Protocol Title

Section 1 Summary

• Addition of compound number for fixed dose combination DTG/3TC
• Change in adolescent weight cut off from 40kg to 25kg.

• Compound numbers for single entities (DTG and 3TC) were included within the original Protocol Title page. Compound number for the DTG/3TC Fixed Dose Combination (FDC) used in this study was added for clarity.
• Current dosing recommendations for 3TC in paediatric patients weighing ≥25kg is 300mg daily and can be taken as 150mg BID or 300mg QD [EPIVIR PI]; Recent pharmacokinetic data from the ODYSSEY study supports use of DTG at the adult dose (50mg) in children weighing ≥25kg.

Medical Monitor/SAE Contact information

• Shifted PPD Medical Monitor and SAE reporting information from footnote to body of table.

• PPD Medical Monitor and Safety Hotline are first line points of contact for sites. Information embedded within table to facilitate reference.

Section 2 Schedule of Activities

• Added Continuation Phase and Continuation Phase assessments every 12 weeks after the Week 144 Visit.
• Added collection of fasting lipids, glucose and HbA1c at the time of withdrawal from the study if the withdrawal visit occurred at weeks 48, 96 or 144.
• Added note stating CSSRS participant level reports should be reviewed, signed by Investigator or Sub-Investigator and files in site source with actions taken for positive findings clearly documented.
• Table was reformatted for clarity. Footnotes were incorporated within each applicable assessment line item. Assessment timepoint markings (‘X’) were reformatted to reflect actual assessment timepoint (such as SC for screening visit, B for baseline visit, etc.).

• A Continuation Phase was added to enable post study drug provision for eligible participants who may benefit from continued treatment.
• Serum lipid and blood glucose levels may increase during antiretroviral therapy. Collection of fasting lipids, glucose and HbA1c at the time of withdrawal from the study at weeks 48, 96 or 144 was added to align with data collection in the adult DOVATO studies (GEMINI-1 and GEMINI-2).
• Investigator review of CSSRS reports, and documentation of the review and any action taken, is important.  A reminder regarding required documentation at the site was added to the table.
• Schedule of Activities table was reformatted to facilitate reference.

Section 3 Introduction

• Added 48-week and 96-week results from GEMINI-1 and GEMINI-2 studies.
• Refenced DOVATO approval

• GEMINI-1 and GEMINI-2 48-week and 96-week study results were incorporated for completeness.  
• Reference to recent DOVATO approvals added for completeness.

Section 3.1 Background

• Added 48-week and 96-week results from GEMINI-1 and GEMINI-2 studies.

• GEMINI-1 and GEMINI-2 48-week and 96-week study results were incorporated for completeness. 

Section 3.3 Benefit:Risk Assessment

• Added DOVATO product label as reference.

• Reference added for completeness.  

Section 3.3.1 Benefit:Risk Assessment- Neural Tube Defect

• Updated risk of neural tube defect to reflect current data (change in rate from 0.9% to 0.3%).  The following update was provided:

In a birth outcome surveillance study in Botswana there have been 5 cases of neural tube defects reported 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.

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.

• Recent data from surveillance study in Botswana added for completeness.

Section 3.3.1 Risk Assessment Section 7.9.2 Prohibited Medications and Non-Drug Therapies

• Addition of fampridine (also known as dalfampridine) to the list of prohibited medications.

• Fampridine (also known as dalfampridine), is a substrate of organic cation transporter 2 (OCT2) with a narrow therapeutic window, similar to dofetilide, that should not be administered concurrently with the DTG containing products due to the potential risk of seizures.

Section 5 Study Design Section 5.3 Participant and Study Completion

• Noted a participant will be considered to have completed the Continuation Phase after completion of the End of Continuation Phase Visit.
• Updated Study Schematic to include Continuation Phase and planned 96-week secondary analysis.

• An End of Continuation Phase Visit will be completed for participants transitioning to approved and locally available supply.
• A planned 96-week secondary analysis was incorporated to assess long-term durability of response and evaluate potential risk of resistance associated substitutions.

Section 5.5 Dose Justification

• Added reference to DOVATO approvals
• Added rationale for modification of weight entry criterion (change from 40 kg to 25kg)

• Reference to recent DOVATO approvals added for completeness.
• Current dosing recommendations for 3TC in paediatric patients weighing ≥25kg is 300mg daily and can be taken as 150mg BID or 300mg QD [EPIVIR PI]; Recent pharmacokinetic data from the ODYSSEY study supports use of DTG at the adult dose (50mg) in children weighing ≥25kg.

Section 6.1 Inclusion Criteria

• Inclusion #2 Change in weight entry criterion from ≥40kg to ≥25kg
• Inclusion #4- Added inclusion of PEP/PrEP dose >6 months from HIV diagnosis or there is documented HIV seronegativity at least 2 months after the last prophylactic dose and prior to the date of HIV diagnosis.

• Inclusion #2: Current dosing recommendations for 3TC in paediatric patients weighing ≥25kg is 300mg daily and can be taken as 150mg BID or 300mg QD [EPIVIR PI]; Recent pharmacokinetic data from the ODYSSEY study supports use of DTG at the adult dose (50mg) in children weighing ≥25kg.
• Inclusion #4- PEP/PrEP guidance added for completeness.

Section 6.2 Exclusion Criteria

• Exclusion #7- Untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening without clear documentation of treatment) is exclusionary. The original criterion required participants complete syphilis treatment at least 14 days prior to screening. The timeframe required for completion of syphilis treatment prior to screening was modified from ‘at least 14 days’ to ‘at least 24 hours’.
• Exclusion #2- Remove WHO Stage 3 exclusion as follows: Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage3 and/or Category C or WHO Stage 3 or 4 disease (Appendix 6, Section 12.6), except cutaneous Kaposi’s sarcoma not requiring systemic therapy and historical or current CD4 cell counts less than 200 cells/mm3 or CD4% <15%.
• Exclusion #21- Addition – exclusion of children who are wards of the state or government.

• Exclusion #7: Patients with active syphilis, untreated or partially treated, may have or develop adverse events as part of their syphilitic disease, which may be confused with a potential IP effect. Thus, completion of syphilis treatment prior to initiation of IP is preferred. Adverse reactions to syphilis treatment, such as Jarisch-Herxheimer reaction, typically occur within 24 hours after completion of treatment [Butler2017; Yang 2010]. The required timeframe for completion of syphilis treatment prior to Day 1 of the study was reduced to at least 24 hours. This change accounts for the timeframe in which adverse reactions may occur, while mitigating risk for delay in assessing eligibility and patient access to study treatment.   
• Exclusion #2: WHO Stage 3 is equivalent to CDC Stage 2, which is not exclusionary.
• Exclusion #21: As per ViiV Healthcare policy, Children who are wards of state (children in care) should not be enrolled in this study.

Section 7.10 Treatment after the End of Study

• Addition of Continuation Phase.
• Addition of End of Continuation Phase Visit

• A Continuation Phase was added to enable post study drug provision for eligible participants who may benefit from continued treatment.
• The purpose of the End of Continuation Phase Visit is to document participant transition to locally approved and available DTG+3TC.

Section 9.6.1.1

Collection of Sparse PK samples – All Participants

• Added footnote reminder -participants are to complete a dosing diary card for 3 days prior to PK sampling Visits.

• Completed Dosing Diary Cards will be collected for Ctrough, sparse and intensive PK visits.

Section 9.6.2

Important Information on collection of PK samples

• Added Sub section 9.6.2.1 for Timing of Sparse PK Samples and Dosing Diary Cards
• Added Sub section 9.6.2.2 and clarification noting dosing diary cards should be collected 3 days prior to scheduled Ctrough, sparse or intensive PK clinic visits.

• Sub heading was added to facilitate reference within the Table of Contents.
• Completed Dosing Diary Cards will be collected for Ctrough, sparse and intensive PK visits.

Section 10.3.1

Efficacy Analyses

• Added details that analyses for Weeks 96 and 144 will be provided in RAP

• For better clarity

Section 10.3.5 Secondary Analyses

• A planned Week 96 secondary analysis was added. At least 3 analyses will be conducted to evaluate the primary and secondary objectives (at Weeks 48,96 and 144). Further data cuts and analyses may be conducted as necessary after Week 144 to support regulatory submissions and publications.
• Timing and triggers for Independent Data Monitoring Committee (IDMC) data looks and meetings were added.

• A planned Week 96 secondary analysis was incorporated to assess long-term durability of response and evaluate potential risk of resistance associated substitutions
• Clarification incorporated to note three planned analyses timepoints and potential for further data cuts and analyses as necessary to support regulatory submissions and publications.
• Timings and triggers for IDMC data looks and meetings were added for completeness and transparency.

Section 11 References

• References updated

• Updated references to align with amendment modifications for completeness.

Section 12.1 (Appendix 1) Abbreviations and Trademark Information

• DOVATO added to ViiV Healthcare group of companies list of trademarks.

• Updated with DOVATO trademark for completeness.

Section 12.11 (Appendix 11) Decision Flow- Screening Tests for Hepatitis B Virus Serology, Interpretation and Action

• A decision flow chart, to assist in the interpretation of hepatitis B virus serology results, was added for reference.

• Added for reference and clarity.

Throughout

• Corrected inconsistencies, links and typos, and updated abbreviations

• To improve quality of the protocol