Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and Antiviral Activity of Dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 Infected Infants, Children and Adolescents
Phase: PHASE1
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Letter of Amendment #1 
Page 1 of 9 
10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
Letter of Amendment #1 for: 
 
IMPAACT P1093 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic Safety, Tolerability and 
Antiviral Activity of Dolutegravir, a Novel Integrase Inhibitor, in Combination 
Regimens in HIV-1 Infected Infants, Children and Adolescents 
 
Version 5.0, dated 12 July 2018 
 
DAIDS Study ID #11773 
IND #110,847 
 
Letter of Amendment Date: 10 June 2020 
 
 
Table of Contents 
 
Information/Instructions to Study Sites from the Division of AIDS ............................................................ 1 
Letter of Amendment Signature Page ........................................................................................................... 2 
Summary of Modifications and Rationale .................................................................................................... 3 
Implementation ............................................................................................................................................. 3 
A. Protocol Team Roster Updates .......................................................................................................... 3 
B. Clarifications and Corrections of Protocol Text from Corrected CM #1, dated 26 September 2018, 
and CM #2, dated 6 January 2019 ..................................................................................................... 4 
C. Operational Guidance from Protocol CM #3, dated 31 March 2020 ................................................ 7 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT P1093 study and 
must be submitted to site Institutional Review Boards and/or Ethics Committees (IRBs/ECs) as soon as 
possible for their review and approval. Approval must also be obtained from other site regulatory entities 
if applicable per the policies and procedures of the regulatory entities. All applicable IRB/EC and 
regulatory entity requirements must be followed. 
 
Upon obtaining all required IRB/EC approvals and any other applicable regulatory entity approvals, each 
site should immediately begin implementing this LoA. Sites are required to submit an LoA registration 
packet to the DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support Center. Sites 
will receive a registration notification for the LoA after the DAIDS PRO verifies that all required 
registration documents have been received and are complete. Sites should not await this notification 
before implementing this LoA.  
 
Please file this LoA, all associated IRB/EC and regulatory entity correspondence, and all correspondence 
with the DAIDS PRO in your essential document files for IMPAACT P1093. If the IMPAACT P1093 
protocol is amended in the future, applicable contents of this LoA will be incorporated into the next 
version of the protocol. 
 
 

Letter of Amendment #1 
Page 2 of 9 
10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
IMPAACT P1093 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic Safety, Tolerability and 
Antiviral Activity of Dolutegravir, a Novel Integrase Inhibitor, in Combination 
Regimens in HIV-1 Infected Infants, Children and Adolescents 
 
DAIDS Study ID #11773 
 
 
Version 5.0, Letter of Amendment #1 
Letter of Amendment Signature Page 
 
 
I will conduct this study in accordance with the provisions of this protocol 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 Council on Harmonization 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) 
 
 

Letter of Amendment #1 
Page 3 of 9 
10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
Summary of Modifications and Rationale 
 
The purpose of this LoA is to update the protocol team roster to reflect current membership and to 
incorporate the contents of previously-issued protocol Clarification Memoranda (CM). 
 
Section A of this LoA includes the protocol team roster updates.  
 
Section B of this LoA includes the corrections and clarifications of protocol text that were included in 
corrected CM #1 (dated 26 September 2018) and CM #2 (dated 6 January 2019).  
 
Section C of this LoA incorporates the contents of CM #3, which was issued on 31 March 2020 to 
safeguard the health and well-being of study participants in the context of circulating SARS-CoV-2 and 
the associated COVID-19 pandemic. CM #3 provided operational flexibility for conducting study visits 
and procedures when needed for participant safety monitoring and to prioritize ongoing access and 
adherence to the study drug regimen. Per the study Sponsor, sites were instructed to implement the 
guidance provided in CM #3 immediately. All sites should continue to follow applicable government, 
health authority, and institutional policies with respect to conduct of study visits and procedures during 
the COVID-19 pandemic, with utmost importance placed on the health and well-being of study 
participants and study staff. Consistent with the instructions provided in CM #3, implementation of 
Section C of this LoA is expected to be time-limited in relation to the COVID-19 pandemic. In 
consultation with IMPAACT Network leadership and the study Sponsor, the IMPAACT P1093 Protocol 
Team will determine when, in the future, the guidance in Section C is no longer applicable. When such a 
determination is made, study sites will be formally notified and instructed to inform IRBs/ECs and other 
applicable regulatory entities. 
 
Implementation 
 
Modifications of protocol text are shown in Sections A and B of this LoA, using strikethrough for 
deletions and bold type for additions where appropriate. Within these sections, modifications are 
generally shown in order of appearance in the protocol. Operational guidance for conducting study visits 
and procedures during the COVID-19 pandemic is provided in Section C of this LoA; conventions for use 
of strikethrough and bolding do not apply in this section. 
 
A. Protocol Team Roster Updates 
 
To reflect current membership, the protocol team roster is updated as follows:  
 
Protocol Statisticians 
Mona Farhad, MS  
Statistical and Data Management Center 
(SDMC)  
Frontier Science Foundation 
1371 Beacon Street, Suite #203 
Brookline, MA 02446, USA  
Phone: 617-632-2000 x4032 
E-mail: mfarhad@sdac.harvard.edu 
 

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10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
Protocol Data Managers 
Mattie Bartlett, MPH 
Frontier Science Foundation  
4033 Maple Road  
Amherst, NY 14226  
Phone: 716-834-0900 x7270  
E-mail: bartlett@frontierscience.org 
 
Yvonne Woolwine-Cunningham 
Frontier Science Foundation  
4033 Maple Road  
Amherst, NY 14226  
Phone: 716-834-0900 x7332 
E-mail: woolwine@frontierscience.org  
 
Laboratory Data Coordinator Manager 
Katelynn Hergott, MPH, MSW  
Kevin Knowles, MA, PhD  
Frontier Science Foundation 
Frontier Science and Technology Research 
Foundation (FSTRF), Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 ext:7238 7212 
E-mail: knowles@frontierscience.org 
hergott@fstrf.org 
 
Protocol Pharmacists 
Shawn Chiambah, PhD, RPh 
Pharmaceutical Affairs Branch, Division of 
AIDS/OCSO/NIAID/NIH 
5601 Fishers Lane 
Room 9A26 MSC 9829 
Rockville, MD 20892-9829 
Phone: 301-761-7336 
E-mail: shawn.chiambah@nih.gov
Laboratory Center Representative 
Dale W. Dayton, RN, BS, CCRA IMPAACT 
Laboratory Center Children’s Hospital Los 
Angeles  
Phone: 301-742-9077  
Email: ddayton@impaactlabcenter.org 
 
Frances Whalen, MPH, MT(ASCP) 
IMPAACT Laboratory Center 
University of California Los Angeles 
11075 Santa Monica Blvd., Suite 200  
Los Angeles, CA 90025  
Phone: 704-422-4055  
E-mail: fwhalen@milabcentral.org 
B. Clarifications and Corrections of Protocol Text from Corrected CM #1, dated 26 September 2018, and 
CM #2, dated 6 January 2019 
 
1. In Sections 2.2, 8.2, and 8.6, the following updates are incorporated to correct inconsistencies in the 
specified timing of safety and tolerability analyses:  
 
Section 2.2, Secondary Objective 5 
To determine the extended long term (≥ > 48 weeks) safety, tolerability and efficacy of DTG in HIV-
1 infected infants, children and adolescents. 
 
Section 8.2.1.1 (section heading) 
Toxicity through Weeks 24 and 48 
 
 

Letter of Amendment #1 
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10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
Section 8.2.3.1 (section heading) 
Toxicity through week 48 and beyond Week 48 
 
Section 8.6.2.1 (section heading) 
Primary Analyses (performed on data through the Week 24 and 48 visits) 
 
Section 8.6.2.2, Key Secondary Analyses, Safety 
Safety assessments will be performed on data collected through Week 48 and long term data. These 
analyses will be similar to the Weeks 24 analyses described in Section 8.6.2.1 above. In addition, 
these analyses will also be performed with participants classified by weight band. 
 
2. In Section 3.1, the following updates are incorporated to clarify screening and enrollment procedures 
for weight-band groups: 
 
• 
Stage 1 Full Cohort and Weight-band Analysis 
 
The study aims to ensure that adequate numbers of participants are enrolled into each of the age-
defined cohorts as well as each of the weight-band groups. To this end, once 10 participants with 
evaluable data are enrolled into a cohort, additional enrollments into that cohort are only 
permitted if a participant will be contributing to achieve the minimum enrollment of 8 evaluable 
in a weight-band group. To ensure continuous enrollment into cohorts during Stage 1, enrollment 
does not close until it has been confirmed that 8 participants with evaluable data have been 
enrolled and completed PK and safety assessments into a weight band. Up to A maximum of an 
additional 2 participants can be enrolled while waiting for determination that the data from 
the minimum of 8 participants in a given weight-band group are evaluable. these results to 
become available. 
 
Participants are enrolled into Stage I weight-band groups based on their weight at 
enrollment. However, if a participant is eligible for a given weight-band group by weight at 
screening but then has a different weight on the day of enrollment that places him/her into a 
different weight-band group, he/she will be allowed to enroll in Stage I, even if the 
minimum accrual targets for that weight-band group have been met. In this case, the 
participant will contribute to the Stage I full cohort and weight-band analysis based on 
weight at enrollment. 
 
3. In Section 6.1.8 and Appendix IG, the following updates are incorporated to clarify the timeline for 
resuming once daily dosing of dolutegravir after discontinuation of rifampin-containing tuberculosis 
treatment: 
 
Section 6.1.8, Management of Participants Co-infected with TB, last bullet, second sentence: 
Approximately two weeks after Upon discontinuation of the rifampin containing anti-TB therapy, 
the participant’s DTG dose will revert back to once daily administration unless on EFV, FPV/r, or 
TPV/r.  
 
Appendix IG, note directly following Schedule of Evaluations, third sentence:  
Approximately two weeks after Upon discontinuation of the rifampin containing anti-TB therapy, 
the participant’s DTG dose will revert back to once daily administration.  
 

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10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
4. In Section 5.2.3, second paragraph and first and second bullets, the following updates are 
incorporated to correct an inconsistency in dispensing procedures for dolutegravir dispersible tablets: 
 
In Stage I and Prior to intensive PK sampling in Stage I, each tablet is to be dispersed using 2 to 5 
mL of water. There are two options for dispensing described below.  
 
• 
Option 1: for older children, pour drinking water into the dosing cup. For 1-2 tablets use 5mL of 
water. For 3-4 tablets use 10mL of water and for 5-6 tablets use 15 of water. For 1-3 tablets use 
5mL of water, for 4-6 tablets use 10mL of water. Add the prescribed number of tablets to the 
water. Swirl the cup gently for 1-2 minutes to fully disperse the tablets. The medicine will be 
cloudy. If any lumps of tablet remain, swirl the cup gently until they are gone. Give Administer 
the prepared dose to the child. Rinse the dosing cup before next use. Pour an additional 5 mL of 
water in the dosing cup, swirl the cup gently for approximately 15 seconds and administer 
the entire volume to the participant. Wash the dosing cup immediately after administration, 
allow to dry and store for the next use. 
 
• 
Option 2: for infants and younger children, prepare medicine in dosing cup as directed in Option 
1. Draw up all the medicine into the syringe. Place the tip of the syringe against the inside of the 
infant’s cheek and administer to give the dose slowly. Swirl Pour an additional a further 2mL 
of water into the dosing cup, draw it into the syringe, and administer the remaining volume 
give it all to the infant. Wash cup and syringe thoroughly. Wash the dosing cup immediately 
after administration, allow to dry and store for the next use 
 
After intensive PK sampling in Stage I and in Stage II each tablet can continue to be dispersed as 
described above or each tablet can be placed directly on the tongue and directly swallowed. 
Dispersible tablets may be given as multiples (up to a maximum of 6 tablets), depending on the 
weight of the child. Once dispersed, the medication should be consumed from administered 
using the supplied dosing cup or syringe, as soon as possible, preferably within 5 five minutes 
but no longer than 30 minutes after preparation.  
 
5. In Appendices IA, IB, IC, ID, and IG, footnote for chemistries, the following updates are incorporated 
to clarifies guidelines for establishing a laboratory normal value for indirect bilirubin: 
 
Electrolytes (sodium, potassium, and HCO3), glucose, creatinine, lipase, phosphorus, and LFTs. 
LFTs should include total bilirubin, indirect bilirubin, direct bilirubin, alkaline phosphatase, AST, 
ALT, and albumin. If indirect bilirubin is not reported by the site laboratory, it should be calculated at 
the site and documented. The following formula can be utilized: indirect bilirubin = total 
bilirubin – direct (or “conjugated”) bilirubin. 
 
The following (listed in order of preference) should be used to determine the upper limit of normal 
(ULN) values for indirect bilirubin.  
a. "ULN" values reported by the laboratory report for the test, or  
b. “ULN" values routinely used/established by the site or 
c. ‘ULN” values as per the most current Harriet Lane Handbook (e.g. the current "ULN" for 
indirect bilirubin as per Harriet Lane Handbook is 0.4) (In the 2018 version of the Harriet Lane 
Handbook, for a full term infant, the ULN for total bilirubin is 1.2 mg/dL (21µmol/L) and 
for direct bilirubin is 0.2 mg/dL (3.4 µmol/L); thus the ULN for indirect bilirubin would be 
1.0 mg/dL (17.6 µmol/L)). 
 

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10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
C. Operational Guidance from Protocol CM #3, dated 31 March 2020 
 
This CM provides operational guidance to study sites from the IMPAACT P1093 Protocol Team. The 
Protocol Team acknowledges that the extent to which site operations may be disrupted by the COVID-
19 pandemic 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. 
Site investigators should continue to follow current protocol specifications for communication with the 
Protocol Team and should contact the team (impaact.teamp1093@fstrf.org) with any questions or 
concerns regarding this CM or management of study participants. 
 
Visit Scheduling 
• 
Sites that anticipate operational disruptions or closures in the near future are advised to conduct study 
visits early in the allowable visit window. Visits conducted prior to opening of the allowable window 
would also be preferred to completely missing a visit. 
• 
Sites that are currently experiencing operational disruptions or closures are advised to conduct 
study visits late in the allowable visit window. Visits conducted after closing of the allowable 
window would also be preferred to completely missing a visit. 
• 
Effective with the issuance of this CM, allowable windows are broadened as follows: 
 
Appendices IA, IB, IC and ID (All Cohorts, Stage I and Stage II) 
- 
Weeks 4, 8, 12 and 16 Visits: ±2 weeks 
- 
Week 24 Visit -6 to +4 weeks 
- 
Weeks 32 and 40 Visits: ±4 weeks 
- 
Week 48 Visit -4 to +6 weeks 
 
Appendix IE (Long-Term Follow-up) 
- 
Week 60 through Week 180 ±6 weeks 
- 
Week 192 Visit -6 to +12 weeks 
 
Appendix IF (Premature Discontinuation of Dolutegravir) 
- 
Week 4 Follow-Up Visit: -2 to +4 weeks 
- 
Every three months until resolved (if applicable): ±6 weeks 
 
Appendix IG (Participants who Start Rifampin) 
- Week 2 Visit ±2 weeks 
- Week 4 Visit -2 to +4 weeks 
- Week 12 and Every 8 weeks until end of rifampin therapy Visits: ±4 weeks 
 
Prioritization of Study Visit Procedures 
• 
Sites with full capacity to conduct study visits in-person at the study clinic should continue to do so 
in full compliance with the protocol. 
• 
Sites may also conduct study visits — in full or in part — off-site if permitted by applicable 
government, health authority, and institutional policies. Where this option is permitted, site 
staff should communicate with the parent/legal guardians to determine in advance where and 
when such visits will take place, with adequate protections for safety, privacy, and 
confidentiality. Off-site 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 occupational health, biohazard 
containment, and specimen and data chain of custody. These staff should also be adequately 
qualified and trained to immediately assess and/or manage any adverse events or social 

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IMPAACT P1093 Protocol Version 5.0 
impacts that may occur during the visits. If adverse events requiring further evaluation or 
management are identified during an off-site 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 in-person scheduled study visits should prioritize 
monitoring for adverse events and provision of study drug. With respect to specimen testing and 
storage, sites should follow the priority listing in the relevant Schedules of Evaluations. At sites 
where specimen collection and processing can be performed per the Laboratory Processing Chart, 
but HIV-1 RNA testing cannot be performed in real time, sites may collect, process, and store 
specimens for later testing (alternate laboratories must adhere to local regulations for clinical 
laboratory testing). 
• 
Sites with no capacity to conduct in-person visits, either on-site or off-site, should consider whether 
any study procedures (e.g., history taking, adherence assessment) can be performed remotely (e.g., 
by telephone). If adverse events requiring further evaluation or management are identified during a 
remote contact, staff conducting the contact should arrange for appropriate clinical management, in 
consultation with the IoR or designee as needed. 
 
Study Drug Supply 
• 
To avoid gaps in drug supply between visits, sites may dispense up to three months’ supply of study 
drug, ensuring safety monitoring and addressing potential needs for dose modification due to weight 
gain. Further considerations are as follows: 
- 
Participants who have been dispensed an extra supply of study drug should still come for 
their scheduled visits, if possible. 
- 
If a participant is expected to grow into a higher weight band requiring a dose increase soon, 
sites should ensure accurate contact information with the family; if an in-person visit is not 
possible, study drug dose modifications may be implemented with dosing instructions provided 
to the participant’s caregiver by telephone based on weight reported by the caregiver. Any such 
instruction should be source documented in the participant’s study chart. 
- 
Sites should also make every effort to ensure adequate supplies of the other antiretroviral 
agents that comprise participants’ optimized background treatment regimens. 
• 
Where feasible, sites are encouraged to implement study drug delivery options involving outdoor 
pick- up or drop-off. Where outdoor pick-up or drop-off is not feasible, the Pharmacy Guidelines 
and Instructions for DAIDS Clinical Trials Networks permit shipment or courier of study drug from 
the site directly to participants. This method should only be used in the short-term and if permissible 
per local institutional and IRB/EC policies. Refer to the Guidelines for additional details on this 
method. 
• 
Sites are encouraged to provide adherence assessment, counseling, and support remotely (e.g., 
by telephone). 
 
Documentation 
• 
Site-specific contingency plans, and the implementation thereof, should be documented in 
essential document files for IMPAACT P1093. 
• 
Documentation should be entered in participant study charts in real-time should any of the 
following occur: 
- Missed visits 
- Out-of-window 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 

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IMPAACT P1093 Protocol Version 5.0 
- Use of alternate laboratories or alternate laboratory assays 
- Alternate provision of study drug 
- Dose modifications implemented remotely 
• 
In consultation with the Division of AIDS, the IMPAACT Network is developing comprehensive 
guidance for documenting and/or reporting protocol deviations that may occur due to limited site 
capacity to conduct study visits or procedures during the COVID-19 pandemic. Similar guidance 
will be provided for documentation of use of alternate laboratories or alternate laboratory assays. 
Once this Network-level guidance is available, it will be provided in a separate communication to 
all sites.