More Options for Children and Adolescents (MOCHA): Oral and Long-Acting Injectable Cabotegravir and Rilpivirine in HIV-Infected Children and Adolescents

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.

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.

Eligibility Criteria:
Inclusion Criteria: Cohort 1 Step 1, Cohort 2 Step 3, and Cohort 2 Step 5

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:

* At enrollment, body weight greater than or equal to 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.
* For Cohort 1, at enrollment, body mass index (BMI) less than or equal to 31.5 kg/m\^2
* At enrollment, willing and able to comply with the study visit schedule and other study requirements, as determined by the site investigator or designee
* Confirmed HIV-1-infection based on documented testing of two samples collected at different time points. More information on this criterion can be found in the protocol.
* 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.
* Has at least one documented plasma HIV-1 RNA less than the lower limit of detection of the assay from a specimen collected 6 to 12 months (defined as 180 to 365 days) prior to entry. OR

Has at least one documented plasma HIV-1 RNA less than the lower limit of detection of the assay from a specimen collected 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.

* At screening, has Grade 2 or lower of all the following laboratory test results:

  * Alanine transaminase (ALT) (u/l)
  * Lipase (u/l)
  * Estimated creatinine clearance (CrCl; Schwartz formula mL/min/1.73m\^2)
  * Platelets (cells/mm\^3)
  * Hemoglobin (g/dL)
  * AST (u/l)
  * Absolute Neutrophil Count (cells/mm3)
  * See study protocol for guidance on severity grading. Laboratory tests may be repeated during the study screening period, with the latest result used for eligibility determination.
* At screening, is on an atazanavir-containing (ATV) cART regimen, and has total bilirubin less than or equal to 1.5 mg/dL or normal direct bilirubin
* At screening, has documented plasma HIV-1 RNA less than 50 copies/mL
* At screening, mean value of Q-T interval (QTc) interval (automated machine readout or calculated using either Bazett or Fredericia) on ECG performed in triplicate, less than or equal to 500 msec.
* For females, has a negative (blood or urine) human chorionic gonadotropin (hCG) laboratory test result at entry
* 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 study protocol 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.
* For Cohort 1 participants enrolling to Cohort 2, have completed all scheduled product injections and completed Week 16 visit in Cohort 1 Step 2

Exclusion Criteria: Cohort 1 Step 1, Cohort 2 Step 3, or Cohort 2 Step 5

Adolescents will be excluded from the study if any of the following are identified during the screening period:

* 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.
* 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).
* For participants enrolling to Cohort 1 Step 1, based on available medical records, currently on either a cART regimen containing both a protease inhibitor (PI) and an integrase strand transfer inhibitor (INSTI), or a cART regimen containing both an INSTI and a non-nucleoside reverse transcriptase inhibitor (NNRTI).
* As determined by the IoR or designee, and based on available medical records, known or suspected resistance to RPV
* As determined by the IoR or designee based on available medical records, known or suspected resistance to INSTIs
* 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
* At entry, known active tuberculosis infection, requiring anti-tuberculosis treatment, as determined by the IoR or designee based on available medical records
* Known hepatitis B or hepatitis C infection, as determined by the IoR or designee based on available medical records
* Clinically significant hepatic disease, as determined by the IoR or designee based on available medical records
* Current or anticipated need for chronic anti-coagulation, as determined by the IoR or designee, based on available medical records
* History of sensitivity to heparin or heparin-induced thrombocytopenia, as determined by the IoR or designee, based on available medical records
* History of known or suspected bleeding disorder including history of prolonged bleeding, as determined by the IoR or designee, based on available medical records
* Known or suspected allergy to study product components
* 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.
* At entry, participant is receiving (or has received in the last 7 days) any disallowed medication listed in the study protocol.
* Current inflammatory skin condition that compromises the safety of intramuscular injections as determined by the IoR or designee.
* 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
* Surgically-placed, or planned, buttock implants, per self-report
* For females, lactating (per self-report and/or parent/guardian report) at entry
* Enrolled in another clinical trial of an investigational agent, device, or vaccine
* 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

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 the study protocol 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:

* Currently enrolled in Cohort 1, Step 1
* 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/1.73m\^2)
  * Platelets (cells/mm\^3)
  * Hemoglobin (g/dL)
  * AST (u/l)
  * Absolute Neutrophil Count (cells/mm3)
  * Note: For a Grade 2 ALT test result from this visit, refer to the study protocol 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.
* For females, at Cohort 1 Step 1 Week 4b study visit, has a negative hCG laboratory test result
* 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:

  * Has permanently discontinued oral study product
  * Occurrence of any grade 3 or higher adverse event assessed as related to study product during participation in Step 1
  * 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.

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 product. See the study protocol 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:

* Currently enrolled in Cohort 2, Step 3
* 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/1.73m\^2)
  * Platelets (cells/mm\^3)
  * Hemoglobin (g/dL)
  * AST (u/l)
  * Absolute Neutrophil Count (cells/mm3)
  * Note: For a Grade 2 ALT test result from this visit, refer to the study protocol 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.
* For females, at Cohort 2 Step 3 Week 4b study visit, has a negative hCG laboratory test result
* 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:

  * Has permanently discontinued oral study products
  * Occurrence of any grade 3 or higher adverse event assessed as related to study product during participation in Cohort 2, Step 3
  * 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.

Inclusion/Exclusion Criteria: Parents/Caregivers

Selected parents or caregivers of adolescents may be enrolled to complete qualitative phone interviews. See the study protocol 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:

* Selected by the protocol team for participation in the study
* Willing and able to provide informed (verbal or written) consent for study participation
* 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
* 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
* 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:

  * 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.