible to get the CAB and RPV study shots. At this visit we 
will:  
• 
Review your medical records.  
• 
Talk with you about your ARV use. 
• 
Do a physical exam. 
• 
Ask you questions about your experience with the study drugs.  
• 
Talk with you about preventing pregnancy.  
• 
Draw about 12mL (about 2-3 teaspoons) blood for tests. These tests will check your HIV viral load. Some 
blood will be saved for later resistance testing.  


 
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• 
Do an electrocardiogram (ECG). This is to test how well your heart is working.  
• 
For participants assigned female at birth, we will also collect urine or blood to test for pregnancy. 
• 
Remind you to bring the oral CAB and oral RPV to the study clinic. 
• 
[Sites: modify language as appropriate to align the three prior doses with the timing (morning or evening) of 
the Week 4b pre-dose PK sample collection. Remind you to take the oral CAB and oral RPV in the morning 
for the three days before this visit.]  
 
If you are not eligible, you will stop taking oral CAB and oral RPV and will start taking your previous ARVs 
again. If you did not participate in Cohort 1, you will complete a final study visit about 4 weeks after your last 
oral CAB and RPV dose (see #14 for more information). If you received shots of CAB or RPV before in Cohort 1 
but are not eligible to get the shots of CAB and RPV in Cohort 2, you will stop taking the study pills and will take 
part in the long-term safety follow-up phase (see #15 below). 
 
If you are eligible, you will take your last dose of oral CAB and oral RPV at the Week 4b visit. At this visit, we 
will also give you the first shot of CAB and the first shot of RPV. We will remind you not to take oral CAB and 
RPV before coming to this visit. You will take oral CAB and RPV at the study clinic before the first shot of CAB 
and the first shot of RPV.  
 
At this visit, we will also look closely at the amount of CAB and RPV in your blood. To do this, we will need to 
draw your blood two times during the visit, before taking oral CAB and RPV and after getting the CAB and RPV 
shots. When you come to the visit, we will draw your blood, then you will take oral CAB and RPV and get CAB 
and RPV shots, and then we will draw your blood again, about two hours later. Each time we will draw 4mL (less 
than 1 teaspoon) for a total of 8mL (about 2 teaspoons). At this visit, about 2 hours after you get a shot of CAB 
and a shot of RPV, we will also do an ECG to look at your heart. 
 
[Sites to include if combined Week 4a and Week 4b visits are planned.] This visit may be combined with the 
previous study visit (Week 4a). 
 
11. You will have 14 more visits (Weeks 5-96) in the study shots phase.  
 
The first visit in  the study shots phase will be the Week 4b visit, which is described in #10 above. After that visit, 
you will have 14 more visits in this phase. Most of these visits will take place about 8 weeks apart, and some of 
these visits will take place 1 week apart. [Sites to modify] Each visit will take about 1-3 hours. At each of these 
visits, we will: 
• 
Review your medical records.  
• 
Talk with you about preventing pregnancy.  
• 
Do a physical exam. At two of these visits (Weeks 24 and 96), this exam will include examination of your 
genitals to see the stage of development. For participants assigned female at birth, this will also include 
looking at the breasts. 
 
At 12 of these visits (Weeks 8-24 and 32-96) you will:  
• 
Get a shot of CAB and a shot of RPV. 
• 
For participants assigned female at birth, we will also collect urine or blood to check for pregnancy.  
 
At 13 of these visits (Weeks 5, 8-24, and 32-96) we will draw about 5mL of blood (about 1 teaspoon) for tests. 
These tests will check: 
• 
Your blood cells 
• 
How well your liver and kidneys are working 
 


 
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At 9 of these visits (Weeks 8-24, 32-48, 64, 80, and 96) we will draw about 12mL of blood (about 2-3 teaspoons) 
for tests. These tests will check: 
• 
Your HIV viral load.  
• 
Some blood will be saved for later resistance testing.  
 
At 12 of these visits (Weeks 5, 8-48, 64, 80, 88, and 96), we will also draw about 4mL of blood (less than 1 
teaspoon) of blood to look at the amount of CAB and RPV in the blood. 
 
At 4 of these visits (Weeks 24, 48, 72 and 96) we will draw about 3mL of blood (about 1 teaspoon) to check your 
CD4 count.  
 
At 4 of these visits (Weeks 8, 24, 48, and 96) we will ask you questions about getting the shots of CAB and RPV.  
 
At 5 of these visits (Weeks 8, 24, 48, 72, and 96) we may also talk with you about how you are doing with the 
visit schedule.  
 
Study staff may ask you to return to the clinic for a study shot before your next visit. If so, then many of the 
procedures described above would also be done again.  
 
If you cannot come to the clinic to receive the CAB and RPV shots, then you may have the option to take the 
CAB and RPV pills until you are able to get the shots again.  If this happens, you may need more frequent CAB 
and RPV shots outside of the scheduled visit days for a few months. If you cannot return to the clinic to get the 
CAB and RPV shots soon, then you may need to stop taking the study ARVs and enter the long-term safety 
follow-up phase (see #15 below). This is not preferred, and it is important to get the shots on the scheduled visit 
day and not miss any CAB and RPV shots. 
 
Study staff will let you know when these procedures will occur ahead of time.  
 
12. In-depth phone interviews [for U.S. sites only] 
 
We are very interested to understand what adolescents think about getting their ARV’s as shots. You may be 
asked if you would like to complete an in-depth phone interview. If you would like to take part in the interview, 
then you may be contacted to have the interview after getting the fourth shot of CAB and RPV. Not all 
participants will be contacted for the interview. You do not have to do the interview to take part in this study. 
 
If contacted, an interviewer will talk to you for about 1-2 hours and will ask how you feel about having shots of 
CAB and RPV. This information will help us understand if CAB shots and RPV shots have any bad side effects 
for adolescents. It will also help us understand how adolescents and families feel about the shots. The interview 
may take place at or in between the Week 24 through 96 visits or during the long-term follow-up safety phase. 
The interview will only take place once. The interview will be audio recorded and written down in a report. Your 
name will not be included in the report.  
 
We may also ask your parent or caregiver to complete an in-depth interview. This interview would ask them how 
they felt about you having shots of CAB and RPV.  
 
13. Adolescents may have an extra visit if their HIV is not controlled. 
 
Participants will have viral load tests at almost all visits to check the amount of HIV in the blood. If tests show 
that the viral load is higher than expected (200 copies/mL or more) you will have repeat testing. This may occur 
as part of another study visit or may occur as an extra study visit.  
 


 
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The extra visit will take about 1-2 hours. At this visit we will: 
• 
Review your medical records. 
• 
Do a physical exam.  
• 
Draw about 16mL (about 3 teaspoons) of blood for tests. The tests will: 
o Check your HIV viral load.  
o Check the amount of CAB and RPV in the blood.  
o We will save some blood for later resistance testing. 
• 
Talk with you about preventing pregnancy. 
• 
For participants assigned female at birth, we will also collect urine or blood to check for pregnancy.  
 
If the repeat test also shows an increased amount of HIV in your blood, you will stop taking the study product and 
start taking your previous ARVs again. If you were getting shots of CAB and RPV, you will enter long-term 
safety follow-up (more information in #15 below).   
 
14. If you are not eligible to receive shots of CAB and RPV you will stop the study early.  
 
If you are not eligible to get shots of CAB and RPV then you will stop taking oral CAB and oral RPV and will 
complete a final study visit about 4 weeks after your last oral dose.  
 
During this visit, we will:  
• 
Review your medical records.  
• 
Do a physical exam. This will include looking at your genitals to see the stage of development. For 
participants assigned female at birth, this will also include looking at the breasts. 
• 
Draw blood for tests. This would be about 15-20mL of blood (about 3-4 teaspoons) for these tests. These tests 
will check:  
o Your blood cells.  
o How well your liver and kidneys are working. 
o Your HIV viral load.  
o Some blood will also be saved for later resistance testing. 
• 
Talk with you about preventing pregnancy.  
• 
For participants assigned female at birth, we will also collect urine or blood to check for pregnancy.  
• 
Ask you questions about what it is like to take the oral CAB and oral RPV.  
• 
We will talk with you about your ARV use.  
 
If you also participated in Cohort 1 and received shots of CAB or RPV in Cohort 1, but are not eligible to get the 
shots of CAB and RPV in Cohort 2, you will stop taking oral CAB and oral RPV and will enter into the Cohort 2 
long-term safety follow-up phase (see #15 below). 
 
15. If you stop the shots of CAB and RPV early or after the Week 96 study visit, you will enter the long-term safety 
follow-up phase. 
 
You will enter the long-term safety follow-up phase after the last shot of study product if you: 
• 
Stop the shots of CAB and RPV early, or  
• 
Do not wish to continue to get the shots of CAB and RPV after the final Cohort 2 visit (Week 96)  
 
If you become pregnant, you will enter this phase of the study after your positive confirmatory pregnancy test 
result, whether you are taking the pill or the shot.  
 
During the long-term safety follow-up phase, you will stop getting shots of CAB and RPV. You will start taking 
your previous ARVs again. There will be 4 visits during the long-term safety follow-up phase.  


 
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These visits will be scheduled 8, 24, 36 and 48 weeks after your last shot of CAB and RPV (or after a positive 
confirmatory pregnancy test result). [Sites to modify] Each of these visits will take about 1-3 hours. At these 
visits, we will:  
• 
Review your medical records.  
• 
Talk with you about preventing pregnancy.  
• 
Do a physical exam. At the final long-term safety follow-up visit, this will include examination of your 
genitals to see the stage of development. For participants assigned female at birth, this will also include 
looking at your breasts. 
• 
Draw blood for tests. This would be about 21mL of blood (about 4 teaspoons) for these tests. These tests will 
check:  
o Your blood cells.  
o How well your liver and kidneys are working. 
o Your HIV viral load.  
o The amount of CAB and RPV in the blood.  
o Some blood will also be saved for future resistance testing. 
• 
For participants assigned female at birth, we will also collect urine or blood to check for pregnancy.  
• 
At two of these visits (8 weeks and 48 weeks after your last shot of CAB and RPV) we will talk with you 
about your ARV use.  
• 
At two of these visits (8 weeks and 48 weeks after your last shot of CAB and RPV), we will also ask you 
questions about getting shots of CAB and RPV.  
 
16. Different tests will be done at different laboratories. 
 
We will do most of the tests of blood or urine here at our laboratory. We will give you the results of most of these 
tests at the next scheduled visit, or sooner, if necessary. We will explain the results and give you counseling and 
referrals as needed.  
 
We will also draw blood to check the amount of CAB and RPV in your blood. This is called a pharmacokinetic 
(PK) test. The PK test will be done at a laboratory in the United States. We will not usually give you the results of 
this test during the study.  
 
If you need a test for resistance (see #13 above), that test will be done at a laboratory in the United States.  You 
will be given the results of this resistance test and referrals if needed.  
 
17. We may take you off of the study. 
 
We may take you off the study ARVs if: 
• 
You are not able to come to the study visits or we determine that you cannot meet the study requirements. 
• 
You are not able to take the study ARVs. 
• 
The study ARVs are not controlling the HIV in your blood. 
• 
Continuing the study ARVs may be harmful to you. 
• 
You request to stop the study ARVs. 
• 
You are not able to follow the birth control requirements of this study. 
• 
You become pregnant 
 
If you stop the oral study ARVs early, we will ask you to come back to the clinic about four weeks after you stop 
the oral study ARVs (see #14 above). You will not have any other visits after this. 
 


 
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If you stop the ARV shots early, we will ask you to come back to the clinic for four additional study visits for 
long-term follow-up (see #15 above). You will not have any other visits after these four visits. 
 
We may also take you off the study early if the study is stopped for any reason.  
 
The study cannot provide other types of ARVs, but we will give you information, counseling, and referrals to 
where you can get care and treatment needed. We will help make sure you can get ARVs from outside of the 
study. If the study stops early, every effort will be made to make certain that there is no interruption in your 
therapy.  
 
18. Please tell us if you want to leave the study. 
 
You are free to leave the study at any time for any reason. The care that you receive at this clinic will not be 
affected, but it is important for us to know about your decision.  
 
If you stop the study ARVs, we may ask you to return to the study clinic for additional study visits described in 
#14 and #15 above. If you stop the study early, we may ask you to return to the study clinic for one final study 
visit, like the last study visit described in #15 above. 
 
We will answer any questions you may have and give you information on how to contact us in the future, if you 
wish. 
 
After the study 
 
19. Receiving the study ARVs after the study is over.  
 
As you come to the end of the study, we will work with you to plan for your care and treatment outside the study. 
It is important that we plan for this in advance, so that there is no gap in your taking ARVs as you finish the 
study. Taking ARVs without interruption is the best-known way for you to stay healthy.  
 
We will tell you where you can go to receive needed care and treatment after you finish the study. If you are 
gaining benefit from the study ARV shots given in the study, the companies that are providing these ARVs (ViiV 
Healthcare and Janssen Pharmaceuticals) will try to provide these ARV shots to you. They will be provided until 
they are otherwise available locally, until you are no longer gaining benefit, or if the company decides to stop 
studying the ARVs. However, there is no guarantee this will be possible. If this is not possible, you will need to 
switch to other oral ARVs that are available locally. We will explain the options to you and help ensure your 
access to ARVs outside the study. We will also contact you again within the first four or eight weeks after you 
finish the study to confirm that you are getting ARVs. 
 
Risks of the study 
 
Taking part in this study may involve some risks and discomfort. The risks are different for each phase of the 
study. Risks during the study pills phase include: risks from blood draws, risks from the study pills (CAB and 
RPV), risks of switching ARVs, and risks to your privacy.  
 
Risks during the study shots phase include: risks from blood draws, risks from receiving the injection, risks from 
the study pills (CAB and RPV) and the study shots (long-acting CAB and RPV), and risks to your privacy.  
 
Risks during the long-term safety and follow-up phase include: risks from blood draws, risks of switching ARVs, 
and risks to your privacy. 
 


 
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20. Risk from blood draws  
 
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted. Rarely, drawing blood 
can cause fainting or infection. 
 
21. Risk from receiving the injection  
 
People in other studies who have received the CAB and RPV shots said they had pain, skin irritation, skin 
redness, bumps, swelling, itching, bruising at the spot where they got the shot. Most reactions go away in a week 
or less but sometimes they can last longer. Most people usually do well with them and rarely need to stop the 
drug.  
 
The shots will be given in the muscles of your buttocks. The injection could be given too deeply or not deeply 
enough, missing the muscle and entering your skin, blood, or a nerve.  
 
The risks of this are not well understood but could make CAB or RPV levels too low or too high. If too low the 
drug may not work against your HIV. If RPV is too high, there could be a change in your heartbeat, which in 
severe cases can be life-threatening. In rare cases, symptoms such as feeling lightheaded, numbness or tingling, 
difficulty breathing, chest or stomach discomfort, sweating, rash, pain (e.g., back and chest), nausea and/or feeling 
anxious have occurred after an injection with RPV LA. In these cases, high blood levels of RPV have been 
observed, which may be due to an accidental injection of part of the medication into a blood vessel instead of the 
muscle. Not all participants in whom an accidental injection in a blood vessel was suspected reported such 
symptoms. Most of the symptoms resolved within minutes. Your doctor may need to administer treatment to help 
resolve these symptoms. Everything possible will be done to decrease this risk, including watching you for 
problems during the study. If your doctor thinks that the injection was not given the right way, you might be 
asked to stay in the clinic up to 3 hours after the injection to watch how you are doing and extra tests may be 
needed to be sure you are safe. We will also draw blood (less than 1 teaspoon) about 2 hours after the study shot 
to look at the amount of study drugs in your blood. If you are worried about this risk, talk to your doctor. 
 
Receiving injections can cause some people to feel lightheaded or feel like they might pass out. Fainting can also 
occur. This reaction, called a ‘vasovagal reaction’, has been reported with other injectable medicines, and resolves 
quickly. 
 
22. There are risks from the study ARVs 
 
All ARVs can cause side effects. This includes the ARVs you are currently taking and the ARVs that are given in 
the study. Some side effects are minor; others can be severe. Some side effects are common; others are rare. Some 
people who take ARVs have some of the side effects. Other people have different side effects, or no side effects.  
 
The most common and most serious side effects of the study ARVs, CAB and RPV, are listed below. This is 
based on what we know now about CAB and RPV used in adults. There may be other side effects that we do not 
know about now. This may be especially true for adolescents, because this is the first study of CAB and RPV in 
adolescents.  
 
This form does not list all possible side effects of all ARVs. If you join the study, we will tell you more about the 
ARVs you will be taking. At each study visit, we will check on whether the ARVs may be causing side effects. 
We will also tell you what to do if you have side effects. If you have questions or concerns at any time, please tell 
us.  
 
23. Some side effects from the CAB pills and the CAB shot 
 


 
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Many people have received CAB pills or the CAB shot in other studies. The table below lists side effects from 
other studies of CAB with people who have HIV. It is not known if CAB, other drugs or the participant’s other 
health problems caused or affected these. Some of these are the same side effects as RPV (see #24 below).  
 
Common and Uncommon Side Effects of CAB 
Very Common Side Effects of 
CAB 
Common Side Effects of CAB 
Uncommon Side Effects of 
CAB 
• Headache 
• Pyrexia (fever), feeling hot, 
body temperature increase  
• Injection Site Reactions (pain 
and discomfort, a hardened 
mass or lump) 
 
• Rash 
• Vomiting (being sick) 
• Nausea (feeling sick to the stomach) 
• Abdominal pain, upper abdominal 
pain (stomach pain and discomfort)  
• Insomnia (problems sleeping)  
• Abnormal dreams/nightmares 
• Anxiety (feeling anxious) 
• Feeling lightheaded (dizziness) 
• Depression (feelings of deep sadness 
and unworthiness) 
• Flatulence (passing gas or wind) 
• Diarrhea or loose stools 
• Myalgia (muscle pain) 
• Fatigue (lack of energy) 
• Asthenia (feeling weak) 
• Malaise (feeling generally unwell) 
• Weight increase 
• Injection Site Reactions (swelling, 
redness, itching, bruising, warmth or 
discoloration) 
• Somnolence (sleepiness or 
Drowsiness) 
• Vasovagal reactions (light-
headedness or fainting, during 
or following an injection) 
• Hepatotoxicity (liver problems) 
• Transaminase increase (blood 
test may show increase in the 
level of liver enzymes) 
• Injection Site Reactions 
(cellulitis [heat, swelling or 
redness], abscess [collection of 
pus], numbness, minor 
bleeding, discoloration) 
 
The following effects have also been seen in some of the people who received CAB pills or the CAB shot in other 
studies: 
 
Abnormal liver tests: 
 
A small number of people across all studies (just over 1% of 1644 participants as of April 2017) had abnormal 
liver tests requiring them to stop CAB. Some abnormal liver tests were explained by other health conditions such 
as a new virus infection, like Hepatitis A, B or C. A small number of people did not have health conditions that 
could explain the abnormal test, so it is possible that a mild form of liver damage happened from taking CAB. 
The liver tests got better after stopping CAB, showing that any damage was temporary. 
 


 
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Blood tests to check the health of your liver will be done during the study. Your study doctor will tell you if you 
need to stop taking the study drugs or if other actions are needed. If you stop taking the study drug, you may be 
able to re-start the study drug or you may need to change your usual ARVs.  
Seizures/convulsions: 
 
Seizures have been seen (rarely) in people with and without HIV who have taken CAB. They are not thought to 
be caused by CAB, but the study staff will ask you about them.  
 
In other studies, two people without HIV had a history of seizures (epilepsy), and had a seizure about 3 months 
and 9 months after starting CAB. One other person with HIV but without a history of seizures, had seizures about 
one year after starting CAB. This participant had a long period of seizures without medical treatment and died. It 
is not known if CAB was part of the reason for seizures in these people. If you have a history of seizures, please 
let your study doctor know. 
 
24. Some side effects from the RPV pills and the RPV shot 
 
Oral RPV (Edurant) is a marketed drug which many people throughout the world have received to manage HIV. 
We know more about the side effects of Edurant than we do about CAB or RPV shots. The following side effects 
have been seen in studies in people with HIV taking RPV.  
 
Common and Uncommon Side Effects of RPV 
Common Side Effects of RPV 
Uncommon Side Effects of RPV 
• 
Dry mouth 
• 
Feeling less hungry (decreased appetite) 
• 
Sleep disorders 
• 
Immune reconstitution syndrome (this can be 
an overreaction of the body’s recovering 
defense system to a previously present 
infection, or problems in the immune system) 
• 
Depressed mood 
• 
Abdominal discomfort (belly ache) 
 
The following effects have also been seen in some people who received RPV in other studies: 
 
Abnormal blood tests: 
 
Other changes in blood tests have also been observed. People with Hepatitis B or C or who have possible liver 
damage before starting RPV may have worse liver tests while taking RPV. A few cases of liver problems were 
found in people taking RPV who did not already have any liver problems. 
 
Sometimes allergic reactions can affect body organs, like the liver and cause liver problems which can lead to 
liver failure. Contact your study doctor right away if you have any of the following signs or symptoms of liver 
problems: 
• 
Yellowing of the skin or whites of the eyes 
• 
Dark or tea colored urine 
• 
Pale colored stools/bowel movements 
• 
Nausea/vomiting 
• 
Loss of appetite 
• 
Pain, aching or tenderness on the right side below the ribs 
• 
Itchy skin  
 


 
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Blood tests to check the health of your liver will be done regularly during the study. Your study doctor will tell 
you if you need to stop taking the study drugs or if other action is needed. If you stop taking the study drug, you 
may be able to re-start the study drug or you may need to change your usual ARVs.  
 
Skin Rash: 
Most rashes were mild or moderate, and happened within the first 4 weeks of taking RPV. Most of rashes got 
better after one week, and the people did not need to stop taking RPV. However, the study ARVs will need to be 
stopped for some types of moderate rash and all types of severe rash, which can be life-threatening. If this 
happens to you, you will need to come for extra study visits to monitor your health. Some people with rash may 
also have other signs and symptoms of allergic reaction. 
 
If you have any type of rash or other skin problems during the study you must tell your study doctor right away, 
and the doctor may tell you to stop taking CAB and/or RPV. 
 
25. There may be other possible risks from the study ARVs. 
 
The study ARV shots stay in your body for a long time 
 
The shots you get in this study are long acting, meaning they stay in your body for a long time. In most people the 
drugs will no longer be in the body one year after an injection, while in some people low levels of CAB and RPV 
may still be in the body after one year. If you develop a side effect to the study drug after the shot, there will be no 
way to remove the drug from your body. If you get a shot of CAB or RPV, we will monitor your health for 48 
weeks after your last shot. If you develop a symptom from these drugs while the drugs are still in your body, 
every effort will be made to treat the side effects. The amount of drug will decrease overtime and will eventually 
disappear. 
 
While the amount of study drugs in your body decrease slowly over time after you stop getting shots, the study 
drugs could stop working against your HIV. When stopping long acting HIV drugs, it will be very important to 
start taking other HIV medications, as your study doctor tells you, so your HIV medications do not stop working 
against your HIV. 
 
Risk of switching ARVs 
 
If you join this study, you will stop taking the ARVs you are currently taking, and start taking ARVs given by the 
study. The study ARVs could cause side effects that you would not have from the ARVs you are currently taking. 
The study ARVs also may not work as well as the ARVs you are currently taking. For example, the study ARVs 
may not work as well to control the amount of HIV in your body. We will test your HIV viral load at most study 
visits to check on this. If your viral load is higher than expected, you will have repeat testing, and your use of the 
study ARVs may be stopped (see #13 above).  
 
Risk of resistance 
 
By stopping your previous ARVs and switching to the study ARVs, you could develop resistance. This could 
happen if the study ARVs don’t work as well to control the amount of HIV in your body. Resistance means that 
the ARVs may not work against HIV if these ARVs are taken again in the future. To stop resistance, it is 
important that you take and/or receive the ARVs as instructed, and do not miss any doses. 
 
Mental illness or depression 
 
Some people with HIV sometimes have feelings of depression or may feel sad or hopeless, feel anxious or 
restless, or may have thoughts of hurting or killing themselves (suicide). A small number of people being treated 


 
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with drugs called integrase inhibitors [INIs] for HIV like CAB, have had suicidal thoughts and actions, 
particularly participants with a prior history of depression or mental health illness.  
 
Tell the study doctor if you have a history of mental health illness. If you have thoughts of hurting or killing 
yourself or have any other unusual or uncomfortable thoughts or feelings during this study, you should tell the 
study doctor or go to the nearest hospital right away.  
 
Possible effects on pregnancy or unborn babies 
 
HIV and ARVs may lead to some pregnancy complications, like early delivery or low weight of the baby at birth. 
We do not know if some ARVs are more likely to cause these effects than others. We do not yet know if CAB is 
safe in pregnancy. RPV does not appear to be a risk to pregnancy and the developing baby based on the 
information we know now, but additional data are still being collected. 
 
There are few data from humans on the effects of CAB in pregnancy. Most of the information we have comes 
from animal studies. In studies done in pregnant rats and their newborns, using very high amounts of CAB, there 
were more baby rats that died when they were born or right after they were born. This did not happen to the baby 
rats when the mother got lower amounts of the drug, or no drug. The amount of CAB that we are giving in this 
study is expected to be more than 7-times lower than the amount given to the pregnant rats. Birth defects have not 
been found in any animal studies of CAB so far. We do not know whether what happened to the baby rats has any 
impact on what will happen in pregnant humans taking this drug. 
 
Early results from one large study in Botswana showed that the ARV called dolutegravir (DTG) may increase the 
risk of serious birth defects of the brain or spine in the new baby. The increased risk was seen among babies 
whose mothers were taking DTG when they became pregnant. These birth defects happen during the first few 
weeks of pregnancy, before mothers may know they are pregnant. These birth defects have not been seen among 
babies whose mothers started taking DTG later in pregnancy.  
 
CAB is not the same drug as DTG. We do know that CAB and DTG belong to the same class of medications and 
work in a similar way to treat HIV infection. We do not know if CAB can cause brain or spine defects in babies.  
 
Participants who are able to become pregnant must agree to use certain effective methods of birth control to be in 
this study (see #6 above). If you become pregnant during the study, please let us know right away. 
 
Immune reconstitution syndrome 
 
In some people with advanced HIV, signs and symptoms from other infections or certain diseases (for example a 
liver condition called autoimmune hepatitis) may occur soon after starting combination ARVs but can also occur 
later. Some of these symptoms may be life threatening. If you start having new symptoms, or if you notice that 
any existing symptoms are getting worse after starting the ARVs, tell your doctor immediately. 
 
Abnormal placement of body fat and wasting 
 
The use of potent antiretroviral drug combinations may be associated with an abnormal placement of body fat and 
wasting. Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 
• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement 
 


 
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26. There could be risks of disclosure of your information. 
 
We will make every effort to keep your information private and confidential. Study records and specimens will be 
kept in secure, locked locations. All specimens and most records will be labeled only with a code number. 
However, your name will be written on some records.  
 
Despite our best efforts to keep your information private, it is possible that the information could be obtained by 
someone who should not have it. If this were to happen, you could be treated badly or unfairly. You could feel 
stress or embarrassment.  
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality that protects us from being 
forced to release information that may identify you, such as by the courts or police. The certificate cannot be used 
in all situations, but it can be used to resist demands for information that would identify you. The certificate does 
not protect against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your participation in the study to 
others, if you wish. 
 
Information collected for this study may be used for other research in the future. For example, researchers may 
use information from this study to try to answer different questions about children or adolescents with HIV. Any 
future research done with the information from this study must be approved by the IMPAACT Network. If any 
future research is done, information about you may be used but your name will not be shared. 
 
Benefits of the study 
 
27. There may be a direct benefit to you from being in the study. 
 
By joining the study, you will be part of the search for ARVs that may be better for adolescents. We do not know 
if being in the study will benefit you in any way. There may be a direct benefit to you by taking part in this study, 
but no guarantee can be made. For example, if you get shots of CAB and RPV, you might prefer having monthly 
shots instead of taking daily pills. The study ARVs may have fewer side effects than the previous ARVs you were 
taking. There may also be benefit if the results from this study lead to a safe and effective dose of the study drugs 
for adolescents. It is also possible that you may receive no direct benefit from this study. Information learned 
from this study may help other adolescents who have HIV. 
 
You will have regular visits here and frequent checks on your health, including tests for amount of HIV in your 
blood, called viral load. It is possible that the study ARVs will slow your HIV infection. Information learned from 
this study may help other adolescents with HIV. 
 
Other information about the study 
 
28. There are no costs from being in the study. 
 
There are no costs to you for study visits, CAB, RPV or procedures.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits. For each visit, you will be given (specify amount).] 
 


 
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29. Study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include:  
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your name or identify you personally.  
 
A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify you. At most, the website will include a summary of the results. You can 
search this website at any time. 
 
Your study information may be given to other authorities if required by law. [Sites add more specific detail here 
as needed; example follows:] For example, we are required to report any significant risk of harm to you or others.  
 
30. If you get sick or injured, contact us immediately. 
 
Your health is important to us. We will make every effort to protect your well-being and minimize risks. It is 
possible, however, that you could have an illness or injury that is study-related. This means that the illness or 
injury occurred as a direct result of the study procedures.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage available 
through clinical trial insurance obtained by the site should be included if applicable; the statement regarding no 
program for compensation through the NIH may not be removed.]  If a study-related illness or injury occurs, we 
will treat you or tell you where you can get treatment. The cost for this treatment may be charged to you or your 
insurance company. There is no program for compensation either through [site name or] the U.S. National 
Institutes of Health.  
 
Whom to contact 
 
31. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about your rights as research participants or concerns about how you are being treated 
in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 
 


 
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• 
If you have any health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you want to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
 
Signatures 
 
If you agree to participate in Cohort 2A of this study, please sign or make your mark below. 
Before deciding whether to participate in this study, make sure you have read this form, or had it read to you, and 
that all of your questions have been answered. You should feel that you understand the study, its risks and 
benefits, and what is expected of you if you decide to join.  
 
If you decide to join, we will tell you any new information from this study or other studies that may affect your 
health, welfare, or willingness to stay in the study. You are welcome to ask questions or request more information 
at any time. If you want the results from this study, please tell the study staff. 
 
You do not give up any rights by signing this form. 
 [Insert signature blocks as required by site IRB/EC policies.] 
 
 
Signature blocks for participants of legal age to provide independent informed consent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 


 
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Signature blocks for parent/legal guardian of adolescent: 
 
 
 
_______________________________  
___________________________________ 
Name of Parent/Legal Guardian (print)  
Signature of Parent/Legal Guardian and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 


 
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Appendix II-C:  Sample Informed Consent Form for Participation in Cohort 2B 
 
for adolescents who can provide independent informed consent for study participation and parents/legal guardians 
of adolescents 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 4.0, dated 27 May 2022 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
If you are the parent or legal guardian of a child who may take part in this study, your permission and the 
permission of your child will be needed.  When “you” appears in this form, it refers to your child except where it 
says otherwise. 
 
Introduction 
 
You are being asked to take part in the research study named above. 
 
This form gives information about the study. Please read it, or have it read to you, and ask any questions you may 
have. We will take as much time as needed for you to fully understand the study. We will ask you questions to see 
if we have explained the study clearly. 
 
Here is a summary of important information about the study: 
 
• 
The study is testing two anti-HIV medicines (ARVs), Cabotegravir (CAB) and Rilpivirine (RPV), taken as 
pills and given as long-acting shots in adolescents 12 to less than 18 years of age.  
• 
Some of the study drugs are already approved in some countries for use in adolescents or adults, but more 
data is needed for use in adolescents.  
• 
There are two parts to this study, Cohort 1 and Cohort 2. The Cohort 2 part to this study also has two groups: 
Cohort 2A and Cohort 2B. This form is about Cohort 2B.  
• 
Adolescents in Cohort 2 will switch from their usual ARVs to the study medicine and will be in this part of 
the study for at least 2 years up to 3 years.  
• 
In Cohort 2, you will have the option to either take the study pills and then get the study shots (this is called 
Cohort 2A) or skip the study pills and only get the study shots (this is called Cohort 2B).  
• 
After entering the study, adolescents in Cohort 2A will stop taking their usual ARVs and start taking daily 
CAB and RPV pills for 4 to 6 weeks. Adolescents will then switch to CAB and RPV shots every 8 weeks for 
about 2 years.  
• 
Adolescents in Cohort 2B will stop taking their usual ARVs and start CAB and RPV shots every 8 weeks for 
about 2 years. 
• 
We will discuss Cohort 2A and Cohort 2B with you and together make a decision that is best for you. 
• 
After the 2 years of getting the CAB and RPV shots, all Cohort 2 adolescents might be able to continue 
getting the same CAB and RPV shots outside of the study. We will explain the options to you and help 
ensure your access to ARVs outside the study. 


 
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• 
Adolescents who stop taking the CAB and RPV shots may be followed for up to 1 year for long-term safety 
follow-up. During this time, adolescents will not take any study medicine (shots or pills) but will take ARVs.   
• 
While in the study, adolescents will have clinic visits with physical examinations and blood draws for 
laboratory tests. Some visits will include a review of adolescents’ medical records and ECG tests to look at 
the adolescent’s heart. Participants assigned female at birth will also be tested for pregnancy.  
• 
If interested, participants in the U.S. may be eligible to do one in-depth phone interview where they will talk 
about their experience getting their ARVs as shots.  
• 
There are some possible risks for adolescents in the study. One possible risk is that the pills or shots being 
tested could cause side effects. The most severe side effects include allergic reaction, liver problems, and 
mental health problems.  These side effects are uncommon. 
• 
There are some possible benefits for adolescents in the study. One possible benefit is not taking daily pills 
while getting the CAB and RPV shots.  Another possible benefit is that the shots being tested will be better 
for your health and HIV care than the usual ARV pills.  
• 
Your decision on your participation in the study will have no effect on the medical care you receive at this 
clinic. Your access to services, and the benefits and rights you normally have, will not be affected. You may 
choose to leave the study at any time. 
 
More information is given in this form about the study, its risks and benefits. You should feel that you understand 
the study before deciding whether you will participate. If you decide to participate, you will be asked to sign or 
make your mark on this form. You will be offered a copy to keep. 
 
About the study 
 
This study is being done by the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
(IMPAACT) and [insert site name]. The person in charge of the study at [insert site name] is [insert name of 
IoR].  
 
The study is being done to test two anti-HIV medicines (antiretrovirals or ARVs) in adolescents 12 to less than 18 
years old who have HIV. The study ARVs are called cabotegravir (CAB) and rilpivirine (RPV). HIV is the virus 
that can lead to AIDS.  
 
The study will include up to 155 adolescents from the United States, Botswana, South Africa, Thailand and 
Uganda. There will be two groups of adolescents, called Cohort 1 and Cohort 2. This form is about Cohort 2. 
Participants in Cohort 2 will be in the study for 2 to 3 years. In Cohort 2, participants will get study product for 92 
or 96 weeks (about 2 years). After this time, participants will leave the study and may continue getting the study 
medicines outside of the study. If you stop getting the study shots early, you will enter long-term safety follow-up 
and continue having study visits for an additional 48 weeks (about 1 year). 
 
The United States National Institutes of Health and the companies that make CAB and RPV, ViiV Healthcare and 
Janssen Pharmaceuticals, are paying for this study.  
 
1. The study is testing CAB and RPV in adolescents. 
 
People living with HIV usually take a combination of ARVs daily to stay healthy. There are not as many ARVs 
available for adolescents as for adults because many ARVs have not yet been tested in adolescents. ARVs can be 
made in different forms, such as liquids, pills, and injections (shots). The study will test CAB and RPV when 
taken as pills and when given as shots in adolescents. The pills are taken every day. The shots can be given every 
4 weeks or every 8 weeks. The shots are being developed because it can be difficult to take pills every day, and 
some people may prefer to have the shots rather than taking pills.  
 


 
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RPV pills (25 mg), RPV shots (600mg and 900mg), CAB pills (30mg), and CAB shots (400mg and 600mg) are 
now approved by the U.S. Food and Drug Administration (FDA) for adults and adolescents living with HIV. The 
approvals are based on this study and studies in adults which showed that CAB and RPV were safe and well 
tolerated. The adult studies also showed that the shots worked well to control HIV.  The study drugs are approved 
by the European Medicines Agency (EMA) for adults. Only the RPV pills (25mg taken once daily) are approved 
by the EMA for adolescents. 
 
This will be the first study of RPV shots, CAB pills and CAB shots in adolescents. The testing in adults has 
shown that the study pills and study shots work as well as other ARVs that are approved. So far, the testing in this 
study has shown that the study pills and study shots also work well for adolescents. However, because these 
ARVs are still being tested, there may be some effects that we do not know about yet. More information is needed 
from this study so that the study drugs can be approved for adolescents in more countries.  
 
This study will test the effects of these ARVs in adolescents. The study will look at whether these ARVs:  
• 
Are being given at the correct dose for adolescents  
• 
Are safe and well-tolerated in adolescents 
• 
Can control HIV in adolescents as well as other ARVs 
 
The study will also look at how willing adolescents are to take these ARVs.  
 
Cohort 1 of this study was done first to test CAB and RPV pills when taken for about 1 month followed by 2 or 3 
CAB and RPV shots when taken 1 month apart. Cohort 2 is now being done to test CAB and RPV  when taken 
together. There are two groups within Cohort 2: 
• 
Adolescents in the Cohort 2A group will take CAB and RPV pills together for about 1 month, followed 
by getting the CAB and RPV shots together.  
• 
Adolescents in the Cohort 2B group will only get the CAB and RPV shots. This group will not take the 
CAB and RPV pills. 
 
Both CAB and RPV shots will be given together about every 8 weeks for up to two years. Each time the shots are 
given, the RPV shot will be 900mg and the CAB shot will be 600mg. Cohort 2 will look at whether these study 
ARVs are safe and can control HIV when adolescents stop taking their previous ARVs.  
 
We will discuss both Cohort 2A and Cohort 2B groups with you to make the decision of which group you will 
enter. If you decide to participate in the study, your signature or mark on this form will also document the 
decision of which Cohort 2 group. You can ask any questions about the groups at any time. You will not be able 
to switch to the other group after they have entered the study.  
 
More information about the study, the Cohort 2B group, and CAB and RPV is given in the rest of this form. 
 
2. Only adolescents who are eligible can participate in the study. 
 
If you decide to join the study, we will first do some tests to find out if you are eligible. More information about 
the tests is given in #5 (see below). If you are eligible, you will be entered in the study. If you are not eligible, you 
cannot be entered in the study.  
 
3. It is your decision whether or not you join the study. 
 
Deciding to join the study is voluntary (your choice). You may choose to join or not join. If you choose to join, 
you can change your mind and leave the study. Your choices will have no effect on the medical care you would 
normally receive. Your access to services, and the benefits and rights you normally have, will not be affected.  
 


 
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Take your time and consider your decision carefully. If you wish, you can talk to other people about the study. 
You can bring other people here to learn about the study with you. 
 
No matter what you decide about the study, it is important for you to keeping taking ARVs. This is the best known 
way for you to stay healthy. 
 
4. There are three phases in Cohort 2: the study pills, the study shots, and the long-term safety follow-up.  
 
For participants in Cohort 2, there are three phases of the study: 
• 
The CAB and RPV pills 
• 
The CAB and RPV shots 
• 
The long-term safety follow-up phase with no study medicines 
 
Not all participants will be in all three phases of the study. Participants in the Cohort 2A group will first take part 
in the CAB and RPV pills and then take part in the CAB and RPV shots phases of the study. In Cohort 2B, 
participants will also stop taking their usual ARVs but will skip the CAB and RPV pills phase and go straight to 
the CAB and RPV shots phase of the study.  
 
Any participant who takes part in the CAB and RPV shot phase but must stop the study shots early will take part 
in the long-term safety follow-up phase. 
 
In Cohort 2A, participants will stop taking their usual ARVs and take CAB and RPV pills. The study pills phase 
lasts for about 4-6 weeks. These participants will be checked to see if they are eligible to get the CAB and RPV 
shots. If eligible then, they will stop taking the CAB and the RPV pills and start getting CAB and RPV shots. 
 
Both Cohort 2A and Cohort 2B participants will have the study shots. The study shots phase lasts 2-3 years.  
 
For Cohort 2B participants, you will not have the study pills phase but go straight to the study shots phase. You 
will have 15 visits over about two years in the study shots phase. At 13 of these visits you will be given one shot 
of CAB and one shot of RPV. Each shot is about 3mL (about 1 teaspoon). The shots are given in the buttocks 
(bottom “cheeks”). The shots may be given on the same side of the buttocks or on different sides. The shots are 
long-acting, meaning the medicine stays in your body for a long time. The first two visits with the CAB and RPV 
shots are 4 weeks apart. Then the CAB and RPV shots are given every 8 weeks. At all of these study visits, we 
will check on how you are doing while getting the shots (see #9 for more information). 
 
After the CAB and RPV shots, you might have the option to continue getting the long-acting injections outside of 
the study (see #17 for more information).  
 
If you no longer want to get the injections, or have to stop the study shots early, you will stop taking the study 
drugs and take part in the long-term safety follow-up phase of the study. This phase lasts about 48 weeks. We will 
check on how you are doing and the amount of study drugs in your blood after stopping the study drugs. You will 
also go back to taking your usual (pre-study) ARVs. There will be 4 visits during long-term follow up (see #12 for 
more information). 
 
Finding out if you are eligible for Cohort 2 
 
5. We will ask questions, examine you, and discuss the study requirements with you. 
 
To find out if you are eligible for the study, we will: 
 


 
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• 
Review your medical records. 
• 
Ask questions about you, your health, and the medications you take.  
• 
Talk with you about birth control (ways to prevent pregnancy). 
• 
Talk with you about the study requirements and if you are able to meet these requirements. 
• 
Talk with you about which group is best for you to join (Cohort 2A or Cohort 2B) 
• 
Do a physical exam. This will include looking at your genitals to see your stage of development. For 
participants assigned female at birth, this will also include looking at your breasts. 
• 
Do an electrocardiogram (ECG). This is to test how well your heart is working.  
• 
Draw about 11-17mL (about 2-3 teaspoons) of blood for tests. The tests will: 
o Check your blood cells. 
o Check how well your liver and kidneys are working. 
o Confirm that you have HIV. There are certain HIV tests that are required for this study. If the required 
tests are not in the medical records, we will do the tests that are needed. 
o Check the amount of HIV in your blood. This is called your HIV viral load.  
 
These procedures will take about 4 hours [here and throughout this form, sites may modify the expected visit 
duration as needed]. 
 
6. For participants assigned female at birth, we will also test for pregnancy. 
 
Participants in this study cannot be pregnant. Participants should not join this study if they are pregnant or intend 
to become pregnant within 30 days after stopping the study ARV pills or within 48 weeks after stopping the study 
shots. Because the effects of the study ARVs on unborn babies are unknown, you should not become pregnant 
while in this study. For all participants assigned female at birth in the study, we will collect urine or blood to test 
for pregnancy.  
 
There are certain effective methods of birth control that participants who are able to become pregnant must use 
while in this study. These effective methods must be continued for 30 days after stopping the study ARV pills, or 
for at least 48 weeks after stopping the study ARV shots. Participants who are able to become pregnant, must 
agree to use these methods in order to take part in the study. We will help make sure you can get effective 
methods by providing them here in the clinic or offering a referral. At study visits when you will receive study 
medicines (either the pill or shot), we will need to confirm that you are using effective birth control before giving 
you the study medicines. 
 
Participants who become pregnant during the study will stop taking the study medicines and enter the long-term 
safety follow-up phase of the study (see #12 below). They must continue taking their usual ARVs. We will 
also contact you to find out the outcome of the pregnancy even if the outcome occurs after leaving the study. 
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure of 
pregnancy results to parents or guardians: As soon as the pregnancy test result is available, we will go over it 
with you in private, without your parents/guardians present. You must give us permission before we can share 
these results with your parents/guardians. If the test shows that you are pregnant, we will give you information on 
where medical care and other services can be received.] 
 
If you are pregnant, your doctor may report your pregnancy to the Antiretroviral Pregnancy Registry. The 
Antiretroviral Pregnancy Registry assists participants and doctors in gauging potential benefits and risks of 
treatment; however, the registry does not collect any identifying information about you, such as your name, 
initials, contact information, or date of birth.  
 
7. We will tell you if you are eligible. 


 
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We will give you the results of all procedures and explain the results to you. We will tell you about getting care, 
treatment and any other services you may need. While waiting for the results, it is important for you to keep 
taking your usual ARVs. 
 
If you are not eligible for the study for any reason, we will tell you this. You will not be entered in the study. You 
can and should continue to receive medical care and treatment outside of the study. We will tell you more about 
getting this care and treatment and any other services you may need.  
 
If you do not enter the study, we will still use some information collected about you (for example age, sex, and 
race). We will use this information to look at patterns or common reasons for not entering the study. 
 
If you are eligible for the study, you will be entered into the study.  
 
Entering the study 
 
8. If you are eligible, you will enter the study. 
 
On the day you enter the study we will:  
• 
Review your medical records.  
• 
Talk with you about your ARV use. 
• 
Talk with you about preventing pregnancy. 
• 
Talk with you about the study visit schedule and taking the study medicines correctly 
• 
Ask you questions about what you think about CAB and RPV 
• 
Do a physical exam.  
• 
Draw about 18mL (about 4 teaspoons) of blood for tests. The tests will: 
o Check your blood cells. 
o Check how well your liver and kidneys are working. 
o Check how much the virus has affected your ability to fight the virus. This is called CD4 cell count. 
o The tests will check your HIV viral load.  
o Some blood will be saved for later testing for resistance to ARVs. This test shows whether different 
ARVs may work against the HIV in your blood. 
• 
For participants assigned female at birth, we will collect urine or blood for a pregnancy test  
• 
Ask if you are willing to complete an in-depth phone interview. [US sites only.] 
 
 At this visit we will again talk with you about which group is best for you to join (Cohort 2A or Cohort 2B). You 
will not be able to switch to the other group after you have entered the study. 
 
If it is decided that you will enter Cohort 2B, then at this visit, you will stop taking your usual ARVs and get one 
shot of CAB and one shot of RPV. We will also draw about 4mL of blood (less than 1 teaspoon) to look at the 
amount of CAB or RPV in your blood. We will also do an ECG to look at your heart. 
 
This visit will take about 4 hours.  
 
Being in the study 
 
9. After entering the study in the Cohort 2B group, you will have 14 more visits (Weeks 1-92) in the study shots 
phase.  
 


 
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The first visit in Cohort 2B will be the study entry visit and is described in #8 above. After that visit, you will 
have 14 more visits in the study shots phase.  Most of these visits will take place about 8 weeks apart, and some of 
these visits will take place 1 week apart. [Sites to modify] Each visit will take about 1-3 hours. At each of these 
visits, we will: 
• 
Review your medical records. 
• 
Talk with you about preventing pregnancy.  
• 
Do a physical exam. At two of these visits (Weeks 20 and 92), this exam will include examination of your 
genitals to see the stage of development. For participants assigned female at birth, this will also include 
looking at the breasts. 
 
At 12 of these visits (Weeks 4-20 and 28-92) you will:  
• 
Get a shot of CAB and a shot of RPV. 
• 
For participants assigned female at birth, we will also collect urine or blood to check for pregnancy.  
 
At 13 of these visits (Weeks 1, 4-20, and 28-92) we will draw about 5mL of blood (about 1 teaspoon) for tests. 
These tests will check: 
• 
Your blood cells 
• 
How well your liver and kidneys are working 
 
At 9 of these visits (Weeks 4-20, 28-44, 60, 76, and 92) we will draw about 12mL of blood (about 2-3 teaspoons) 
for tests. These tests will check: 
• 
Your HIV viral load.  
• 
Some blood will be saved for later resistance testing.  
 
At 12 of these visits (Weeks 1, 4-44, 60, 76, 84, and 92), we will also draw about 4mL of blood (less than 1 
teaspoon) of blood to look at the amount of CAB and RPV in the blood. 
 
At 4 of these visits (Weeks 20, 44, 68, and 92) we will draw about 3mL of blood (about 1 teaspoon) to check your 
CD4 count.  
 
At 4 of these visits (Weeks 4, 20, 44, and 92) we will ask you questions about getting the shots of CAB and RPV.  
 
At 5 of these visits (Weeks 4, 20, 44, 68, and 92) we may also talk with you about how you are doing with the 
visit schedule.  
 
Study staff may ask you to return to the clinic for a study shot before your next visit. If so, then many of the 
procedures described above would also be done again.  
 
If you cannot come to the clinic to receive the CAB and RPV shots, then you may have the option to take the 
CAB and RPV pills until you are able to get the shots again.  If this happens, you may need more frequent CAB 
and RPV shots outside of the scheduled visit days for a few months. If you cannot return to the clinic to get the 
CAB and RPV shots soon, then you may need to stop taking the study ARVs and enter the long-term safety 
follow-up phase (see #12 below). This is not preferred, and it is important to get the shots on the scheduled visit 
day and not miss any CAB and RPV shots. 
 
[Sites to modify] On rare occasions, we may offer some of the visit activities off-site, or by phone. The study staff 
will discuss the location and best time to visit you so that the visit is at a convenient time and the visit is done at a 
place you feel comfortable and confidentiality can be maintained. 
 
Study staff will let you know when these procedures will occur ahead of time.  


 
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10. In-depth phone interviews [for U.S. sites only] 
 
We are very interested to understand what adolescents think about getting their ARV’s as shots. You may be 
asked if you would like to complete an in-depth phone interview. If you would like to take part in the interview, 
then you may be contacted to have the interview after getting the fourth shot of CAB and RPV. Not all 
participants will be contacted for the interview. You do not have to do the interview to take part in this study. 
 
If contacted, an interviewer will talk to you for about 1-2 hours and will ask how you feel about having shots of 
CAB and RPV. This information will help us understand if CAB shots and RPV shots have any bad side effects 
for adolescents. It will also help us understand how adolescents and families feel about the shots. The interview 
may take place at or in between the Week 20 through 92 visits or during the long-term follow-up safety phase. 
The interview will only take place once. The interview will be audio recorded and written down in a report. Your 
name will not be included in the report.  
 
We may also ask your parent or caregiver to complete an in-depth interview. This interview would ask them how 
they felt about you having shots of CAB and RPV. 
 
11. Adolescents may have an extra visit if their HIV is not controlled. 
 
Participants will have viral load tests at almost all visits to check the amount of HIV in the blood. If tests show 
that the viral load is higher than expected (200 copies/mL or more) you will have repeat testing. This may occur 
as part of another study visit or may occur as an extra study visit.  
 
The extra visit will take about 1-2 hours. At this visit we will: 
• 
Review your medical records. 
• 
Do a physical exam.  
• 
Draw about 16mL (about 3 teaspoons) of blood for tests. The tests will: 
o Check your HIV viral load.  
o Check the amount of CAB and RPV in the blood.  
o We will save some blood for later resistance testing. 
• 
Talk with you about preventing pregnancy. 
• 
For participants assigned female at birth, we will also collect urine or blood to check for pregnancy.  
 
If the repeat test also shows an increased amount of HIV in your blood, you will stop taking the study product and 
start taking your previous ARVs again. If you were getting shots of CAB and RPV, you will enter long-term 
safety follow-up (more information in #12 below).   
 
12. If you stop the shots of CAB and RPV early or after the Week 92 study visit, you will enter long-term safety 
follow-up phase. 
 
You will enter the long-term safety follow-up phase after the last shot of study product if you: 
• 
Stop the shots of CAB and RPV early, or  
• 
Do not wish to continue to get the shots of CAB and RPV after the final Cohort 2 visit (Week 92)  
 
If you become pregnant, you will enter this phase of the study after your positive confirmatory pregnancy test 
result, whether you are taking the pill or the shot.  
 
During the long-term safety follow-up phase, you will stop getting shots of CAB and RPV. You will start taking 
your previous ARVs again. There will be 4 visits during the long-term safety follow-up phase.  


 
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These visits will be scheduled 8, 24, 36 and 48 weeks after your last shot of CAB and RPV (or after a positive 
confirmatory pregnancy test result). [Sites to modify] Each of these visits will take about 1-3 hours. At these 
visits, we will:  
• 
Review your medical records.  
• 
Talk with you about preventing pregnancy.  
• 
Do a physical exam. At the final long-term safety follow-up visit, this will include examination of your 
genitals to see the stage of development. For participants assigned female at birth, this will also include 
looking at your breasts. 
• 
Draw blood for tests. This would be about 21mL of blood (about 4 teaspoons) for these tests. These tests will 
check:  
o Your blood cells.  
o How well your liver and kidneys are working. 
o Your HIV viral load.  
o The amount of CAB and RPV in the blood.  
o Some blood will also be saved for future resistance testing. 
• 
For participants assigned female at birth, we will also collect urine or blood to check for pregnancy.  
• 
At two of these visits (8 weeks and 48 weeks after your last shot of CAB and RPV) we will talk with you 
about your ARV use.  
• 
At two of these visits (8 weeks and 48 weeks after your last shot of CAB and RPV), we will also ask you 
questions about getting shots of CAB and RPV.  
 
13. If you leave the study early, you will complete a final study visit.  
 
If you need to leave the study early, then you will complete a final study visit about 4 weeks after your last CAB 
and RPV shots.  
 
During this visit, we will:  
• 
Review your medical records.  
• 
Do a physical exam. This will include looking at your genitals to see the stage of development. For 
participants assigned female at birth, this will also include looking at the breasts. 
• 
Draw blood for tests. This would be about 15-20mL of blood (about 3-4 teaspoons) for these tests. These tests 
will check:  
o Your blood cells.  
o How well your liver and kidneys are working. 
o Your HIV viral load.  
o Some blood will also be saved for later resistance testing. 
• 
Talk with you about preventing pregnancy.  
• 
For participants assigned female at birth, we will also collect urine or blood to check for pregnancy.  
• 
Ask you questions about what it is like to take the oral CAB and oral RPV.  
• 
We will talk with you about your ARV use.  
 
14. Different tests will be done at different laboratories. 
 
We will do most of the tests of blood or urine here at our laboratory. We will give you the results of most of these 
tests at the next scheduled visit, or sooner, if necessary. We will explain the results and give you counseling and 
referrals as needed.  
 


 
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We will also draw blood to check the amount of CAB and RPV in your blood. This is called a pharmacokinetic 
(PK) test. The PK test will be done at a laboratory in the United States. We will not usually give you the results of 
this test during the study.  
 
If you need a test for resistance (see #11 above), that test will be done at a laboratory in the United States.  You 
will be given the results of this resistance test and referrals if needed.  
 
15. We may take you off of the study. 
 
We may take you off the study ARVs if: 
• 
You are not able to come to the study visits or we determine that you cannot meet the study requirements. 
• 
You are not able to take the study ARVs. 
• 
The study ARVs are not controlling the HIV in your blood. 
• 
Continuing the study ARVs may be harmful to you. 
• 
You request to stop the study ARVs. 
• 
You are not able to follow the birth control requirements of this study. 
• 
You become pregnant 
 
If you stop the ARV shots early, we will ask you to come back to the clinic for four additional study visits for 
long-term follow-up (see #12 above). You will not have any other visits after these four visits. 
 
We may also take you off the study early if the study is stopped for any reason.  
 
The study cannot provide other types of ARVs, but we will give you information, counseling, and referrals to 
where you can get care and treatment needed. We will help make sure you can get ARVs from outside of the 
study. If the study stops early, every effort will be made to make certain that there is no interruption in your 
therapy. 
 
16. Please tell us if you want to leave the study. 
 
You are free to leave the study at any time for any reason. The care that you receive at this clinic will not be 
affected, but it is important for us to know about your decision.  
 
If you stop the study early, we may ask you to return to the study clinic for one final study visit, like the last study 
visit described in #13 above. 
 
We will answer any questions you may have and give you information on how to contact us in the future, if you 
wish. 
 
After the study 
 
17. Receiving the study ARVs after the study is over.  
 
As you come to the end of the study, we will work with you to plan for your care and treatment outside the study. 
It is important that we plan for this in advance, so that there is no gap in your taking ARVs as you finish the 
study. Taking ARVs without interruption is the best-known way for you to stay healthy.  
 
We will tell you where you can go to receive needed care and treatment after you finish the study. If you are 
gaining benefit from the study ARV shots given in the study, the companies that are providing these ARVs (ViiV 
Healthcare and Janssen Pharmaceuticals) will try to provide these ARV shots to you. They will be provided until 


 
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they are otherwise available locally, until you are no longer gaining benefit, or if the company decides to stop 
studying the ARVs. However, there is no guarantee this will be possible. If this is not possible, you will need to 
switch to other oral ARVs that are available locally. We will explain the options to you and help ensure your 
access to ARVs outside the study. We will also contact you again within the first four or eight weeks after you 
finish the study to confirm that you are getting ARVs. 
 
Risks of the study 
 
Taking part in this study may involve some risks and discomfort. The risks are different for each phase of the 
study. Cohort 2B risks include: risks from blood draws, risks from receiving the injection, risks from the study 
shots (long-acting CAB and RPV), and risks to your privacy. Some participants may need to take the study pills 
even during Cohort 2B (see #9 above). When this happens there is also risks from the study pills (CAB and RPV). 
 
Risks during the long-term safety follow-up phase include: risks from blood draws, risks of switching ARVs, and 
risks to your privacy. 
 
18. Risk from blood draws  
 
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted. Rarely, drawing blood 
can cause fainting or infection. 
 
19. Risk from receiving the injection  
 
People in other studies who have received the CAB and RPV shots said they had pain, skin irritation, skin 
redness, bumps, swelling, itching, bruising at the spot where they got the shot. Most reactions go away in a week 
or less but sometimes they can last longer. Most people usually do well with them and rarely need to stop the 
drug.  
 
The shots will be given in the muscles of your buttocks. The injection could be given too deeply or not deeply 
enough, missing the muscle and entering your skin, blood, or a nerve.  
 
The risks of this are not well understood but could make CAB or RPV levels too low or too high. If too low the 
drug may not work against your HIV. If RPV is too high, there could be a change in your heartbeat, which in 
severe cases can be life-threatening. In rare cases, symptoms such as feeling lightheaded, numbness or tingling, 
difficulty breathing, chest or stomach discomfort, sweating, rash, pain (e.g., back and chest), nausea and/or feeling 
anxious have occurred after an injection with RPV LA. In these cases, high blood levels of RPV have been 
observed, which may be due to an accidental injection of part of the medication into a blood vessel instead of the 
muscle. Not all participants in whom an accidental injection in a blood vessel was suspected reported such 
symptoms. Most of the symptoms resolved within minutes. Your doctor may need to administer treatment to help 
resolve these symptoms. Everything possible will be done to decrease this risk, including watching you for 
problems during the study. If your doctor thinks that the injection was not given the right way, you might be 
asked to stay in the clinic up to 3 hours after the injection to watch how you are doing and extra tests may be 
needed to be sure you are safe. We will also draw blood (less than 1 teaspoon) about 2 hours after the study shot 
to look at the amount of study drugs in your blood. If you are worried about this risk, talk to your doctor. 
 
Receiving injections can cause some people to feel lightheaded or feel like they might pass out. Fainting can also 
occur. This reaction, called a ‘vasovagal reaction’, has been reported with other injectable medicines, and resolves 
quickly. 
 
20. There are risks from the study ARVs 
 


 
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All ARVs can cause side effects. This includes the ARVs you are currently taking and the ARVs that are given in 
the study. Some side effects are minor; others can be severe. Some side effects are common; others are rare. Some 
people who take ARVs have some of the side effects. Other people have different side effects, or no side effects.  
 
The most common and most serious side effects of the study ARVs, CAB and RPV, are listed below. This is 
based on what we know now about CAB and RPV used in adults. There may be other side effects that we do not 
know about now. This may be especially true for adolescents, because this is the first study of CAB and RPV in 
adolescents.  
 
This form does not list all possible side effects of all ARVs. If you join the study, we will tell you more about the 
ARVs you will be taking. At each study visit, we will check on whether the ARVs may be causing side effects. 
We will also tell you what to do if you have side effects. If you have questions or concerns at any time, please tell 
us.  
 
21. Some side effects from the CAB pills and the CAB shot 
 
Many people have received CAB pills or the CAB shot in other studies. The table below lists side effects from 
other studies of CAB with people who have HIV. It is not known if CAB, other drugs or the participant’s other 
health problems caused or affected these. Some of these are the same side effects as RPV (see #22 below).  
 


 
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Common and Uncommon Side Effects of CAB 
Very Common Side Effects of 
CAB 
Common Side Effects of CAB 
Uncommon Side Effects of 
CAB 
• Headache 
• Pyrexia (fever), feeling hot, 
body temperature increase  
• Injection Site Reactions (pain 
and discomfort, a hardened 
mass or lump) 
 
• Rash 
• Vomiting (being sick) 
• Nausea (feeling sick to the stomach) 
• Abdominal pain, upper abdominal 
pain (stomach pain and discomfort)  
• Insomnia (problems sleeping)  
• Abnormal dreams/nightmares 
• Anxiety (feeling anxious) 
• Feeling lightheaded (dizziness) 
• Depression (feelings of deep sadness 
and unworthiness) 
• Flatulence (passing gas or wind) 
• Diarrhea or loose stools 
• Myalgia (muscle pain) 
• Fatigue (lack of energy) 
• Asthenia (feeling weak) 
• Malaise (feeling generally unwell) 
• Weight increase 
• Injection Site Reactions (swelling, 
redness, itching, bruising, warmth or 
discoloration) 
• Somnolence (sleepiness or 
Drowsiness) 
• Vasovagal reactions (light-
headedness or fainting, during 
or following an injection) 
• Hepatotoxicity (liver problems) 
• Transaminase increase (blood 
test may show increase in the 
level of liver enzymes) 
• Injection Site Reactions 
(cellulitis [heat, swelling or 
redness], abscess [collection of 
pus], numbness, minor 
bleeding, discoloration) 
 
The following effects have also been seen in some of the people who received CAB pills or the CAB shot in other 
studies: 
 
Abnormal liver tests: 
 
A small number of people across all studies (just over 1% of 1644 participants as of April 2017) had abnormal 
liver tests requiring them to stop CAB. Some abnormal liver tests were explained by other health conditions such 
as a new virus infection, like Hepatitis A, B or C.  A small number of people did not have health conditions that 
could explain the abnormal test, so it is possible that a mild form of liver damage happened from taking CAB. 
The liver tests got better after stopping CAB, showing that any damage was temporary. 
 
Blood tests to check the health of your liver will be done during the study. Your study doctor will tell you if you 
need to stop taking the study drugs or if other actions are needed. If you stops taking the study drug, you may be 
able to re-start the study drug or you may need to change your usual ARVs.  
 
Seizures/convulsions: 


 
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Seizures have been seen (rarely) in people with and without HIV who have taken CAB. They are not thought to 
be caused by CAB, but the study staff will ask you about them.  
 
In other studies, two people without HIV had a history of seizures (epilepsy), and had a seizure about 3 months 
and 9 months after starting CAB. One other person with HIV but without a history of seizures, had seizures about 
one year after starting CAB. This participant had a long period of seizures without medical treatment and died. It 
is not known if CAB was part of the reason for seizures in these people. If you have a history of seizures, please 
let your study doctor know. 
 
22. Some side effects from the RPV pills and the RPV shot 
 
Oral RPV (Edurant) is a marketed drug which many people throughout the world have received to manage HIV. 
We know more about the side effects of Edurant than we do about CAB or RPV shots. The following side effects 
have been seen in studies in people with HIV taking RPV.  
 
Common and Uncommon Side Effects of RPV 
Common Side Effects of RPV 
Uncommon Side Effects of RPV 
• 
Dry mouth 
• 
Feeling less hungry (decreased appetite) 
• 
Sleep disorders 
• 
Immune reconstitution syndrome (this can be 
an overreaction of the body’s recovering 
defense system to a previously present 
infection, or problems in the immune system) 
• 
Depressed mood 
• 
Abdominal discomfort (belly ache) 
 
The following effects have also been seen in some people who received RPV in other studies: 
 
Abnormal blood tests: 
 
Other changes in blood tests have also been observed. People with Hepatitis B or C or who have possible liver 
damage before starting RPV may have worse liver tests while taking RPV. A few cases of liver problems were 
found in people taking RPV who did not already have any liver problems. 
 
Sometimes allergic reactions can affect body organs, like the liver and cause liver problems which can lead to 
liver failure. Contact your study doctor right away if you have any of the following signs or symptoms of liver 
problems: 
• 
Yellowing of the skin or whites of the eyes 
• 
Dark or tea colored urine 
• 
Pale colored stools/bowel movements 
• 
Nausea/vomiting 
• 
Loss of appetite 
• 
Pain, aching or tenderness on the right side below the ribs 
• 
Itchy skin  
 
Blood tests to check the health of your liver will be done regularly during the study. Your study doctor will tell 
you if you need to stop taking the study drugs or if other action is needed. If you stop taking the study drug, you 
may be able to re-start the study drug or you may need to change your usual ARVs.  
 


 
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Skin Rash: 
 
Most rashes were mild or moderate, and happened within the first 4 weeks of taking RPV. Most of rashes got 
better after one week, and the people did not need to stop taking RPV. However, the study ARVs will need to be 
stopped for some types of moderate rash and all types of severe rash, which can be life-threatening. If this 
happens to you, you will need to come for extra study visits to monitor your health. Some people with rash may 
also have other signs and symptoms of allergic reaction. 
 
If you have any type of rash or other skin problems during the study you must tell your study doctor right away, 
and the doctor may tell you to stop taking CAB and/or RPV. 
 
23. There may be other possible risks from the study ARVs. 
 
The study ARV shots stay in your body for a long time 
 
The shots you get in this study are long acting, meaning they stay in your body for a long time. In most people the 
drugs will no longer be in the body one year after an injection, while in some people low levels of CAB and RPV 
may still be in the body after one year. If you develop a side effect to the study drug after the shot, there will be no 
way to remove the drug from your body. If you get a shot of CAB or RPV, we will monitor your health for 48 
weeks after your last shot. If you develop a symptom from these drugs while the drugs are still in your body, 
every effort will be made to treat the side effects. The amount of drug will decrease overtime and will eventually 
disappear. 
 
While the amount of study drugs in your body decrease slowly over time after you stop getting shots, the study 
drugs could stop working against your HIV. When stopping long acting HIV drugs, it will be very important to 
start taking other HIV medications, as your study doctor tells you, so your HIV medications do not stop working 
against your HIV. 
 
Risk of switching ARVs 
 
If you join this study, you will stop taking the ARVs you are currently taking, and start taking ARVs given by the 
study. The study ARVs could cause side effects that you would not have from the ARVs you are currently taking. 
The study ARVs also may not work as well as the ARVs you are currently taking. For example, the study ARVs 
may not work as well to control the amount of HIV in your body. We will test your HIV viral load at most study 
visits to check on this. If your viral load is higher than expected, you will have repeat testing, and your use of the 
study ARVs may be stopped (see #11 above).  
 
Risk of resistance 
 
By stopping your previous ARVs and switching to the study ARVs, you could develop resistance. This could 
happen if the study ARVs don’t work as well to control the amount of HIV in your body. Resistance means that 
the ARVs may not work against HIV if these ARVs are taken again in the future. To stop resistance, it is 
important that you take and/or receive the ARVs as instructed, and do not miss any doses. 
 
Mental illness or depression 
 
Some people with HIV sometimes have feelings of depression or may feel sad or hopeless, feel anxious or 
restless, or may have thoughts of hurting or killing themselves (suicide). A small number of people being treated 
with drugs called integrase inhibitors [INIs] for HIV like CAB, have had suicidal thoughts and actions, 
particularly participants with a prior history of depression or mental health illness.  
 


 
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Tell the study doctor if you have a history of mental health illness. If you have thoughts of hurting or killing 
yourself or have any other unusual or uncomfortable thoughts or feelings during this study, you should tell the 
study doctor or go to the nearest hospital right away.  
 
Possible effects on pregnancy or unborn babies 
 
HIV and ARVs may lead to some pregnancy complications, like early delivery or low weight of the baby at birth. 
We do not know if some ARVs are more likely to cause these effects than others. We do not yet know if CAB is 
safe in pregnancy. RPV does not appear to be a risk to pregnancy and the developing baby based on the 
information we know now, but additional data are still being collected. 
 
There are few data from humans on the effects of CAB in pregnancy. Most of the information we have comes 
from animal studies. In studies done in pregnant rats and their newborns, using very high amounts of CAB, there 
were more baby rats that died when they were born or right after they were born. This did not happen to the baby 
rats when the mother got lower amounts of the drug, or no drug. The amount of CAB that we are giving in this 
study is expected to be more than 7-times lower than the amount given to the pregnant rats. Birth defects have not 
been found in any animal studies of CAB so far. We do not know whether what happened to the baby rats has any 
impact on what will happen in pregnant humans taking this drug. 
 
Early results from one large study in Botswana showed that the ARV called dolutegravir (DTG) may increase the 
risk of serious birth defects of the brain or spine in the new baby. The increased risk was seen among babies 
whose mothers were taking DTG when they became pregnant. These birth defects happen during the first few 
weeks of pregnancy, before mothers may know they are pregnant. These birth defects have not been seen among 
babies whose mothers started taking DTG later in pregnancy.  
 
CAB is not the same drug as DTG. We do know that CAB and DTG belong to the same class of medications and 
work in a similar way to treat HIV infection. We do not know if CAB can cause brain or spine defects in babies.  
 
Participants who are able to become pregnant must agree to use certain effective methods of birth control to be in 
this study (see #6 above). If you become pregnant during the study, please let us know right away. 
 
Immune reconstitution syndrome 
 
In some people with advanced HIV infection, signs and symptoms from other infections or certain diseases (for 
example a liver condition called autoimmune hepatitis) may occur soon after starting combination ARVs but can 
also occur later. Some of these symptoms may be life threatening. If you start having new symptoms, or if you 
notice that any existing symptoms are getting worse after starting the ARVs, tell your doctor immediately. 
 
Abnormal placement of body fat and wasting 
 
The use of potent antiretroviral drug combinations may be associated with an abnormal placement of body fat and 
wasting. Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 
• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement 
 
24. There could be risks of disclosure of your information. 
 


 
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We will make every effort to keep your information private and confidential. Study records and specimens will be 
kept in secure, locked locations. All specimens and most records will be labeled only with a code number. 
However, your name will be written on some records.  
 
Despite our best efforts to keep your information private, it is possible that the information could be obtained by 
someone who should not have it. If this were to happen, you could be treated badly or unfairly. You could feel 
stress or embarrassment.  
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality that protects us from being 
forced to release information that may identify you, such as by the courts or police. The certificate cannot be used 
in all situations, but it can be used to resist demands for information that would identify you. The certificate does 
not protect against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your participation in the study to 
others, if you wish. 
 
Information collected for this study may be used for other research in the future. For example, researchers may 
use information from this study to try to answer different questions about children or adolescents with HIV. Any 
future research done with the information from this study must be approved by the IMPAACT Network. If any 
future research is done, information about you may be used but your name will not be shared. 
 
Benefits of the study 
 
25. There may be a direct benefit to you from being in the study. 
 
By joining the study, you will be part of the search for ARVs that may be better for adolescents. We do not know 
if being in the study will benefit you in any way. There may be a direct benefit to you by taking part in this study, 
but no guarantee can be made. For example, if you get shots of CAB and RPV, you might prefer having monthly 
shots instead of taking daily pills. The study ARVs may have fewer side effects than the previous ARVs you were 
taking. There may also be benefit if the results from this study lead to a safe and effective dose of the study drugs 
for adolescents. It is also possible that you may receive no direct benefit from this study. Information learned 
from this study may help other adolescents who have HIV. 
 
You will have regular visits here and frequent checks on your health, including tests for amount of HIV in your 
blood, called viral load. It is possible that the study ARVs will slow your HIV infection. Information learned from 
this study may help other adolescents with HIV. 
 
Other information about the study 
 
26. There are no costs from being in the study. 
 
There are no costs to you for study visits, CAB, RPV or procedures.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits. For each visit, you will be given (specify amount).] 
 
27. Study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include:  
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 


 
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• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your name or identify you personally.  
 
A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify you. At most, the website will include a summary of the results. You can 
search this website at any time. 
 
Your study information may be given to other authorities if required by law. [Sites add more specific detail here 
as needed; example follows:] For example, we are required to report any significant risk of harm to you or others.  
 
28. If you get sick or injured, contact us immediately. 
 
Your health is important to us. We will make every effort to protect your well-being and minimize risks. It is 
possible, however, that you could have an illness or injury that is study-related. This means that the illness or 
injury occurred as a direct result of the study procedures.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage available 
through clinical trial insurance obtained by the site should be included if applicable; the statement regarding no 
program for compensation through the NIH may not be removed.]  If a study-related illness or injury occurs, we 
will treat you or tell you where you can get treatment. The cost for this treatment may be charged to you or your 
insurance company. There is no program for compensation either through [site name or] the U.S. National 
Institutes of Health.  
 
Whom to contact 
 
29. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about your rights as research participants or concerns about how you are being treated 
in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 
 
• 
If you have any health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you want to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 


 
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Signatures 
 
If you agree to participate in Cohort 2B of this study, please sign or make your mark below. 
Before deciding whether to participate in this study, make sure you have read this form, or had it read to you, and 
that all of your questions have been answered. You should feel that you understand the study, its risks and 
benefits, and what is expected of you if you decide to join.  
 
If you decide to join, we will tell you any new information from this study or other studies that may affect your 
health, welfare, or willingness to stay in the study. You are welcome to ask questions or request more information 
at any time. If you want the results from this study, please tell the study staff. 
 
You do not give up any rights by signing this form. 
 [Insert signature blocks as required by site IRB/EC policies.] 
 
Signature blocks for participants of legal age to provide independent informed consent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 
Signature blocks for parent/legal guardian of adolescent: 
 
 
 
_______________________________  
___________________________________ 
Name of Parent/Legal Guardian (print)  
Signature of Parent/Legal Guardian and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 
 


 
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Appendix II-D:  Sample Informed Consent Form for Specimen Storage and Future Use 
 
for adolescents who can provide independent informed consent for study participation and parents/legal guardians 
of adolescents 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 4.0, dated 27 May 2022 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
If you are the parent or legal guardian of a child who may take part in this study, your permission and the 
permission of your child will be needed.  When “you” appears in this form, it refers to your child except where it 
says otherwise. 
 
You have decided to join the study named above. As part of the study, you will have blood and urine collected. 
After these samples are tested for the study, some samples may be left over. We call these extra samples. The 
IMPAACT Network would like to keep these extra samples and use them for other research in the future. 
 
This form gives information about use of extra samples. Please read it, or have it read to you, and ask any 
questions you may have. After we discuss the information with you, you will record your decisions on use of 
extra samples at the end of the form.  
 
1. It is your decision whether or not to allow the extra samples to be used.  
 
You are free to say yes or no, and to change your mind at any time. Your decision will not affect your 
participation in the study. If you say no, all extra samples will be destroyed.  
 
2. If you agree, your extra samples will be kept in a repository.  
 
A repository is a secure facility that is used to store samples. The IMPAACT Network repository is in the United 
States. If you agree to have extra samples stored, the samples will be kept in this repository. There is no limit on 
how long the samples will be kept [sites may insert time limits or additional site-specific requirements here if 
required by local authorities]. 
 
3. Extra samples could be used for different types of research.  
 
Extra samples may be used for research on HIV, the immune system, and other diseases. The research may be 
done in the United States or in other locations.  
 
If you agree, the extra samples could also be used for research that looks at your genes. Genes are passed to 
children from their birth parents. They affect how people look and how their bodies work. Differences in people’s 
genes can help explain why some people get a disease while others do not. Your samples would only be used to 
look at genes related to HIV and the immune system. Testing of all your genes, which is sometimes called whole 
genome sequencing, will not be done.  
 


 
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Any research done with the extra samples must be reviewed and approved by the IMPAACT Network. The 
research must also be approved by an ethics committee. The role of an ethics committee is to review the research 
plan and protect the rights and well-being of the people whose samples will be used.  
 
The research done with extra samples is not expected to give any information relevant to your health. Therefore, 
the results will not be given to the study staff or to you. The results also will not be placed in your study records. 
 
4. There is little risk to you.  
 
When extra samples are used for research, they are labeled with a code number only. To protect your privacy, no 
names are used. However, information such as age, sex, HIV status, and other health information may be linked to 
the samples. Information on the ARVs you received in the study may also be linked to the samples. The only link 
between the code number and your name is kept here at [site name]. Your name will not be given to other 
researchers. 
 
There may be some risks from tests of your genes. If others found out the results of these tests, they could treat 
you badly or unfairly. However, this is almost impossible because the results will not be given to the study staff, 
or to you, and will not be in your study records. 
 
5. There may be no benefit to you.  
 
By allowing extra samples to be used for research, you will be part of the search for new information that may 
benefit people with HIV in the future. However, the research done with the extra samples is not expected to 
directly benefit you in any way.  
 
6. You will not be paid for use of your samples. 
 
There is no cost to you for use of your extra samples. The samples will not be sold, and you will not be paid for 
use of the samples. It is possible that research done with the samples could lead to a new discovery or a new 
product. If this happens, there is no plan to share any money with you.  
 
7. Information from research using extra samples may be reviewed by groups that oversee the research. 
 
These groups include:   
• 
The IMPAACT Network  
• 
The ethics committees that review and approve the research  
• 
Government and other agencies that pay for the research  
• 
Government and other agencies that monitor the research  
• 
Other local, US, or international regulatory entities  
 
The people who do research with the extra samples and the groups listed above are required to make efforts to 
keep information private and confidential. 
 
The results of research done with the extra samples may be presented publicly or published. However, no 
presentation or publication will use your name or identify you personally.  
 
8. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about use of your extra samples:  
[insert name and telephone number of investigator or other study staff].  


 
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• 
If you later change your mind about use of your extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you have questions about your rights as a research participant or concerns about how you are being treated 
in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization].  
 
Signatures 
 
Before deciding whether your extra samples to be used for research, make sure you have read this form, or had it 
read to you. Make sure all of your questions have been answered. You should feel that you understand your 
options and the possible risks and benefits before making your decision. 
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies and the IRB/EC determination if the level 
of risk to children in the categories specified in 45 CFR 46.404-407. Separate consent decisions must be 
documented for genetic testing]. 
 
For YOUR extra samples, write your initials or make your mark next to your choice.  
 
__________ 
I allow my extra samples to be used for research on HIV, the immune system, ARVs, and other 
diseases. I also allow my samples to be used for tests of my genes.  
 
__________ 
I allow my extra samples to be used for research on HIV, the immune system, ARVs, and other 
diseases. I do not allow my samples to be used for tests of my genes.  
 
__________ 
I do not allow my extra samples to be used for any research.  
 
 
Signature blocks for participants of legal age to provide independent informed consent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 


 
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Signature blocks for parent/legal guardian of adolescent: 
 
 
 
_______________________________  
___________________________________ 
Name of Parent/Legal Guardian (print)  
Signature of Parent/Legal Guardian and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 
 


 
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Appendix III: Sample Informed Assent Forms  
 
Appendix III-A: Sample Informed Assent Form for Participation in Cohort 1 
for adolescents who cannot provide independent informed consent for study participation 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 4.0, dated 27 May 2022 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
Introduction 
 
You are being asked to take part in a research study. To take part in this study, you must give your permission. 
Your parent/guardian must also give their permission.  
 
This form gives information about the study. Please read it, or have it read to you, and ask any questions you may 
have. We will take as much time as you need to understand the study. We will ask you questions to see if we have 
explained the study clearly. 
 
After you understand the study, if you decide to take part, you will sign or make your mark on this form. You will 
be offered a copy to keep.  
 
About the study 
 
This study is for 12 to 17-year-olds who are living with HIV. The study will test two anti-HIV medicines 
(antiretrovirals or ARVs). The ARVs are called cabotegravir (CAB) and rilpivirine (RPV).  
 
People living with HIV take a combination of ARVs to stay healthy. There are not as many ARVs available for 
children and teenagers as for adults, because many ARVs have only been tested in adults. ARVs can be made in 
different forms, such as liquids, pills, and injections (shots). The study will test CAB and RPV pills and shots. 
The pills are taken every day. The shots are given every 4 or 8 weeks. The shots are being developed because it 
can be difficult to take pills every day, and some people may prefer having shots instead of taking pills.  
 
The study drugs have approved by the US Food and Drug Administration (FDA) for adults and adolescents living 
with HIV. The FDA is the part of the government that regulates medicines in the United States. The approvals are 
based on information learned from this study and from studies which showed that CAB and RPV were safe and 
well tolerated in adults. The adult studies also showed that the CAB and RPV shots worked well to control HIV.  
So far, the testing in this study has shown that the study drugs also work well for adolescents. However, because 
these are still being tested, there may be some effects that we do not know about yet. More information is needed 
from this study so that the study drugs can be approved for adolescents in more countries.   
 
There will be three groups in the study, called Cohort 1, Cohort 2A and Cohort 2B. This form is about Cohort 1.  
 
What happens in the study 
 


 
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If you decide to take part in the study, we will check your medical records and examine you to see if you qualify. 
This will include looking at your genitals to see how developed you are. We will ask you and your 
parent/guardian questions about your health and the medications you take. We will collect blood for tests. We will 
also do a test of your heart called an ECG. 
 
For participants assigned female at birth, we will do a pregnancy test. If you are pregnant, you cannot take part in 
the study. Participants who are able to become pregnant must agree to use certain methods of birth control in 
order to take part in the study. If you become pregnant during the study, you will stop getting CAB or RPV pills 
or shots and will enter the long-term follow-up safety phase of the study. We will also contact you to find out the 
outcome of the pregnancy, even if the outcome occurs after leaving the study. 
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure of 
pregnancy results to parents or guardians: As soon as the pregnancy test result is available, we will go over it 
with you in private, without your parents/guardians present. We will not share these results with your 
parents/guardians unless you tell us it is okay to share the results. If the test shows that you are pregnant, we will 
give you information on where medical care and other services can be received.] 
 
We give you your test results and explain them to you. If you qualify, you can join the study. If you do not join 
the study, we will still use some information collected about you (for example age, sex, and race). We will use 
this information to look at patterns or common reasons for not entering the study. 
 
First phase of the study 
 
The study has three phases. If you join, you will start in the first phase. You will be given CAB or RPV pills to 
take in addition to the other ARVs you are already taking. The RPV pills should be taken with a meal. It is 
important to keep taking all your ARVs as instructed.  
 
You will have 3 study visits over 4-6 weeks (about one month). At these visits, we will: 
 
• 
Collect information from your medical records. 
• 
Ask questions about your health, ARVs, and other medications. 
• 
Give you a physical exam. 
• 
Collect blood for tests. This will be done using a needle in your arm. 
• 
For participants assigned female at birth, collect blood or urine for a pregnancy test.  
 
Each visit will take about 1-3 hours.  
 
At the second visit, we will look very closely at the amount of CAB or RPV in your blood. To do this, we will 
collect your blood different times over 8 hours (one full day). If you are taking CAB, we will collect your blood 6 
times. If you are taking RPV, we will collect your blood 3 times. [Sites: modify language as appropriate to 
indicate procedures for the intensive PK collection: A small tube will be placed in your arm and attached to a 
plastic needle to draw your blood, so we do not need to stick you with a needle each time. The plastic tube may 
stay in place for 8 hours. You may need to stay at the clinic or hospital for up to 8 hours. If the study clinic is able, 
you may be able to stay at the clinic the night before and during this visit.] 
 
Second phase of the study 
 
At the fourth study visit, we will review all your test results to see if you qualify for the second phase of the study. 
This visit could be combined with your third visit. 
 


 
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• 
If you do not qualify, you will stop taking CAB or RPV pills. You will have one more visit about 4 weeks 
later. This visit will be like the other visits described above. 
• 
If you qualify, you can enter the second phase of the study 
 
In the second phase of the study you will have 5 more study visits over 12 weeks (about 3 months). At these 
visits, we will:  
• 
Collect information from your medical records. 
• 
Ask questions about your health, ARVs, and other medications. 
• 
Give you a physical exam. At the last visit, we will also look at your genitals again to see how developed you 
are.  
• 
Collect blood for tests. This will be done using a needle in your arm.  
• 
For participants assigned female at birth, collect blood or urine for a pregnancy test.  
• 
At two of these visits, we may do an ECG test to look at your heart. 
 
Each visit will take about 1-3 hours. 
 
During the second phase of the study, you will not take CAB or RPV pills. Instead, you will be given shots of 
CAB or RPV. The shots will be given 2 times (4 weeks apart). You will get one shot in the buttocks (bottom, 
“cheeks”) each time. You will keep taking your other ARVs while getting the shots.  
 
[U.S. sites only] You may also be contacted to answer questions over the phone about how you feel about the 
shots.  
 
After 12 weeks, we will review your tests to see if you are eligible for Cohort 2.  
• 
If you do not qualify, or if Cohort 2 isn’t ready yet, you will stop getting shots of CAB or RPV. You will 
enter into the third phase, which is also called the long-term safety follow-up phase of the study. This is 
described below. 
• 
If you qualify, and when Cohort 2 is ready, you can enter Cohort 2. 
 
[Sites to modify] Some visit activities may be offered off-site or by phone. This might only happen if you are 
unable to come the clinic. The study staff will discuss this with you if it is an option.  They will also discuss the 
location and time to visit you so that the visit is at a time and place when you feel comfortable and confidentiality 
can be maintained. 
 
Long-term safety follow-up phase of the study 
 
You will have 3 or 4 study visits over 48 weeks (about 1 year). The visits will be like the visits described above.  
 
You will not be given CAB or RPV pills or shots. You will keep taking your other ARVs.  
 
Risks of the study 
 
Having blood collected may cause pain, bleeding, bruising, swelling, or infection where the needle goes in your 
arm.  
 
Having shots of CAB or RPV may cause pain, irritation, redness, bumps, swelling, itching, or bruising on the 
buttocks (where the shot is given). When CAB and RPV are given as shots, they stay in the body for much longer 
than when CAB and RPV are taken as pills.  
 


 
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The shots will be given in the muscles of your buttocks. The shot could be given too deeply or not deeply enough, 
missing the muscle and entering your skin, blood, or a nerve. The side effects of shot missing the muscle are not 
well understood but could make CAB or RPV levels too low or too high. If too low the drug may not work against 
your HIV. If RPV is too high, there could be a change in your heartbeat, which in severe cases can be life-
threatening. In rare cases, symptoms such as feeling lightheaded, numbness or tingling, difficulty breathing, chest 
or stomach discomfort, sweating, rash, pain (e.g., back and chest), nausea and/or feeling anxious have occurred 
after RPV shot. Not all participants reported such symptoms. Most of the symptoms resolved within minutes. 
Your doctor may need to administer treatment to help resolve these symptoms.  Everything possible will be done 
to decrease this risk, including watching you for problems during the study. We will also draw blood (less than 1 
teaspoon) about 2 hours after the study shot to look at the amount of study drugs in your blood. 
 
CAB and RPV can cause other side effects. These side effects are common, but not everyone will have them. You 
may have pain, feel sick to your stomach, or vomit (throw up). You may have diarrhea. You may have a 
headache, fever, runny nose, sore throat, dry mouth, or rash. You may have trouble sleeping or a lack of energy. 
You may not want to eat as much as you usually do. You may feel lightheaded or sad. You may have problems in 
other parts of the body, such as your liver.  
 
We do not yet know if CAB or RPV are safe in pregnancy. Early results from one study showed that the ARV 
called dolutegravir (DTG) may increase the risk of serious birth defects in the new baby. These mothers were 
taking the drug before they knew they were pregnant. The birth defects have not been seen when mothers started 
taking DTG later in pregnancy. CAB is not the same drug as DTG. We do not know if CAB can cause the same 
defects in babies. 
 
Participants who are able to become pregnant must agree to use certain methods of birth control to be in this 
study. If you become pregnant during the study, please let us know right away. 
 
We will check for side effects at each study visit. Please tell us if you have any side effects or don’t feel well. We 
will also check the amount of HIV in your blood. If you have side effects, or if the amount of HIV in your blood 
is higher than expected, you may have extra visits. We will talk with you and your parent/guardian about this, and 
tell you what to do about any side effects. We will also tell you if you can keep taking CAB or RPV. In some 
cases, you may have to stop taking CAB or RPV.  
 
All information collected for this study will be kept private and confidential. However, it is possible that 
information could be obtained by someone who should not have it. If this were to happen, you could be treated 
badly or unfairly. You could feel stressed or embarrassed. 
 
Other information about the study 
 
Study records may be reviewed by study staff and groups that oversee the study. Groups that oversee the study 
include:  
 
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 


 
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• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your name or identify you personally.  
 
A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify you. At most, the website will include a summary of the results. You can 
search this website at any time. 
 
[Sites may modify this paragraph to reflect local reporting requirements and legal statues: Your study 
information may be shared with other authorities if required by law. Public health authorities are required by law 
to receive information for the prevention or control of disease, injury or disability. (We must follow laws 
requiring the reporting of suspected child abuse and neglect).]   
 
Benefits of the study 
 
By joining the study, you will be part of the search for new ARVs for adolescents. The information learned in this 
study could someday lead to better ARVs for adolescents. However, being in this study may not be of any benefit 
to you. 
 
Your rights  
 
Taking part in this study is voluntary. You can say yes or no. If you say yes now, you can change your mind later. 
Your decision will have no effect on the medical care you normally receive. 
 
Who to contact 
 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
If you have questions about your rights or how you are treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 
 
If you have problems related to being in the study:  
[insert name and telephone number of investigator or other study staff] 
 
If you want to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
Signatures 
 
If you want to take part in this study, sign or make your mark below. 
 
Before deciding whether to take part in this study, make sure you have read this form, or had it read to you. Make 
sure all your questions have been answered. You should feel that you understand the study, its risks and benefits, 
and what is expected of you if you decide to take part.  
 


 
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We will tell you and your parent/guardian any new information that may affect your willingness to stay in the 
study. You can ask questions or ask for more information at any time.  
 
You do not give up any rights by signing this form. 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Participant (print) 
 
Signature of Participant   
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Assent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
(as appropriate; print) 
 
 


 
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Appendix III-B:  Sample Informed Assent Form for Participation in Cohort 2 
for adolescents who cannot provide independent informed consent for study participation 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 4.0, dated 27 May 2022 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
Introduction 
 
You are being asked to take part in a research study. To take part in this study, you must give your permission. 
Your parent/guardian must also give their permission.  
 
This form gives information about the study. Please read it, or have it read to you, and ask any questions you may 
have. We will take as much time as you need to understand the study. We will ask you questions to see if we have 
explained the study clearly. 
 
After you understand the study, if you decide to take part, you will sign or make your mark on this form. You will 
be offered a copy to keep.  
 
About the study 
 
This study is for 12 to 17-year-olds who are living with HIV. The study will test two anti-HIV medicines 
(antiretrovirals or ARVs). The ARVs are called cabotegravir (CAB) and rilpivirine (RPV).  
 
People living with HIV take a combination of ARVs to stay healthy. There are not as many ARVs available for 
children and teenagers as for adults, because many ARVs have only been tested in adults. ARVs can be made in 
different forms, such as liquids, pills, and injections (shots). The study will test CAB and RPV pills and shots. 
The pills are taken every day. The shots are given every 4 or 8 weeks. The shots are being developed because it 
can be difficult to take pills every day, and some people may prefer having shots instead of taking pills.  
 
The study drugs have approved by the US Food and Drug Administration (FDA) for adults and adolescents living 
with HIV. The FDA is the part of the government that regulates medicines in the United States. The approvals are 
based on information learned from this study and from studies which showed that CAB and RPV were safe and 
well tolerated in adults. The adult studies also showed that the CAB and RPV shots worked well to control HIV.  
So far, the testing in this study has shown that the study drugs also work well for adolescents. However, because 
these are still being tested, there may be some effects that we do not know about yet. More information is needed 
from this study so that the study drugs can be approved for adolescents in more countries. 
There will be three groups in the study, called Cohort 1, Cohort 2A and Cohort 2B. This form is about Cohort 
2A and Cohort 2B.  
 
What happens in the study 
 
If you decide to take part in the study, we will check your medical records and examine you to see if you qualify. 
This will include looking at your genitals to see how developed you are. We will ask you and your 


 
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parent/guardian questions about your health and the medications you take. We will collect blood for tests. We will 
also do a test of your heart called an ECG. We will also talk with you about whether you should join Cohort 2A or 
Cohort 2B. Participants in Cohort 2A take the study pills and then get the study shots. Participants in Cohort 2B 
will only get the study shots. Once you have entered the study, you cannot switch to the other group. 
 
For participants assigned female at birth, we will do a pregnancy test. If you are pregnant, you cannot take part in 
the study. Participants who are able to become pregnant must agree to use certain methods of birth control in 
order to take part in the study. If you become pregnant during the study, you will stop getting CAB and RPV pills 
or shots and will enter the long-term follow-up safety phase of the study. We will also contact you to find out the 
outcome of the pregnancy, even if the outcome occurs after leaving the study. 
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure of 
pregnancy results to parents or guardians: As soon as the pregnancy test result is available, we will go over it 
with you in private, without your parents/guardians present. We will not share these results with your 
parents/guardians unless you tell us it is okay to share the results. If the test shows that you are pregnant, we will 
give you information on where medical care and other services can be received.] 
 
We give you your test results and explain them to you. If you qualify, you can join the study. If you do not join 
the study, we will still use some information collected about you (for example age, sex, and race). We will use 
this information to look at patterns or common reasons for not entering the study. 
 
The first phase of the study is only for the Cohort 2A group 
 
The study has three phases. If you join, you will start in the first phase. You will be given CAB and RPV pills to 
start taking. The pills should be taken with a meal. You will stop taking the other ARVs you were taking before.  
 
You will have 3 study visits over 4-6 weeks (about one month). At these visits, we will: 
 
• 
Collect information from your medical records. 
• 
Ask questions about your health, ARVs, and other medications. 
• 
Give you a physical exam. 
• 
Collect blood for tests. This will be done using a needle in your arm. 
• 
For participants assigned female at birth, collect blood or urine for a pregnancy test.  
 
Each visit will take about 1-3 hours.  
 
At the second visit, we will look at the amount of CAB and RPV in your blood. To do this, we will collect your 
blood once before you take CAB and RPV and again about 3 hours after you have taken CAB and RPV. [Sites: 
modify language as appropriate to indicate procedures for the intensive PK collection: A small tube will be 
placed in your arm and attached to a plastic needle to draw your blood, so we do not need to stick you with a 
needle each time. The plastic tube may stay in place for 3 hours.] 
 
If you join in the Cohort 2A group, then at the fourth study visit we will review all your test results to see if you 
qualify for the second phase of the study. This visit could be combined with your third visit. 
 
• 
If you do not qualify for the second phase of the study, you will stop taking CAB or RPV pills. You will have 
one more visit about 4 weeks later. This visit will be like the other visits described above. 
• 
If you qualify, you can enter the second phase of the study 
 
The second phase of the study is for both the Cohort 2A and the Cohort 2B groups 


 
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In the second phase of the study, you will have 14 study visits over about 2 years. The visits will be like the visits 
described above. At two of these visits, we will also look at your genitals again to see how developed you are. 
 
During the second phase of the study, you will be given shots of CAB and RPV. The shots will be given at 13 of 
the study visits (4 weeks and then 8 weeks apart). You will get one shot of CAB and one shot of RPV each time. 
The shots will be in the buttocks (bottom, “cheeks”). The shots may be given on the same side of the buttocks or 
on different sides. 
 
[U.S. sites only] You may also be contacted to answer questions over the phone about how you feel about the 
shots.  
 
If you join in the Cohort 2A group, then you will need to complete the first phase of the study (the study pills 
phase) before starting this second phase of the study.  
 
If you join in the Cohort 2B group, then you will skip the first phase and go directly to the second phase of the 
study (the study shots phase). At the first visit, we will also do an ECG test of your heart. 
 
After you finish the study visits in Cohort 2, you might be able to keep getting shots of CAB and RPV. If you do 
not want to keep getting shots of CAB and RPV at your last study visit, or if you have to stop the shots early 
during your study visits, then you will enter the third phase. This phase is described below. 
 
[Sites to modify] Some visit activities may be offered off-site or by phone. This might only happen if you are 
unable to come the clinic. The study staff will discuss this with you if it is an option.  They will also discuss the 
location and time to visit you so that the visit is at a time and place when you feel comfortable and confidentiality 
can be maintained. 
 
Study staff may ask you to return to the clinic for a study shot before your next visit. If so, then many of the 
procedures described above would also be done again. 
 
If you cannot come to the clinic for a visit when you need the study shots, then you might have the option to take 
the study pills again.  You would take the study pills until you are able to come back to the clinic to get the study 
shot.  If this happens, then you may need to get the study shots 4 weeks apart and then 8 weeks apart. If you 
cannot return to the clinic to get the study shots soon, then you may need to stop taking the study ARVs and enter 
the long-term safety follow-up phase. This is not preferred, and it is important to get the study shots on the 
scheduled day and not miss any visits. 
 
The third phase of the study is called the long-term safety follow-up phase  
 
The third phase of the study is for participants who have to stop the study shots early in the Cohort 2A or Cohort 
2B groups. Participants who become pregnant will also stop their study medicines and join the third phase of the 
study. This phase is also called the long-term safety follow-up phase. You will have 4 study visits over 48 weeks 
(about 1 year). The visits will be like the visits described above.  
 
You will not be given CAB and RPV pills or shots. You will go back to taking your other ARVs.  
 
Risks of the study 
 
Having blood collected may cause pain, bleeding, bruising, swelling, or infection where the needle goes in your 
arm.  
 


 
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Having shots of CAB or RPV may cause pain, irritation, redness, bumps, swelling, itching, or bruising on the 
buttocks (where the shot is given). When CAB and RPV are given as shots, they stay in the body for much longer 
than when CAB and RPV are taken as pills.  
 
The shots will be given in the muscles of your buttocks. The shot could be given too deeply or not deeply enough, 
missing the muscle and entering your skin, blood, or a nerve. The side effects of shot missing the muscle are not 
well understood but could make CAB or RPV levels too low or too high. If too low the drug may not work against 
your HIV. If RPV is too high, there could be a change in your heartbeat, which in severe cases can be life-
threatening. In rare cases, symptoms such as feeling lightheaded, numbness or tingling, difficulty breathing, chest 
or stomach discomfort, sweating, rash, pain (e.g., back and chest), nausea and/or feeling anxious have occurred 
after RPV shot. Not all participants reported such symptoms. Most of the symptoms resolved within minutes. 
Your doctor may need to administer treatment to help resolve these symptoms.  Everything possible will be done 
to decrease this risk, including watching you for problems during the study. We will also draw blood (less than 1 
teaspoon) about 2 hours after the study shot to look at the amount of study drugs in your blood. 
 
CAB and RPV can cause other side effects. These side effects are common, but not everyone will have them. You 
may have pain, feel sick to your stomach, or vomit (throw up). You may have diarrhea. You may have a 
headache, fever, runny nose, sore throat, dry mouth, or rash. You may have trouble sleeping or a lack of energy. 
You may not want to eat as much as you usually do. You may feel lightheaded or sad. You may have problems in 
other parts of the body, such as your liver.  
 
We do not yet know if CAB or RPV are safe in pregnancy. Early results from one study showed that the ARV 
called dolutegravir (DTG) may increase the risk of serious birth defects in the new baby. These mothers were 
taking the drug before they knew they were pregnant. The birth defects have not been seen when mothers started 
taking DTG later in pregnancy. CAB is not the same drug as DTG. We do not know if CAB can cause the same 
defects in babies.  
 
Participants who are able to become pregnant must agree to use certain methods of birth control to be in this 
study. If you become pregnant during the study, please let us know right away. 
  
We will check for side effects at each study visit. Please tell us if you have any side effects or don’t feel well. 
There is also a risk that the CAB and RPV pills and shots won’t control the HIV as well as the ARVs you were 
taking before. We will check the amount of HIV in your blood at each study visit. If you have side effects, or if 
the amount of HIV in your blood is higher than expected, you may have extra visits. We will talk with you and 
your parent/guardian about this, and tell you what to do about any side effects. We will also tell you if you can 
keep taking CAB and RPV. In some cases, you may have to stop taking CAB and RPV.  
 
All information collected for this study will be kept private and confidential. However, it is possible that 
information could be obtained by someone who should not have it. If this were to happen, you could be treated 
badly or unfairly. You could feel stressed or embarrassed. 
 
Other information about the study 
 
Study records may be reviewed by study staff and groups that oversee the study. Groups that oversee the study 
include:  
 
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 


 
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• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your name or identify you personally.  
 
A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify you. At most, the website will include a summary of the results. You can 
search this website at any time. 
 
[Sites may modify this paragraph to reflect local reporting requirements and legal statues: Your study 
information may be shared with other authorities if required by law. Public health authorities are required by law 
to receive information for the prevention or control of disease, injury or disability. (We must follow laws 
requiring the reporting of suspected child abuse and neglect).]   
 
Benefits of the study 
 
By joining the study, you will be part of the search for new ARVs for adolescents. The information learned in this 
study could someday lead to better ARVs for adolescents. However, being in this study may not be of any benefit 
to you. 
 
Your rights  
 
Taking part in this study is voluntary. You can say yes or no. If you say yes now, you can change your mind later. 
Your decision will have no effect on the medical care you normally receive. 
 
Who to contact 
 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
If you have questions about your rights or how you are treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 
 
If you have problems related to being in the study:  
[insert name and telephone number of investigator or other study staff] 
 
If you want to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
Signatures 
 
If you want to take part in this study, sign or make your mark below. 
 


 
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Before deciding whether to take part in this study, make sure you have read this form, or had it read to you. Make 
sure all your questions have been answered. You should feel that you understand the study, its risks and benefits, 
and what is expected of you if you decide to take part.  
 
We will tell you and your parent/guardian any new information that may affect your willingness to stay in the 
study. You can ask questions or ask for more information at any time.  
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies.] 
 
Please write your initials or make your mark next to your choice of either the Cohort 2A or the Cohort 2B group:  
 
__________ 
I agree to join the Cohort 2A group. I understand that this group will have the study pills first and 
then the study shots. I understand that I cannot switch the group after entering the study.  
 
__________ 
I agree to join the Cohort 2B group. I understand that this group will have the study shots and 
skip the study pills phase. I understand that I cannot switch the group after entering the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Participant (print) 
 
Signature of Participant   
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Assent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
(as appropriate; print) 
 
 
 


 
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Appendix III-C: Sample Informed Assent Form for Specimen Storage and Future Use for Participants 
who cannot provide independent informed consent 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 4.0, dated 27 May 2022 
 
[Throughout this form sites may modify to remove mentions of HIV and ARVs for participants who do not know 
their status].  
 
Introduction 
 
As part of the study, you will have blood and urine collected. After these samples are tested for the study, some 
samples may be left over. We call these extra samples. The IMPAACT Network would like to keep these extra 
samples and use them for other research in the future. 
 
You are being asked for permission to keep your extra samples and use them for other research in the future. Your 
parent/guardian will also be asked for permission.  
 
This form gives information about extra samples. Please read it, or have it read to you, and ask any questions you 
may have. After we talk about the information with you, you will record your decisions at the end of the form. 
 
What happens with extra samples 
 
If you allow your extra samples to be kept, there is no limit on how long they will be kept.  
 
The samples may be used for research on HIV, the immune system, and other diseases.  
 
If you agree, the samples could be used for research that looks at your genes. Genes are passed to children from 
their birth parents. They affect how people look and how their bodies work. Differences in people’s genes can 
help explain why some people get a disease while others do not. Your samples would only be used to look at 
genes related to HIV and the immune system. All your genes will not be tested. 
 
The results of tests done with your samples will not be given to you or your parent/guardian. 
 
Risks and benefits 
 
When extra samples are kept for research, they are labeled with a code number only. No names are used. 
Therefore, there is very little risk to your privacy. Your name will not be given to other researchers. 
 
By allowing extra samples to be used for research, you will be part of the search for new information that may 
benefit people with HIV in the future. However, the research done with extra samples is not expected to be of 
benefit to you. 
 
Information from research using extra samples may be reviewed by groups that oversee the research 
 
These groups include:   


 
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• 
The IMPAACT Network  
• 
The ethics committees that review and approve the research  
• 
Government and other agencies that pay for the research  
• 
Government and other agencies that monitor the research  
• 
Other local, US, or international regulatory entities  
 
The people who do research with the extra samples and the groups listed above are required to make efforts to 
keep information private and confidential. 
 
The results of research done with the extra samples may be presented publicly or published. However, no 
presentation or publication will use your name or identify you personally.  
 
Your rights  
 
It is up to you and your parent/guardian to decide if your extra samples can be used for research. You can say yes 
or no. If you say yes now, you can change your mind later. Your decision will have no effect on your participation 
in the study. If you say no, all extra samples will be destroyed. 
 
Who to contact 
 
If you have questions about use of your extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
If you change your mind about use of your extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
If you have questions about your rights or how you are treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate person/organization] 
 
Signatures 
 
Before deciding whether to allow your extra samples to be used for research, make sure you have read this form, 
or had it read to you. Make sure all your questions have been answered. You should feel that you understand your 
choices and the possible risks and benefits before making your decision. 
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies. Separate consent decisions must be 
documented for genetic testing]. 
 
Please write your initials or make your mark next to your choices:  
 
 
__________ 
I allow my extra samples to be used for research on HIV, the immune system, and other diseases.  
 
__________ 
I allow my extra samples to be used for tests of my genes.  
 
 
__________ 
I do not allow my extra samples to be used for any research.  
 


 
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Name of Participant (print) 
 
Signature of Participant   
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Assent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
(as appropriate; print) 
 
 
 


 
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Appendix IV: Parent/Caregiver Participation in Qualitative Phone Interviews  
(U.S. Sites Only) 
 
Appendix IV-A: Parent/Caregiver Qualitative Phone Interviews 
 
Parents or caregivers of adolescent participants enrolled at U.S. study sites will be selected by the 
protocol interview team for enrollment into the study to conduct a single in-depth qualitative phone 
interview, with the purpose of evaluating their perceptions of adolescent acceptability and tolerability of 
CAB LA and/or RPV LA. The phone interviews with parents/caregivers will be conducted separately and 
apart from any phone interviews conducted with adolescent participants. 
 
The protocol interview team will notify sites to initiate recruitment of the selected parent/caregiver. After 
obtaining consent, sites will confirm eligibility for the parent/caregiver to take part in the interview. 
Parents/caregivers meeting eligibility criteria will be enrolled as study participants, and site staff will 
work with the protocol interview team and the enrolled parent/caregiver to schedule and conduct the 
phone interview. Further details relating to these processes and procedures are provided below. 
 
Protocol Section 11 provides information and details regarding the qualitative phone interviews with the 
adolescent participants. 
 
1 
Sample Size, and Selection Process 
 
Enrolled adolescent participants at U.S. study sites will be selected by the protocol interview team for 
their parent/caregiver to be recruited by site staff to take part in a single in-depth qualitative interview for 
a maximum of 60 completed phone interviews: 30 phone interviews completed by parents/caregivers of 
Cohort 1 adolescent participants, and 30 phone interviews completed by parents/caregivers of Cohort 2 
adolescent participants. The sample size is based on the likely number of interviews needed to achieve 
thematic saturation. Parent/caregiver selection for the interviews will continue until there is either 
saturation of themes among the parent/caregiver interview data, or the parent/caregiver maximum sample 
size is reached. See Protocol Section 11.6 regarding thematic saturation and qualitative interview data 
analyses. 
 
Parent/caregiver selection is based on the adolescent participant’s reported demographics from the 
adolescent’s Screening and Entry visits, with the goal of balancing interviewed parents/caregivers across 
participants assigned female/male at birth and older/younger adolescent participants. Additionally, 
parents/caregivers of participants who permanently discontinue injectable study product will be 
purposefully selected. This will ensure that perspectives from parents/caregivers across the range of 
enrolled participants are reflected in the final analysis. Parents/caregivers will be selected across multiple 
sites, but restricted to those willing and able to conduct the interview in English. 
 
When possible, parents/caregivers of adolescents also participating in interviews will be selected to allow 
for dyadic comparisons between the parents’/caregivers’ and adolescents’ perspectives. However, a 
parent/caregiver of an adolescent participant may be selected to take part in the qualitative phone 
interview even if their adolescent participant is not selected or does not complete a (separate) qualitative 
phone interview. 
 
The interviews must be completed within the applicable specified interview window (see Appendix IV-A 
Section 2 below). Parents/caregivers will be selected on an on-going basis, and as their adolescent 
participant approaches the parent/caregiver interview procedural window. Parents/caregivers of 


 
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adolescent participants enrolling to the study early will be selected for interviews first, as their adolescent 
participant will be the first to receive the injectable study products. The selection process will continue 
until thematic saturation or the sample size is reached for each Cohort; therefore, some parents/caregivers 
may be selected after entering the interview procedure window. Parents/caregivers who complete an 
interview for Cohort 1 will not be eligible to complete an interview for Cohort 2.  
 
2 
Phone Interview Procedural Windows 
 
The qualitative phone interviews will be conducted with selected parents/caregivers of adolescent 
participants within the following timeframes:  
• 
Parents/caregivers of Cohort 1 adolescent participants: Between the adolescent participant’s 
Week 4b and Week 12 visits (inclusive), or during LSFU visits.  
 
• 
Parents/caregivers of Cohort 2A adolescent participants: Between the adolescent participant’s 
Week 24 and Week 96 visits (inclusive), or during LSFU visits.  
 
• 
Parents/caregivers of Cohort 2B adolescent participants: Between the adolescent participant’s 
Week 20 and Week 92 visits (inclusive), or during LSFU visits. 
 
3 
Recruitment Considerations 
 
The protocol interview team will notify sites of an adolescent participant’s PID to then initiate the 
recruitment of the adolescent participant’s parent/caregiver. Recruitment of the parent/caregiver will 
generally rely on the enrolled adolescent participant identifying the potentially eligible parent/caregiver 
and referring him/her to site staff for the qualitative interview; site staff may also identify a potentially 
eligible parent/caregiver (of the selected adolescent participant) as they present to the study clinic.  
 
Sites must source document notification by the protocol interview team of adolescent participant selection 
for parent/caregiver recruitment, all attempts to contact the adolescent participant for parent/caregiver 
recruitment. Sites must follow their IRB/EC approved recruitment methods for approaching a potential 
parent/caregiver participant. Further guidance on recruitment considerations and processes is provided in 
the IMPAACT 2017 MOP. 
 
Eligibility criteria for parents/caregivers are provided in Protocol Section 4.5, and details regarding 
confirmation of eligibility criteria and the enrollment process are provided in Appendix IV-A Section 5 
below.    
 
4 
Consenting Considerations 
 
Parents/caregivers must provide consent prior to enrollment and conducting the phone interview. After 
recruitment of a selected and potentially eligible parent/caregiver, study staff will provide information, 
education, and counseling as part of the study informed consent process for the qualitative phone 
interview. The consent process will include information exchange, discussion, and assessment of 
understanding of all required elements of informed consent, including the potential risks, benefits, and 
alternatives to study participation. Study staff will also provide time to address any questions or concerns 
the parent/caregiver may have, and an assessment of understanding, before proceeding to a consenting 
decision.  
 


 
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Obtaining informed consent from the parent/caregiver for the phone interview is ideally conducted in 
person and in writing by the parent/caregiver signing the informed consent form. Appendix IV-B provides 
a sample written informed consent form for parent/caregiver study participation in the qualitative phone 
interview which sites may modify for use. If the parent/caregiver is unable to read, the process for 
consenting illiterate participants, as defined or approved by the local IRB/EC, should be followed. 
 
Sites have the option of seeking a waiver from their IRB/EC of the requirement to obtain written 
documentation of the consent process for parent/caregiver participation in the qualitative phone interview. 
Consistent with DAIDS policies on the requirements for obtaining informed consent 
(https://ohsr.od.nih.gov/public/SOP_12_v5_5-22-2017.pdf), when the IRB/EC considers waiving the 
requirement to obtain written documentation of the consent process, the IRB/EC reviews a written 
description of the information that will be provided, either verbally or in writing, to the 
parents/caregivers. Appendix IV-C provides a sample of a script or statement which sites may modify for 
use, should an IRB/EC grant a waiver of written documentation.  
 
Additionally, sites also have the option of seeking IRB/EC approval for obtaining parent/caregiver 
consent by telephone, rather than in person. In such instances, a witness to the consent process (e.g., 
another study or non-study staff member) must be present at the time of the study site staff obtaining 
consent from the parent/caregiver, and should ideally also listen in to the consenting discussion between 
the parent/caregiver and study staff member. Appendix IV-C may be modified for use as a verbal script to 
obtain consent by telephone. If telephone consent is used and the parent/caregiver is seen at the site prior 
to conducting the phone interview, it is recommended to re-confirm the parent/caregiver’s understanding 
of the phone interview and willingness to participate through an additional, brief consent process, as 
required by the IRB. 
 
Study sites are permitted to develop a separate parent/caregiver consent form and/or script for this study, 
if required by site or IRB/EC policies and procedures. Sites must establish and maintain an informed 
consent SOP with written procedures describing standards for obtaining informed consent, and roles and 
responsibilities of study staff involved in obtaining informed consent for all the consenting options being 
utilized for the parents/caregivers (i.e., written signed consent, waiver of written consent, and/or verbal 
consent by telephone), reflective of applicable IRB/EC guidance. For sites seeking IRB/EC approval for 
obtaining consent by telephone, the site’s informed consent SOP should include procedures for 
subsequently obtaining a written signed consent form from the parent/caregiver (unless the IRB waives 
written consent), and how a copy of the consent form (or script) will be provided to the parent/caregiver.  
 
Regardless of a waiver of written consent, all the informed consent processes will be fully source 
documented, consistent with the DAIDS policies referenced in Protocol Section 12.2.  
 
5 
Eligibility Confirmation and Enrollment Process 
 
Eligibility criteria for parents/caregivers are provided in Protocol Section 4.5. Inclusion criteria include 
confirmation from both the parent/caregiver as well as the adolescent participant that the identified 
parent/caregiver has knowledge of how the adolescent participant tolerated the study product, and lives 
with or has regular supportive contact with the adolescent participant. As these inclusion criteria require 
reporting from separate individuals, parent/caregiver eligibility may be assessed at multiple timepoints 
after obtaining consent and prior to enrollment and may be assessed in-person at the study clinic or by 
telephone. It is generally expected that site staff will ascertain adolescent participant report of 
parent/caregiver eligibility during the adolescent’s study visit. Eligibility criteria must be confirmed, and 
source documented after obtaining informed consent.  
 


 
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Eligibility determination for parents/caregivers must also be included in site SOPs, which describe how 
(whether in-person or over the phone), where and when recruitment and confirmation of eligibility criteria 
will be performed; roles and responsibilities for assessing (whether in-person or over the phone) and 
confirming eligibility; and procedures for documenting the process.  
 
The DMC system will not be used for tracking parent/caregiver screening process. However, sites will 
source document reasons for any consenting parent/caregiver found to be ineligible. For 
parents/caregivers found to be eligible, enrollment into the study will occur upon successful entry of 
required eligibility data into the IMPAACT Data Management Center (DMC) Subject Enrollment System 
(SES). Successful entry into the SES will generate a study identification number (SID).  
 
The IMPAACT 2017 MOP provides further guidance on operational and logistical considerations of 
assessing and confirming eligibility, and enrolling the parent/caregiver to the study prior to the phone 
interview being conducted. 
 
6 
Scheduling and Conducting Phone Interviews 
 
Site staff will work with the protocol interview team and the parent/caregiver to schedule the phone 
interview at a time that is convenient for the parent/caregiver and within the applicable interview 
procedural window. Scheduling of the interview may occur at any point with the intention to minimize 
the number of scheduled but uncompleted interviews. Parents/caregivers must be consented, confirmed as 
eligible, and enrolled prior to conducting the phone interview. 
 
Once the phone interview is scheduled, site staff will provide the parent/caregiver with detailed 
instructions and guidance on accessing the phone interview platform. Phone interviews may be completed 
either in the study clinic during their adolescent participant’s scheduled study visit, or from a phone 
outside the study clinic. All phone interviews will be conducted by a protocol interview team member 
external to participating clinical research sites, following an interview guide, and will be audio recorded 
and transcribed.  
 
After obtaining consent, sites must source document all attempts to contact the parent/caregiver and 
interview scheduling attempts, and enter into eCRFs demographics and the date the phone interview 
occurred. Operational and logistical details regarding communication with the protocol interview team 
members and site staff are provided in the IMPAACT 2017 MOP. 
 
7 
Human Subjects Protections 
 
Protocol Section 14.1 provides information regarding IRB/EC review and approval requirements in 
relation to the IMPAACT 2017 study. Informed consent considerations are provided in Appendix IV-A 
Section 4 above. 
 
There may be no direct benefit to parents/caregivers who take part in the qualitative phone interviews. 
Information learned in this study may be of benefit to adolescent participants and others in the future, 
particularly information that may lead to more treatment options for HIV-infected children and 
adolescents. Parents/caregivers may also appreciate the opportunity for themselves to contribute to HIV-
related research. 
 
Despite all efforts to maintain confidentiality, involvement in the qualitative phone interview could 
become known to others, possibly leading to unfair treatment, discrimination, or other social impacts 
(e.g., because adolescent participants could become known as having HIV). For example, adolescent 


 
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participants could be treated unfairly or discriminated against or could have problems being accepted by 
their families and/or communities.  
 
Pending IRB/EC approval, parents/caregivers may be reimbursed for their time and any costs associated 
with completing the qualitative phone interview. Reimbursement amounts will be specified in the site-
specific consent, verbal script, or other materials if applicable per IRC/EC policies and procedures.  
 
All study procedures will be conducted in private and every effort will be made to protect 
parent/caregiver privacy and confidentiality to the extent possible. Parent/caregiver information will not 
be released without written permission to do so except as necessary for review, monitoring, and/or 
auditing as described in Protocol Section 13. Refer to Protocol Section 14.7 for further information on 
privacy and confidentiality. 
 
8 
Disclosure of Harm 
 
As described above, the purpose of conducting in-depth qualitative phone interviews with 
parents/caregivers is to evaluate their perceptions of adolescent acceptability and tolerability of CAB LA 
and/or RPV LA. Conducting the interviews is not expected to increase the likelihood or risk of self-harm 
or harm to others.    
 
During the consent process, parents/caregivers will be informed that the information they provide in the 
interview will be kept confidential, with the exception of disclosures of significant risk for harm, 
including suicidality, or at risk of committing harm toward others, including abuse, violence or 
homicidality. 
 
If at any time during a qualitative phone interview, a parent/caregiver divulges that s/he is at significant 
risk for harm or at significant risk of committing harm toward the adolescent participant, or if harm is 
suspected or likely, or if the parent/caregiver states s/he is suicidal or homicidal, the following will occur: 
• 
The protocol interview team member conducting the interview will immediately contact the site 
IoR or designee and share any time-sensitive, potentially life-threatening information received 
from the parent/caregiver as part of the phone interview discussions. 
• 
The IoR or designee contacted with this information will follow local policies for management of 
such situations including engaging immediate/first responders as applicable. 
• 
The IoR or designee will also follow local reporting policies and legal statutes, including 
reporting to child protection or other appropriate agencies, as well as arranging referrals to 
appropriate support, counseling or treatment resources. 
 
For disclosure of safety concerns to the parent/caregiver, the IoR or designee will notify the CMC after 
completing the steps above. No further safety reporting of the parents/caregivers is required, and Protocol 
Section 7 Safety Assessment, Monitoring, and Reporting does not apply for the parents/caregivers.  
 
For disclosure by the parent/caregiver of safety concerns to the adolescent participant, the IoR or designee 
will notify the CMC after completing the steps above, and document and report the event as applicable 
per Protocol Section 7.  
 
To facilitate rapid communications, the IoR or designee is expected to provide up-to-date contact 
information to the protocol interview team while phone interviews are being scheduled and conducted 
with participants from the site.  
 
9 
Data Management, Clinical Site Monitoring, and Administrative Procedures 


 
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Protocol Section 11.6 provides details on the qualitative phone interview data analyses, and Protocol 
Section 12 provides details on the management, handling, and record keeping of the qualitative phone 
interview data. Protocol Section 13 provides information on clinical site monitoring, and Protocol Section 
15 provides information on overarching administrative procedures for the IMPAACT 2017 study. 
 
 


 
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Appendix IV-B: Parent/Caregiver Phone Interview Sample Informed Consent Form 
for parents/caregivers of adolescents enrolled in: 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 4.0, dated 27 May 2022 
 
Introduction 
 
You are being asked to take part in the research study named above.  
 
This form gives information about your role in the study. Please read it, or have it read to you, and ask any 
questions you may have. We will take as much time as needed for you to fully understand your role in the study. 
At the end, we will ask you questions to see if we have explained your role in the study clearly. 
 
After you understand your role in the study, and if you decide that you will participate, you will be asked to sign 
or make your mark on this form. You will be offered a copy to keep. 
 
It is your decision whether or not you join the study. 
 
Deciding to join the study is voluntary. You may choose to join or not join. If you choose to join, you can change 
your mind and stop the study at any time. Your choice will have no effect on your child’s medical care at this 
clinic or your child participating in the study. Access to services and the benefits and rights you and your child 
normally have will not be affected.  
 
Your role in the study 
 
If you agree, you may be asked to complete one phone interview about how you felt and how you think your child 
felt about the shots they receive in this study. Not all parents/caregivers of adolescents who receive shots will be 
asked to complete a phone interview. Some, but not all adolescents who receive shots will also be asked to 
complete a phone interview.  
 
If you are eligible and selected to complete an interview, we will help you to schedule the interview at a time that 
works for you. During the interview, you will be asked questions about how you felt about your child receiving 
shots of CAB or [and] RPV. The interview will be audio recorded. The words that you say will then be written 
down. This information will help us understand if CAB shots and RPV shots have any bad side effects for 
adolescents. It will also help us understand how adolescents and families feel about them receiving the shots.  
 
The interview may take place at or in between your child’s Week 4b through their Week 12 study visits in Cohort 
1 [Week 24 through 96 visits in Cohort 2A; Week 20 through 92 visits in Cohort 2B] or during the long-term 
follow-up visits. The interview could also take place at or in between any of the long-term follow-up visits if your 
child enters into long-term follow-up. You will only complete one interview. Your part in the study should take 
about 1-2 hours.  
 
 


 
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There are no costs from being in the study. 
 
There are no costs to you for this phone interview.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for your time, and 
given (specify amount).] 
 
Possible Risks 
 
There could be risks of disclosure of your information. We will make every effort to keep your information 
private and confidential. Your and your child’s names will not be included in the recording of the interview. The 
interview will only be labeled with a code number. 
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality that protects us from being 
forced to release information that may identify you, such as by the courts or police. The certificate cannot be used 
in all situations, but it can be used to resist demands for information that would identify you. The certificate does 
not protect against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your participation in the study to 
others, if you wish. 
 
Possible Benefits 
 
By joining the study, you will be part of the search for ARVs that may be better for adolescents. There may be no 
direct benefit to you from taking part in this study. There may be a benefit if the results from this study lead to a 
safe and effective dose of the study drugs for adolescents. Information learned from this study may help other 
adolescents who have HIV. 
 
Other information about the study 
 
Study records may be reviewed by study staff and groups that oversee the study. Groups that oversee the study 
include:  
 
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your child’s name or identify your child personally.  
 


 
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A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify your child. At most, the website will include a summary of the results. You 
can search this website at any time. 
 
[Sites may modify this paragraph to reflect local reporting requirements and legal statues: Your child’s study 
information may be disclosed to other authorities if required by law. Public health authorities are required by law 
to receive information for the prevention or control of disease, injury or disability. (We must comply with laws 
requiring the reporting of suspected child abuse and neglect).]   
 
Signatures 
 
If you agree to participate in this study, please sign or make your mark below. 
 
Before deciding whether to participate in this study, make sure you have read this form, or had it read to you, and 
that all of your questions have been answered. You should feel that you understand the study, its risks and 
benefits, and what is expected of you if you decide to join. You are welcome to ask questions or request more 
information at any time.  
 
You do not give up any rights by signing this form. 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
Signature blocks for participants of legal age to provide independent informed consent 
 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
 
 
 
 
 
              
 
 
 
 
 
 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix IV-C: Parent/Caregiver Phone Interview Sample Informed Consent Verbal Script 
for parents/caregivers of adolescents enrolled in: 
 
IMPAACT 2017 
Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting 
Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected 
Children and Adolescents 
 
Version 4.0, dated 27 May 2022 
 
Introduction 
 
You are being asked to take part in the research study named above.  
 
This form gives information about your role in the study. Please read it, or have it read to you, and ask any 
questions you may have. We will take as much time as needed for you to fully understand your role in the study. 
At the end, we will ask you questions to see if we have explained your role in the study clearly. 
 
After you understand your role in the study, and if you decide that you will participate, you will be asked to sign 
or make your mark on this form. You will be offered a copy to keep. 
 
It is your decision whether or not you join the study. 
 
Deciding to join the study is voluntary. You may choose to join or not join. If you choose to join, you can change 
your mind and stop the study at any time. Your choice will have no effect on your child’s medical care at this 
clinic or your child participating in the study. Access to services and the benefits and rights you and your child 
normally have will not be affected.  
 
Your role in the study 
 
If you agree, you may be asked to complete one phone interview about how you felt and how you think your child 
felt about the shots they receive in this study. Not all parents/caregivers of adolescents who receive shots will be 
asked to complete a phone interview. Some, but not all adolescents who receive shots will also be asked to 
complete a phone interview.  
 
If you are eligible and selected to complete an interview, we will help you to schedule the interview at a time that 
works for you. During the interview, you will be asked questions about how you felt about your child receiving 
shots of CAB or [and] RPV. The interview will be audio recorded. The words that you say will then be written 
down. This information will help us understand if CAB shots and RPV shots have any bad side effects for 
adolescents. It will also help us understand how adolescents and families feel about them receiving the shots.  
 
The interview may take place at or in between your child’s Week through their Week 12 study visits in Cohort 1 
[Week 24 through 96 visits in Cohort 2A; Week 20 through 92 visits in Cohort 2B], or during the long-term 
follow-up visits. The interview could also take place at or in between any of the long-term follow-up visits if your 
child enters into long-term follow-up. You will only complete one interview. Your part in the study should take 
about 1-2 hours.  
 
 


 
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There are no costs from being in the study. 
 
There are no costs to you for this phone interview.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for your time, and 
given (specify amount).] 
 
Possible Risks 
 
There could be risks of disclosure of your information. We will make every effort to keep your information 
private and confidential. Your and your child’s names will not be included in the recording of the interview. The 
interview will only be labeled with a code number. 
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality that protects us from being 
forced to release information that may identify you, such as by the courts or police. The certificate cannot be used 
in all situations, but it can be used to resist demands for information that would identify you. The certificate does 
not protect against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your participation in the study to 
others, if you wish. 
 
Possible Benefits 
 
By joining the study, you will be part of the search for ARVs that may be better for adolescents. There may be no 
direct benefit to you from taking part in this study. There may be a benefit if the results from this study lead to a 
safe and effective dose of the study drugs for adolescents. Information learned from this study may help other 
adolescents who have HIV. 
 
Other information about the study 
 
Study records may be reviewed by study staff and groups that oversee the study. Groups that oversee the study 
include:  
 
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
ViiV Healthcare (the company that makes CAB) 
• 
Janssen Pharmaceuticals (the company that makes RPV) 
 
The study staff and these groups are required to keep study records private and confidential.  
 
The results of the study may be presented publicly or published. However, no presentation or publication will use 
your child’s name or identify your child personally.  
 


 
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A description of this study will be available on ClinicalTrials.gov as required by U.S. law. This website will not 
include information that can identify your child. At most, the website will include a summary of the results. You 
can search this website at any time. 
 
[Sites may modify this paragraph to reflect local reporting requirements and legal statues: Your child’s study 
information may be disclosed to other authorities if required by law. Public health authorities are required by law 
to receive information for the prevention or control of disease, injury or disability. (We must comply with laws 
requiring the reporting of suspected child abuse and neglect).]   
 
Agreement to participate  
 
Before deciding whether to participate in this study, please ask me any questions that you have. You should feel 
that you understand the study, its risks and benefits, and what is expected of you if you decide to join. You are 
welcome to ask questions or request more information at any time.  
 
You do not give up any rights by agreeing to participate.  
 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
Signature blocks for witnesses to verbal consent of parents/guardians of legal age to provide independent informed 
consent 
 
 
 
 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 
 


 
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Appendix V:  Injectable Study Product Preparation 
 
This appendix provides requirements for injectable study product preparation for both CAB LA and RPV 
LA.  The study product regimen, administration, formulation, storage requirements, supply and other 
relevant information is described in protocol Section 5 Study Product.  The IMPAACT 2017 MOP 
provides additional details and guidance regarding study product ordering, prescribing, short-term 
storage, and administration. 
 
The investigational pharmacist(s) must be proficient in the preparation of study products using aseptic 
technique under a pharmacy biological safety cabinet (BSC) Class II or better isolator. Local regulations 
and site institutional policies and procedures for use of personal protective equipment, such as gloves, 
gowns, masks, and safety glasses, must be followed.  
 
Suggested supplies for CAB LA and RPV LA:  
 
- 
BD 5-mL syringe, Luer-Lok Tip, Reference No.: 309646, or equivalent 
- 
BD 3-mL syringe, Luer-Lok Tip, Reorder No.: 309585, 309657, or equivalent 
- 
Needle for aspiration: BD Precision Glide Needle, 21G 1 inch, Reference No.: 305165, or equivalent 
- 
Needle for intramuscular injection: 
▪ 
21G x 1.5" SurGuard Safety Hypodermic Needle CE MARKED Mfg Catalog Number: SG3-2138 
(Central Supply as applicable per country) 
▪ 
23G x 1.5" SurGuard Safety Hypodermic Needle CE MARKED Mfg Catalog Number: SG3-2338 
(Central Supply as applicable per country) 
▪ 
BD Precision Glide Needle, 23G 1.5", Reference No.: 305194, or equivalent 
 
Variable needle lengths and/or needles with different gauge (1.5 inch, 2 inch; CAB LA: 21 to 25 gauge; 
RPV LA: 21 to 23 gauge) are permitted if needed to accommodate individual body types. 
NOTE: 25G needle is not permitted for administration of RPV LA. 
 
Appendix V-A: Preparation of CAB LA 
 
1 
Preparation of CAB LA 600mg/3mL (using one 600 mg/3mL vial or two 400 mg/2 mL vials) 
 
One syringe containing 3 mL (600 mg) of CAB LA study product must be prepared using aseptic 
technique under a pharmacy BSC/isolator.  
 
1. Remove one 3-mL CAB LA vial or two 2-mL CAB LA vials (as available) from storage. If CAB LA 
vials are stored in the refrigerator (2°C to 8°C), remove vial(s) from the refrigerator and wait at least 15 
minutes to equilibrate to room temperature. Record the time when vial(s) were removed from the 
refrigerator. 
 
2. Remove vial(s) from the carton and vigorously shake the vial for a full 10 seconds by shaking the vial 
with long arm movements. 
 
3. Invert the vial(s) and inspect to ensure complete re-suspension. If sediments are observed, repeat Steps 
2-3 until all material is uniformly suspended. After re-suspending, it is recommended to use the 
suspension immediately. 
 


 
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4. using aseptic technique under a pharmacy biological safety cabinet, flip off the plastic cap from the 
vial(s). Wipe the top of the vial(s) with disinfecting tissue of isopropyl alcohol 70% or similar and allow 
the alcohol to dry. 
 
5. Remove one 5-mL syringe and aspiration needles from the blister pouch (see suggested supplies). Take 
one aspiration needle and attach the needle to the Luer-Lok connection of the syringe. 
 
6. If using two 2-mL CAB LA vials: 
• 
With the sheath on the needle, pull back on the syringe plunger to allow approximately 1 mL of 
air into the syringe.  Pull the needle sheath off the needle with a straight pull. 
• 
Push the needle through the stopper of the first vial and inject 1 mL of air into the vial by putting 
the vial in the inverted position while the needle and syringe are in the upright position. 
• 
Withdraw 1.5 mL of suspension from the first vial and put vial aside. 
• 
Remove the needle from the syringe and attach a new aspiration needle. Repeat the steps above to 
withdraw 1.5 mL of suspension from the second vial, for a total of 3 mL from two vials. Because 
the suspension can contain some air after having shaken the vial, take out enough suspension in 
order to be able to de-aerate the syringe properly (Step 9).  
• 
Record for each individual vial the time withdrawn into the syringe.  
 
 
7. If using one 3-mL CAB LA vial: 
• 
With the sheath on the needle, pull back on the syringe plunger to allow approximately 1 mL of 
air into the syringe.  Pull the needle sheath off the needle with a straight pull. 
• 
Push the needle through the stopper of the vial and inject 1mL of air into the vial by putting the 
vial in the inverted position while the needle and syringe are in the upright position.  
• 
Withdraw the entire contents (3 mL) of the vial into the syringe. Because the suspension can 
contain some air after having shaken the vial, take out enough suspension in order to be able to 
de-aerate the syringe properly (Step 9).  
• 
Record the time withdrawn into the syringe.  
 
8. Keep the syringe with the needle in the upright position and remove the needle that was used to 
withdraw the suspension and discard it appropriately. Attach the needle for intramuscular administration 
to the Luer-Lok connection of the syringe or attach a syringe cap (per site’s SOP). Consult with clinic 
staff regarding the recommended needle for IM administration (see suggested supplies). 
 
9. De-aerate the syringe by first tapping with a finger against the syringe and then by moving the plunger 
rod carefully forward with the needle in upright position until a drop of suspension appears. Remove the 
excess suspension in order to administer the correct volume (3 mL). 
 
10. Label the syringe appropriately. 
 
After withdrawal of the suspension from the vial(s) into a syringe, it is recommended to administer the 
suspension immediately. Do not exceed 2 hours between the time the vial(s) were removed from 
refrigerated storage (if applicable) or withdrawing the contents of the vial(s) into a syringe, 
whichever occurs first, and time of administration to the study participant.   
 
The prepared CAB LA suspension in a syringe must be stored at controlled room temperature between 
20°C to 25°C from the time it is withdrawn into a syringe to the time it is administered. 
 


 
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Any entered vials or expired filled syringes should be disposed of in accordance with institutional or 
pharmacy policy. 
 
2 
Preparation of CAB LA 400mg/2mL (using one 400 mg/2 mL vial) 
 
One syringe containing 2 mL (400 mg) of CAB LA study product must be prepared using aseptic 
technique under a pharmacy BSC/isolator.  
 
1. Remove one 2-mL CAB LA vial from storage. If CAB LA vials are stored in the refrigerator 
(2°C to 8°C), remove vial from the refrigerator and wait at least 15 minutes to equilibrate to room 
temperature. Record the time when vial was removed from the refrigerator. 
2. Removed vial from the carton and vigorously shake the vial for 10 seconds by shaking the vial 
with long arm movements. 
3. Invert the vial and inspect the vial to ensure complete re-suspension. If sediments are observed, 
repeat Steps 2-3 until all material is uniformly suspended. After re-suspending, it is 
recommended to use the suspension immediately. 
4. Using aseptic technique under a pharmacy biological safety cabinet, flip off the plastic cap from 
the vial. Wipe the top of the vial with a 70% isopropyl alcohol pad or similar and allow the 
alcohol to dry. 
5. Remove one 3-mL syringe and one aspiration needle from the blister pouch (see suggested 
supplies). Attach the needle to the Luer-Lok connection of the syringe. 
6. With the sheath on the needle, pull back on the syringe plunger rod to allow approximately 1 mL 
of air into the syringe.  Pull the needle sheath off the needle with a straight pull. 
7. Push the needle through the stopper of the vial and inject 1 mL of air into the vial by putting the 
vial in the inverted position while the needle and syringe are in the upright position.  
8. Withdraw the entire contents (2 mL) from the vial. Since the suspension can contain some air 
after shaking, take out all suspension in order to be able to de-aerate the syringe properly (Step 
10). 
Record the time that the suspension is withdrawn into the syringe.  
9. Keep the syringe with the needle in the upright position and remove the needle that was used to 
withdraw the suspension and discard it appropriately. Attach the needle for intramuscular 
administration to the Luer-Lok connection of the syringe or attach a syringe cap (per site’s SOP). 
Consult with clinic staff regarding the recommended needle for IM administration (see suggested 
supplies). 
10. De-aerate the syringe by first tapping with a finger against the syringe and then by moving the 
plunger rod carefully forward with the needle in upright position until a drop of suspension 
appears. Remove the excess suspension in order to administer the correct volume (2 mL).   
11. Label the syringe appropriately. 
  
After withdrawal of the suspension from the vial into a syringe, it is recommended to administer the 
suspension immediately. Do not exceed 2 hours between the time the vial was removed from 
refrigerated storage (if applicable) or withdrawing the contents of the vial into a syringe, whichever 
occurs first, and time of administration to the study participant.   
 
The prepared CAB LA suspension in a syringe must be stored at controlled room temperature between 
20°C to 25°C from the time it is withdrawn into a syringe to the time it is administered. 
 


 
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Any entered vials or expired filled syringes should be disposed of in accordance with institutional or 
pharmacy policy. 
 
Appendix V-B: Preparation of RPV LA 
 
1 
Preparation of RPV LA 900mg/3mL (using one 900mg/3 mL vial or two 600 mg/2 mL vials) 
 
1. Remove one 3-mL RPV LA vial or two 2-mL RPV vials (as available) from the refrigerator and 
allow the vial(s) to sit for 15 minutes to come to room temperature (keep vial in the carton while 
coming to room temperature). RPV LA may sit at room temperature for a maximum of 24 hours 
at 25°C. During this period, excursions are allowed up to 30°C for a maximum of 2 hours. Record 
the time when vial(s) were removed from the refrigerator. 
2. Remove the vial(s) from the carton and vigorously shake the vial(s  a full 10 seconds by shaking 
the vial with long arm movements.  
3. Invert the vial(s) and inspect to ensure complete re-suspension. If sediments are observed, repeat 
Steps 2-3 until all material is uniformly suspended. After re-suspending, it is recommended to use 
the suspension immediately. 
4. Using aseptic technique under a pharmacy biological safety cabinet, flip off the plastic cap from 
the vial(s). Wipe the top of the vial(s) with a 70% isopropyl alcohol pad or similar and allow the 
alcohol to dry. 
5. Remove one 5-mL syringe and one aspiration needle from the blister pouch (see suggested 
supplies). Remove 2 needles if using two 2-mL vials. Attach one needle to the Luer connection of 
the syringe. 
6. If using two 2-mL RPV vials: 
• 
With the sheath on the needle, pull the syringe plunger rod slowly to allow approximately 
1 mL of air into the syringe.  Pull the needle sheath off of the needle with a straight pull.  
• 
Push the needle through the stopper of the first vial and inject 1 mL of air into the vial by 
putting the vial in the inverted position while the needle and syringe are in the upright 
position. 
• 
Withdraw approximately 1.5 mL of suspension from the vial into the syringe. 
• 
Remove the needle from the syringe and attach a new aspiration needle. Repeat the steps 
above to withdraw 1.5 mL of suspension from the second vial, for a total of 3 mL from 
two vials. Because the suspension can contain some air after having shaken the vial, take 
out enough suspension in order to be able to de-aerate the syringe properly (Step 9).  
• 
Record for each individual vial the time withdrawn into the syringe.  
7. If using one 3-mL RPV vial: 
• 
With the sheath on the needle, pull back on the syringe plunger to allow approximately 1 
mL of air into the syringe.  Pull the needle sheath off the needle with a straight pull. 
• 
Push the needle through the stopper of the vial and inject 1 mL of air into the vial by 
putting the vial in the inverted position while the needle and syringe are in the upright 
position.  


 
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• 
Withdraw the entire contents (3 mL) of the vial into the syringe. Because the suspension 
can contain some air after having shaken the vial, take out enough suspension in order to 
be able to de-aerate the syringe properly (Step 9).  
• 
Record the time the vial was withdrawn into the syringe. 
 
8. Keep the syringe with the needle in the upright position and remove the needle that was used to 
withdraw the suspension and discard it appropriately. Attach the needle for intramuscular 
administration to the Luer-Lok connection of the syringe or attach a syringe cap (per site’s SOP). 
Consult with clinic staff regarding the recommended needle for IM administration (see suggested 
supplies). 
9. De-aerate the syringe by first tapping with a finger against the syringe and then by moving the 
plunger rod carefully forward with the needle in upright position until first drop appear. Remove 
the excess suspension in order to administer the correct volume (3 mL).   
10. Label the syringe appropriately. 
 
After withdrawal of the suspension from the vial into a syringe, it is recommended to administer the 
suspension immediately. If required, the prepared syringe containing RPV LA may remain at room 
temperature for a maximum period of 2 hours between the time the vial(s) were removed from the 
refrigerator  and time of administration to the study participant.  The prepared RPV-LA syringe must 
be protected from light (e.g., syringe covered or enclosed within an amber bag) until ready to administer.  
 
Any entered vials or expired filled syringes should be disposed of in accordance with institutional or 
pharmacy policy. 
 
2 
Preparation of RPV LA 600mg/2mL (using one 600mg/2 mL vial) 
 
1. Remove one 2-mL RPV LA vial from the refrigerator. Document the time at which the vial was 
removed from the refrigerator.  Allow the vial to sit for 15 minutes to come to room temperature 
(keep vial in the carton while coming to room temperature). RPV LA may sit at room temperature 
for a maximum of 24 hours at 25°C. During this period, excursions are allowed up to 30°C for a 
maximum of 2 hours.  
2. Remove the vial from the carton and vigorously shake the vial for a full 10 seconds by shaking 
the vial with long arm movements.  
3. Invert the vial and inspect the vial to ensure complete re-suspension. If sediments are observed, 
repeat Steps 2-3 until all material is uniformly suspended. After re-suspending, it is recommended 
to use the suspension immediately. 
4. Using aseptic technique under a pharmacy biological safety cabinet, flip off the plastic cap from 
the vial. Wipe the top of the vial with a 70% isopropyl alcohol pad or similar and allow the 
alcohol to dry. 
5. Remove one 3-mL syringe and one aspiration needle from the blister pouch (see suggested 
supplies). Attach the aspiration needle to the Luer connection of the syringe. 
6. With the sheath on the needle, pull the syringe plunger rod to allow approximately 1 mL of air 
into the syringe.  Pull the needle sheath off the needle with a straight pull. 
7. Push the needle through the stopper of the vial and inject 1 mL of air into the vial by putting the 
vial in the inverted position while the needle and syringe are in the upright position. 


 
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8. Withdraw the entire contents (2 mL) from the vial. Since the suspension can contain some air 
after shaking, take out all suspension in order to be able to de-aerate the syringe properly (Step 
12).  
9. Keep the syringe with the needle in the upright position and remove vial from the needle, 
10. Record the time withdrawn from the vial.  
11. Remove the needle that was used to withdraw the suspension and discard it appropriately. Attach 
the needle for intramuscular administration to the Luer-Lok connection of the syringe or attach a 
syringe cap (per site’s SOP). Consult with clinic staff regarding the recommended needle for IM 
administration (see suggested supplies). 
12. De-aerate the syringe by first tapping with a finger against the syringe and then by moving the 
plunger rod carefully forward with the needle in upright position until the first drop appears. 
Remove the excess suspension in order to administer the correct volume (2 mL).   
13. Label the syringe appropriately.  
 
After withdrawal of the suspension from the vial into a syringe, it is recommended to administer the 
suspension immediately. If required, the prepared syringe containing RPV LA may remain at room 
temperature for a maximum period of 2 hours between the time the vial was removed from the 
refrigerator and time of administration to the study participant.  The prepared RPV-LA 
syringe must be protected from light (e.g., syringe covered or enclosed within an amber bag) until 
ready to administer.  
Any entered vials or expired filled syringes should be disposed of in accordance with institutional or 
pharmacy policy. 
 
 


 
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Appendix VI:  Guidance for Study Implementation at Sites Experiencing Operational 
Disruptions Due to COVID-19 
 
To safeguard the health and well-being of study participants and study staff in the context of circulating 
SARS-CoV-2 and the associated coronavirus disease 2019 (COVID-19), the guidance provided in this 
appendix may be implemented at sites experiencing disruptions due to COVID-19. 
 
The extent to which site operations may be disrupted by COVID-19 may vary across sites and over time. 
All sites should follow applicable government, health authority, and institutional policies with 
respect to conduct of study visits and procedures, with utmost importance placed on the health and 
well-being of study participants and study staff. All sites must also comply with any directives 
received from the study sponsor, the IMPAACT Network, and/or the IMPAACT 2017 Protocol Team. 
Should a determination be made in the future that the guidance provided in this appendix is no longer 
applicable, sites will be formally notified and instructed to inform their IRBs/ECs and other applicable 
regulatory entities. 
 
Study Products and Background cART Regimens 
• 
For Cohort 1 participants and all LSFU participants: Sites should provide adherence counseling and 
support at each study visit regarding the importance of correctly and consistently taking background 
cART regimens. 
• 
For Cohort 1 Step 1 and Cohort 2 Step 3 participants: Oral study product may be dispensed at the off-
site Week 2 or Week 4a visits in accordance with protocol Section 6.1.3.   
• 
For Cohort 1 Step 2, Cohort 2A Step 4, and Cohort 2B Step 5 participants: Injectable study products 
(CAB LA, RPV LA) must be administered on-site. Sites should carefully assess their ability to utilize 
alternative approaches (as provided below) for monitoring participant safety, in the event of 
disruptions or limitations to conducting on-site visits for non-injection follow-up visits. Sites should 
only consider administering injectable study products if there is adequate assurance that participant 
safety monitoring can be conducted through one of the alternative approaches provided below. In 
addition, injectable study products should only be administered if collection, processing, and storage 
of PK specimens, consistent with the Laboratory Processing Chart (LPC), remains possible for the 
injection visit and for the subsequent non-injection visits.  
- At sites where these conditions can be met, administration of injectable study products may 
continue; the procedures listed in protocol Section 6.9 must be performed before administration. 
- At sites where these conditions cannot be met, Cohort 1 Step 2 participants with study product 
injections remaining should be permanently discontinued from injectable study product and 
followed per the long-term safety and washout PK follow-up (LSFU) visit schedule. The 
IMPAACT 2017 CMC should be consulted for guidance on short-term oral bridging options for 
Cohort 2A Step 4 and Cohort 2B Step 5 participants. 
 
Prioritization of Study Visit Procedures 
• 
Sites with limited capacity to conduct study visits in-person at the study clinic may conduct study 
visits — in full or in part — off-site or remotely (e.g., by telephone or other IRB-approved method) as 
follows:  
- Sites attempting to minimize in-person contact with potential study participants may obtain 
informed consent/assent remotely. Likewise, sites attempting to minimize in-person contact with 
enrolled participants may conduct split study visits with some visit procedures conducted 
remotely, as outlined below, and other visit procedures conducted in-person at the clinical 
research site (or off-site for non-injection follow-up study visits). As noted above, study product 
injections must be administered at the clinical research site and the procedures listed in protocol 
Section 6.9 must be performed before injectable study product administration. 


 
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- The Entry and Week 4b visits (for both Cohort 1 and Cohort 2A) may not be split and must be 
conducted in-person at the clinical research site. 
- See protocol Section 6.1.3 for detailed guidance on conducting off-site (in-person) non-injection 
follow-up visits.  
- Prior to conducting remote study visits or study visit procedures (for a split visit), site staff should 
communicate with participants/parents/guardians as applicable to determine in advance how and 
when such visits will take place, with adequate protections for safety, privacy, and 
confidentiality. Remote visit procedures should be conducted by site staff who are adequately 
qualified and trained to conduct the procedures, as determined by the site Investigator of Record 
(IoR), with attention paid to data chain of custody. These staff should also be adequately qualified 
and trained to immediately assess and/or manage any adverse events or social impacts that may 
occur during the visits. If adverse events requiring further evaluation or management are 
identified during a remote visit, staff conducting the visit should arrange for appropriate clinical 
management, in consultation with the IoR or designee as needed. 
• 
Sites with limited capacity to conduct study visits (whether on-site, off-site or remotely) should 
prioritize the following procedures: 
- Adherence counseling and support for the background cART regimen (for Cohort 1 and LSFU 
participants); this may be done remotely. 
- Clinical procedures; local institutional guidance may be followed for prioritization of clinical 
procedures, guided by participant safety. Medical and medication histories may be obtained 
remotely. Identify/review/update adverse events may also be performed remotely; clinical signs 
or symptoms determined to be Grade 2 or lower may continue to be assessed remotely and per 
protocol Section 8. Adherence assessments may also be performed remotely but only if observed 
by site staff; see the IMPAACT 2017 MOP for further guidance regarding remote observations of 
the adherence assessment.  
- Laboratory procedures (see protocol Section 6.16.1 for specimen prioritization).  
- Provision of study product (injections may only be administered on-site). 
- Contraceptive counseling; this may be done remotely.  
- Acceptability/tolerability questionnaires; these may be administered remotely or skipped/missed. 
• 
For visits at which PK specimen collection is expected per protocol, before any PK specimen is 
collected, sites should verify that they are able to process and store PK samples, as described in the 
LPC.  If this cannot be verified, the samples should not be collected. As noted above, sites that are not 
able to collect, process, and store PK specimens consistent with the LPC should not administer 
injectable study products. 
- For sites with limited capacity to ship PK or genotypic and phenotypic resistance samples to the 
designated testing laboratory, the ability to store the samples locally must be verified prior to 
sample collection.  
• 
If laboratory tests (other than PK testing) cannot be performed consistent with a site’s Protocol 
Analyte List (non-US sites) or at a CAP/CLIA-certified laboratory, the tests may be performed in 
alternate laboratories using alternate assays (alternate laboratories must adhere to local regulations for 
clinical laboratory testing), in consultation with the CMC.  
 
Documentation 
• 
Site-specific COVID-19 contingency plans, and the implementation thereof, should be documented in 
essential document files for IMPAACT 2017.  
• 
Documentation should be entered in participant study charts in real-time (or close to real-time) should 
any of the following occur: 
- Missed visits  
- Off-site visits (document the location of the visit) 
- Incomplete or partial visits (document which procedures were performed, and which were not) 


 
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- Remote contacts performed in lieu of in-person visits (document method used to complete the 
contact and which procedures were performed) 
- Any other participant contacts  
- Use of alternate laboratories or alternate laboratory assays 
• 
In consultation with the Division of AIDS, the IMPAACT Network has developed and disseminated 
guidance for documenting and/or reporting protocol deviations that may occur due to limited site 
capacity to conduct study visits or procedures due to COVID-19. Please contact the IMPAACT 
Operations Center Clinical Research Managers with any questions related to documentation and 
reporting requirements.