Conditions: HIV-1 Infection
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 122
Healthy volunteers: no

Brief summary:
This study was done to see if the combination of two anti-HIV medicines, dolutegravir (DTG, Tivicay) and lamivudine (3TC, Epivir) taken once a day, provide a safe, effective, and well-tolerated treatment for HIV. DTG is a type of HIV medicine called an integrase inhibitor; 3TC is a type of HIV medicine called a reverse transcriptase inhibitor. DTG works by blocking integrase and 3TC works by blocking reverse transcriptase, two HIV proteins (enzymes). This prevents HIV from multiplying and lowers the viral load (amount of HIV in the blood). Both DTG and 3TC are currently part of Food and Drug Administration (FDA) recommended regimens along with a third active drug. Since some HIV medicines have side effects and are costly, there is interest in whether HIV can be successfully controlled with fewer than three HIV drugs.

Detailed description:
This study was a phase II, single-arm, open-label pilot study designed to estimate the efficacy of dolutegravir (DTG) plus lamivudine (3TC) as initial combination ART (antiretroviral therapy) in HIV-1 infected treatment naive participants. The target enrollment was 120 participants with a cap of N=90 participants with screening HIV-1 RNA \<= 100,000 copies/mL. The study aimed to enroll \>= 20% women. The expected follow-up for each participant was 52 weeks.

Visits occurred at screening, entry, and weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 from study entry. All signs/symptoms within 30 days prior to entry were recorded. Subsequently, grade 2 or higher rash and all other grade 3 or higher signs and symptoms were recorded. All participants underwent routine monitoring including plasma HIV-1 RNA levels, CD4+ cell count, hematology, chemistry, urinalysis, and pregnancy testing (for women of reproductive potential).

Population-based protease (PR), reverse transcriptase (RT) and integrase genotyping were done at the time of confirmed virologic failure. Plasma samples were stored for potential future studies to assess the impact of adherence, drug-resistant minority viral variants, and DTG exposure on virologic and CD4+ cell count responses to DTG plus 3TC. All participants also underwent UGT1A1 genotyping.

Arms:
arm 1: Dolutegravir 50mg and Lamivudine 300mg, orally daily

Interventions: intervention 1: Dolutegravir intervention 2: Lamivudine
Intervention descriptions: intervention 1: Participants were prescribed 50 mg of DTG orally daily intervention 2: Participants were prescribed 300 mg of 3TC orally daily.

Protocol document:
Prot_001.pdf: 
A5353 
A Study to Evaluate Dolutegravir plus Lamivudine Dual 
Therapy for the Treatment of Naïve HIV-1-infected 
Participants 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 12057 
This file contains the current ACTG A5353 protocol, which 
includes the following documents, presented in reverse 
chronological order:  
• Clarification Memorandum #2, dated 28 January 2016
• Clarification Memorandum #1, dated 12 January 2016
• Protocol Version 1.0, dated 14 August 2015


  Page 1 of 2 
26 January 2016 
Clarification Memorandum #2 
ACTG A5353 Protocol Version 1.0 
Clarification Memorandum #2 for: 
ACTG A5353 
A Study to Evaluate Dolutegravir plus Lamivudine Dual Therapy for the Treatment 
of Naïve HIV-1-infected Participants 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 12057 
Clarification Memo Date: 28 January 2016 
This clarification memo does not result in a change in the protocol informed consent 
document. The Division of AIDS does not require you to forward it to your IRB/EC; 
however, as always, you must follow your IRB's/EC’s policies and procedures. If IRB/EC 
review of clarification memos is required at your site, please submit this document for 
review. 
Each site should file a copy of this clarification memo with the protocol for reference. 
The protocol clarifications contained in this memo should be implemented immediately. 
These updates will be included in the next version of the A5353 protocol if it is amended 
at a future date. 
The purpose of this memo is to clarify that integrase genotyping at screening does not have to 
be repeated if previously performed as part of clinical care. 
The following are clarifications to protocol A5353, Version 1.0, dated 08/14/16: 
 4.1.4    No evidence of any RT, any integrase, or major protease resistance mutation 
(according to the 2014 IAS-USA drug resistance mutations list, available at 
https://www.iasusa.org/sites/default/files/tam/22-3-642.pdf) based on pre-ARV 
treatment genotype performed any time prior to study entry.  
 NOTE: Integrase genotyping must be performed at screening and will be 
provided by the study, if not previously performed as part of clinical care. RT 
and PR genotyping must be performed at screening as part of routine clinical 
care if not previously performed. 
6.3.7   Virologic Studies 
HIV Genotype 
Genotypic resistance testing may be performed any time prior to study entry and 
results must be available prior to study entry. For the screening genotype, 
previous results verifiable by reports from a local CLIA-certified laboratory are 
acceptable as long as the results are available at entry. In the unlikely event that 


Clarification Memorandum #2 
  Page 2 of 2 
26 January 2016 
ACTG A5353 Protocol Version 1.0 
the candidate has more than one prior genotype, consult with the protocol team 
before screening. 
Integrase genotyping must be performed at screening and will be provided by the 
study through Quest Diagnostics-Baltimore, if not previously performed as 
part of clinical care. since screening for integrase resistance before ART 
initiation is not standard of care.  
NOTE: Plasma samples should be stored at screening per instructions in 
the Laboratory Processing Chart, regardless if integrase genotyping is 
performed.    
RT and PR genotyping should be performed at screening as part of routine 
clinical care if not previously performed. 
When a participant is suspected to have virologic failure or has HIV-1 RNA of 50-
200 copies/mL at weeks 24 or 48, a plasma sample for real-time genotyping will 
be collected 7 to 28 days from the initial sample. The specimen collected for 
genotyping at this visit will be sent as per the instructions in the LPC for 
resistance testing if virologic failure is confirmed. Real-time results will be shared 
with sites.  


Clarification Memorandum #1 
  Page 1 of 3 
12 January 2016 
ACTG A5353 Protocol Version 1.0 
Clarification Memorandum #1 for: 
ACTG A5353 
A Study to Evaluate Dolutegravir plus Lamivudine Dual Therapy for the Treatment 
of Naïve HIV-1-infected Participants 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 12057 
Clarification Memo Date: 12 January 2016 
This clarification memo does not result in a change in the protocol informed consent 
document. The Division of AIDS does not require you to forward it to your IRB/EC; 
however, as always, you must follow your IRB's/EC’s policies and procedures. If IRB/EC 
review of clarification memos is required at your site, please submit this document for 
review. 
Each site should file a copy of this clarification memo with the protocol for reference. 
The protocol clarification contained in this memo should be implemented immediately.  This 
update will be included in the next version of the A5353 protocol. 
The main purpose of this memo is to clarify that in section 6.1, Schedule of Events, footnote #3, 
plasma HIV RNA, HIV genotype, stored plasma for minority viral variants, and stored plasma for 
random DTG levels, are required only if virologic failure is suspected or HIV RNA is ≥ (greater 
than or equal to) 50 copies/mL at week 48 visit.   


Clarification Memorandum #1 
 Page 2 of 3 
12 January 2016 
ACTG A5353 Protocol Version 1.0 
6.1 Schedule of Events 
Evaluation 
Pre-Treatment 
Entry (Day 0) 
On-Treatment Evaluations 
Visit To 
Confirm 
HIV-1 RNA 
Premature 
Treatment 
Discontinuation 
and 
Premature Study 
Discontinuation 
Evaluations 
Day/Week 
Screening 
(-45 Days) 
Week 2 
Week 4 
Week  8 
Week  12 
Week 16 
Week  20 
Week 24 
Week 32 
Week 40 
Week 48 
Week 52 
Visit Window 
± 3 
Days 
± 7 Days 
± 14 Days 
7-28 Days 
After Initial 
Sample 
Documentation of 
HIV 
X 
Medical/ Medication 
History 
X 
X 
Complete Physical 
Exam 
X 
Targeted Physical 
Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistries 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Creatinine 
Clearance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting Lipids 
X 
X 
Hepatitis B Surface 
Antigen 
X 
Hepatitis C 
Antibody1 
X 
Urinalysis 
X 
X 
X 
Pregnancy Test 
X 
X 
Whenever pregnancy suspected 
CD4+ Cell Count 
X 
X 
X 
X 
X 
X 


Clarification Memorandum #1 
Page 3 of 3 
12 January 2016 
ACTG A5353 Protocol Version 1.0 
Evaluation 
Pre-Treatment 
Entry (Day 0) 
On-Treatment Evaluations 
Visit To 
Confirm 
HIV-1 RNA 
Premature 
Treatment 
Discontinuation 
and 
Premature Study 
Discontinuation 
Evaluations 
Day/Week 
Screening 
(-45 Days) 
Week 2 
Week 4 
Week  8 
Week  12 
Week 16 
Week  20 
Week 24 
Week 32 
Week 40 
Week 48 
Week 52 
Visit Window 
± 3 
Days 
± 7 Days 
± 14 Days 
7-28 Days 
After Initial 
Sample 
Plasma HIV-1 RNA 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
HIV Genotype 
X 
X3 
X 
Stored Plasma for 
Minority Viral 
Variants 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
Stored Plasma for 
Random DTG 
Levels 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
Stored Blood for 
Pharmacogenomics 
X 
Phone Call 
Reminder 
Weeks 1 (± 3 days) , 6 and 10  (±7 days) and whenever non-adherence is suspected 
Adherence 
Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study 
Drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. Required only in participants with no prior positive hepatitis C antibody.
2. Screening HIV RNA within 90 days of entry.
3. Required only if virologic failure is suspected or HIV RNA is ≥ (greater than or equal to) 50 copies/mL at week 48 visit. These evaluations are identical to the Visit to
Confirm HIV-1 RNA. 


A5353 
A Study to Evaluate Dolutegravir plus Lamivudine Dual Therapy for the Treatment 
of Naïve HIV-1-infected Participants 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
Sponsored by: 
The National Institute of Allergy 
and Infectious Diseases 
Industry Support Provided by: 
ViiV Healthcare Ltd. 
IND # or non-IND Protocol 
The Antiretroviral Therapy Strategies (ARTS) 
Subcommittee of the Inflammation  
Transformative Science Group:  
 
Babafemi Taiwo, MBBS, Chair 
Protocol Co-Chairs: 
Roy Gulick, MD, MPH  
Babafemi Taiwo, MBBS 
DAIDS Clinical Representative: 
Catherine Godfrey, MD 
Clinical Trials Specialist: 
Elizabeth Hawkins, MA 
FINAL Version 1.0 
August 14, 2015 


A5353 
 
 
FINAL Version 1.0 
 
 
08/14/15  
 
 
 
 
 
CONTENTS 
 
 
Page 
SITES PARTICIPATING IN THE STUDY .................................................................................... 4 
PROTOCOL TEAM ROSTER ..................................................................................................... 5 
STUDY MANAGEMENT ............................................................................................................. 8 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 10 
SCHEMA .................................................................................................................................. 11 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 12 
1.1 
Hypothesis ......................................................................................................... 12 
1.2 
Primary Objective ............................................................................................... 12 
1.3 
Secondary Objectives ........................................................................................ 12 
2.0 
INTRODUCTION ........................................................................................................... 12 
2.1 
Background ........................................................................................................ 12 
2.2 
Rationale ........................................................................................................... 14 
3.0 
STUDY DESIGN ........................................................................................................... 17 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 18 
4.1 
Inclusion Criteria ................................................................................................ 18 
4.2 
Exclusion Criteria ............................................................................................... 20 
4.3 
Study Enrollment Procedures............................................................................. 20 
4.4 
Coenrollment Guidelines .................................................................................... 22 
5.0 
STUDY TREATMENT ................................................................................................... 22 
5.1 
Regimens, Administration, and Duration ............................................................ 22 
5.2 
Study Product Formulation and Preparation ....................................................... 23 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 23 
5.4 
Concomitant Medications ................................................................................... 23 
5.5 
Adherence Assessment ..................................................................................... 24 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 25 
6.1 
Schedule of Events ............................................................................................ 25 
6.2 
Timing of Evaluations ......................................................................................... 27 
6.3 
Instructions for Evaluations ................................................................................ 28 
7.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 34 
7.1 
Toxicity Management ......................................................................................... 34 
7.2 
Rash .................................................................................................................. 35 
7.3 
Nausea/Vomiting................................................................................................ 36 
7.4 
AST/ALT Elevations ........................................................................................... 36 
7.5 
Calculated Creatinine Clearance (CrCl) ............................................................. 37 
7.6 
Allergic Reaction ................................................................................................ 37 
7.7 
Suicidal Ideation ................................................................................................ 37 
7.8 
Pregnancy.......................................................................................................... 38 


A5353 
 
 
FINAL Version 1.0 
 
 
08/14/15 
 
CONTENTS (Cont’d) 
Page 
 
8.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 38 
8.1 
Permanent Study Treatment Discontinuation ..................................................... 38 
8.2 
Premature Study Discontinuation ....................................................................... 38 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 39 
9.1 
General Design Issues ....................................................................................... 39 
9.2 
Outcome Measures ............................................................................................ 39 
9.3 
Randomization and Stratification ........................................................................ 40 
9.4 
Sample Size and Accrual ................................................................................... 40 
9.5 
Monitoring .......................................................................................................... 41 
9.6 
Analyses ............................................................................................................ 42 
10.0 
PHARMACOLOGY PLAN .............................................................................................. 43 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 43 
11.1 
Records to Be Kept ............................................................................................ 43 
11.2 
Role of Data Management ................................................................................. 43 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 44 
11.4 
Expedited Adverse Event Reporting to DAIDS ................................................... 44 
12.0 
PARTICIPANTS ............................................................................................................ 45 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 45 
12.2 
Participant Confidentiality ................................................................................... 46 
12.3 
Study Discontinuation ........................................................................................ 46 
13.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 46 
14.0 
BIOHAZARD CONTAINMENT ...................................................................................... 46 
15.0 
REFERENCES .............................................................................................................. 47 
 
APPENDIX I:  SAMPLE INFORMED CONSENT 
 


 
4 
A5353 
 
 
FINAL Version 1.0 
 
 
08/14/15 
 
SITES PARTICIPATING IN THE STUDY 
 
A5353 is open to all U.S. AIDS Clinical Trials Group (ACTG) clinical research sites (CRSs). 
 
 
 
 
 
 


 
5 
A5353 
 
 
FINAL Version 1.0 
 
 
08/14/15 
 
PROTOCOL TEAM ROSTER 
 
Co-Chairs 
Roy Gulick, MD, MPH  
Division of Infectious Diseases 
Weill Cornell Medical College Box 125 
1300 York Avenue 
New York, NY 10065 
Phone: 212-746-6320 
Fax: 212-746-8675 
Email: rgulick@med.cornell.edu 
 
Babafemi Taiwo, MBBS 
Division of Infectious Diseases 
Northwestern University CRS 
Feinberg School of Medicine 
645 N. Michigan Avenue, Suite 900 
Chicago, IL 60611 
Phone: 312-695-4994 
Fax: 312-695-5088 
Email: b-taiwo@northwestern.edu 
 
DAIDS Clinical Representative  
Catherine Godfrey, MD  
HIV Research Branch  
TRP, DAIDS, NIAID, NIH  
5601 Fishers Lane, Room 9E49 
Rockville, MD 20852 
Phone: 240-627-3074 
Fax: 301-432-9282 
Email: cgodfrey@niaid.nih.gov 
 
Clinical Trials Specialist 
Elizabeth Hawkins, MA  
ACTG Network Coordinating Center  
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3335 
Fax: 301-628-3309 
Email: ehawkins@s-3.com 
 
Statistician 
Lu (Summer) Zheng, PhD 
Statistical and Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 613 
651 Huntington Avenue 
Boston, MA 02115-6017 
Phone: 617-432-3021 
Fax: 617-432-2843 
Email: szheng@sdac.harvard.edu 
 
Data Manager 
Melissa Mineo, MLS 
Frontier Science and Technology  
Research Foundation 
4033 Maple Road 
Amherst NY 14226 
Phone: 716-834-0900 x7294  
Fax: 716-834-8432 
Email: mineo@fstrf.org 
 
DAIDS Pharmacist 
Oladapo Alli, PharmD 
Pharmaceutical Affairs Branch 
DAIDSOCSO/NIAID/NIH 
5601 Fishers Lane 
Room 9E16 MSC #9832 
Rockville, MD 20892 
Phone: 240-627-3593  
Fax: 240-627-3112 
Email: oladapo.alli@nih.gov  
 
Virologist  
Carole Wallis, Msc (MED), PhD 
BARC-SA/Lancet Laboratories 
11 Napier Road 
Richmond 
Johannesburg, Gauteng 
SOUTH AFRICA 
Phone: 27-11-358-0816 
Email: carole.wallis@lancet.co.za 
 


6 
A5353 
FINAL Version 1.0 
PROTOCOL TEAM ROSTER (Cont'd) 
08/14/15 
Investigators 
David Haas, MD 
Vanderbilt Therapeutics CRS 
Vanderbilt Health-One Hundred Oaks 
719 Thompson Lane, Suite 47183 
Nashville, TN 37204 
Phone: 615-936-8594 
Fax: 615-936-2644 
Email: david.haas@vanderbilt.edu 
Johnstone Kumwenda, FRCP 
College of Medicine-Johns Hopkins Project 
Chipatala Avenue 
P.O. Box 1131 
Blantyre 
MALAWI 
Phone: 265-1870132, ext 307 
Phone: 264-816454347 
Email: jkumwenda@jhu.medcol.mw  
Amesika Nyaku, MD 
Division of Infectious Diseases 
Northwestern University 
Feinberg School of Medicine 
645 N Michigan Ave, Suite 900 
Chicago, IL 60611 
Phone: 312-695-2490 
Fax: 312-695-5088 
Email: a-nyaku@northwestern.edu 
Paul Sax, MD  
Brigham and Women's Hospital, PBBA4 
75 Francis Street 
Boston, MA 02115 
Phone: 617-732-8881 
Fax: 617-732-6829 
Email: psax@partners.org 
Field Representatives 
Baiba Berzins, MPH  
Division of Infectious Diseases 
Northwestern University 
645 North Michigan Avenue, Suite 900 
Chicago, IL 60611 
Phone: 312-695-5012 
Fax: 312-695-5088 
Email: baiba@northwestern.edu 
Field Representatives (cont’d) 
Tanisha Sullivan, BA 
Infectious Disease/Dept of Medicine 
The Ponce de Leon Center CRS 
341 Ponce de Leon, Suite 331 
Atlanta, GA 30308 
Phone: 404-251-8942 
Email: tjorsli@emory.edu 
Laboratory Technologist 
Gerald Tegha, BSc, MSc 
Malawi CRS, UNC Project 
P.O. Box A-104 
100 Mzimba Road 
Kamzu Central Hospital 
Lilongwe 00000 
MALAWI 
Phone:  265 1 750 610  
Fax: 265-1755954 
Email: gtegha@unclilongwe.org 
Community Scientific Subcommittee (CSS) 
Representative 
Angel L. Hernandez, BA 
Puerto Rico-AIDS CRS 
Barrio Saltos 
Road 566 Int Road 593, KM 0.2 
Orocovis PR 00720 
Puerto Rico 
Phone: 787-919-6145 
Email: angelhdz2863@gmail.com  
Industry Representatives  
Belinda Ha, PhD 
GlaxoSmithKline 
5 Moore Drive 
Research Triangle Park, NC 27709 
Phone: 919-483-8284  
Fax: 919-483-8999  
Email: belinda.f.ha@gsk.com 


7 
A5353 
FINAL Version 1.0 
PROTOCOL TEAM ROSTER (Cont'd) 
08/14/15 
Industry Representatives (cont’d) 
Kimberly Y. Smith, MD, MPH 
ViiV Healthcare Ltd. 
Five Moore Drive 
P.O. Box 13398 
Durham, NC 27709 
Phone: 919-491-2167 
Email: kimberly.y.smith@viivhealthcare.com 
Laboratory Data Manager 
Adam Manzella, MA 
Frontier Science and Technology 
Research Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x7418 
Fax: 716-833-0655 
Email: manzella@fstrf.org 


 
8 
A5353 
 
 
FINAL Version 1.0 
 
 
08/14/15 
 
STUDY MANAGEMENT 
 
All questions concerning this protocol should be sent to actg.teama5353@fstrf.org. The 
appropriate team member will respond with a "cc" to actg.teamA5353@fstrf.org. A response 
should generally be received within 24 hours (Monday-Friday). 
 
Protocol Email Group 
Sites should contact the Computer Support Group at the Data Management Center (DMC) as 
soon as possible to have the relevant personnel at the site added to the actg.protA5353 email 
group. Include the protocol number in the email participant line.  
• 
Send an email message to actg.user.support@fstrf.org  
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact the protocol team. 
• 
Send an email message to actg.teama5353@fstrf.org. Include the protocol number, 
participant identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to virology laboratory tests, contact the protocol virologist or 
laboratory technologist.  
• 
Send an email message to actg.teama5353@fstrf.org (ATTN: Carole Wallis). 
 
Data Management 
For nonclinical questions about transfers, inclusion/exclusion criteria, case report forms (CRF), 
the CRF schedule of events, randomization/registration, delinquencies, and other data 
management issues, contact the data manager. CRFs can be downloaded from the FSTRF 
website at www.fstrf.org. 
• 
For transfers, reference the Participant Transfer from Site to Site SOP 119, and contact 
[Melissa Mineo] directly.  
• 
For other questions, send an email message to actg.teama5353@fstrf.org (ATTN: Melissa 
Mineo).  
• 
Include the protocol number, PID, and a detailed question. 
 
Participant Registration  
For participant registration questions or problems and study identification number SID lists.  
• 
Send an email message to rando.support@fstrf.org or call the Statistical and Data Analysis 
Center (SDAC)/DMC Randomization Desk at 716-834-0900, extension 7301.  
 
Computer and Screen Problems  
Contact the SDAC/DMC programmers. 
• 
Send an email message to actg.support@fstrf.org  or call 716-834-0900, extension 7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the clinical trials specialist.  
• 
Send an email message to actg.teama5353@fstrf.org (ATTN: Elizabeth Hawkins). 
 


 
9 
A5353 
 
 
FINAL Version 1.0 
 
STUDY MANAGEMENT (Cont'd) 
08/14/15 
 
 
Copies of the Protocol 
To request a hard copy of the protocol, send a message to ACTGNCC@s-3.com (ATTN: Diane 
Delgado) via email. Electronic copies can be downloaded from the ACTG Web site 
(https://www.actgnetwork.org). 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an email message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation, contact the clinical trials specialist (Elizabeth 
Hawkins, ehawkins@s-3.com) or ACTG Site Coordination group at actgsitecoordination@s-
3.com.  
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, 
contact the DAIDS pharmacist (Oladapo Alli at 240-627-3593).  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
The IND number will be available on the PSWP within 30 days of the submission to the FDA. 
For any questions related to the IND submission, contact the DAIDS RSC at Regulatory@tech-
res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Phone Calls 
Sites are responsible for documenting any phone calls made to A5353 team members. 
Send an email to actg.teama5353@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 


 
10 
A5353 
 
 
FINAL Version 1.0 
 
 
08/14/15 
 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
 
3TC 
 
 
Lamivudine, Epivir 
ATV  
 
 
Atazanavir 
BID 
 
 
Twice a day 
CrCl   
 
Calculated creatinine clearance 
DRV/r   
 
Darunavir/ritonavir  
DTG 
 
 
Dolutegravir, Tivicay  
E/CIA   
 
Chemiluminescence immunoassay 
EFV 
 
 
Efavirenz  
FTC 
 
 
Emtricitabine 
G-CSF  
 
Granulocyte colony-stimulating factor 
IAS 
 
 
International Antiviral Society 
INSTI   
 
Integrase strand transfer inhibitor 
LPV/r   
 
Lopinavir/ritonavir 
MVC  
 
Maraviroc 
 
 
 
NNRTI  
 
Non-nucleoside reverse transcriptase inhibitor 
NRTI  
 
Nucleos(t)ide reverse transcriptase inhibitor 
PR 
 
 
Protease 
PrEP  
 
Pre-exposure prophylaxis 
PEP 
 
 
Post-exposure prophylaxis 
QD 
 
 
Once a day 
RAL 
 
 
Raltegravir 
RT 
 
 
Reverse transcriptase 
TAF 
 
 
Tenofovir alafenamide 
TB 
 
 
Tuberculosis 
TDF 
 
 
Tenofovir disoproxil fumarate 
TDF/FTC  
 
Tenofovir/emtricitabine 
UDP 
 
 
Uridine diphosphate 
UGT 
 
 
Uridine glucuronosyltransferases  
VF 
 
 
Virologic failure 
ZDV 
 
 
Zidovudine  


 
11 
A5353 
 
 
FINAL Version 1.0 
 
 
08/14/15 
 
SCHEMA 
 
A5353 
 
A Study to Evaluate Dolutegravir plus Lamivudine Dual Therapy for the Treatment of Naïve HIV-
1-infected Participants 
 
 
DESIGN 
This is a phase II, single-arm, open-label, pilot study of dolutegravir 
(DTG) plus lamivudine (3TC).  
 
All participants will undergo routine monitoring including plasma HIV-1 
RNA levels, CD4+ cell count, hematology, chemistry, and urinalysis.  
 
Population-based protease (PR), reverse transcriptase (RT) and 
integrase genotyping will be done at the time of confirmed virologic 
failure. Plasma samples will be stored for potential future studies to 
assess the impact of adherence, drug-resistant minority viral variants, and 
DTG exposure on virologic and CD4+ cell count responses to DTG plus 
3TC. All participants will also undergo UGT1A1 genotyping. 
 
 
DURATION 
52 weeks 
 
 
SAMPLE SIZE 
120 participants 
 
 
POPULATION 
HIV-1 infected, antiretroviral (ARV) naïve men and women, 18 years and 
older, with plasma HIV-1 RNA ≥1,000 copies/mL and <500,000 
copies/mL, and with no evidence of a major PR mutation, any RT or any 
integrase mutations as defined by the 2014 International Antiviral Society 
(IAS)-USA drug resistance mutations list. At least 25% (N=30) of the 
participants will have screening HIV-1 RNA >100,000 copies/mL. The 
study will aim to enroll ≥20% women.  
 
 
REGIMEN  
DTG 50 mg once a day (QD) plus 3TC 300 mg QD for 52 weeks 
 
 
 
 
 


 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
In treatment-naive participants, dual therapy with DTG plus 3TC is efficacious and well 
tolerated. 
 
1.2 
Primary Objective 
 
To estimate the virologic success rate at week 24 after initiating DTG plus 3TC.  
 
1.3 
Secondary Objectives 
 
1.3.1 To compare the efficacy of DTG plus 3TC in participants with baseline HIV-1 
RNA ≤100,000 versus >100,000 copies/mL  
 
1.3.2 To estimate the virologic success rate of DTG plus 3TC therapy at weeks 12 and 
48.  
 
1.3.3 To describe emergent integrase and RT resistance in participants with virologic 
failure.  
 
1.3.4 To evaluate the safety and tolerability of DTG plus 3TC. 
 
1.3.5 To evaluate changes in CD4+ cell counts and serum lipids. 
 
1.3.6 To store plasma samples for future studies of the impact of drug-resistant 
minority viral variants on response to DTG plus 3TC. 
 
1.3.7 To describe the relationships between functional genetic variants in selected 
UGT1A1 and other human genes relevant to the study drugs and responses 
(virologic and immunologic) as well as adverse events observed with DTG plus 
3TC. 
 
1.3.8 To store random-timed plasma samples that may be used to characterize 
associations between plasma DTG exposure, adherence, responses (virologic 
and immunologic) as well as adverse events observed with DTG plus 3TC.  
 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
All recommended first-line antiretroviral therapy (ART) regimens consist of three active 
antiretroviral (ARV) drugs, and some include a pharmacologic booster. While this 
strategy has saved millions of lives and slowed the spread of HIV, results of the recent 
GARDEL study [1] and advances in the potency, resistance profile and tolerability of 
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ART. In the GARDEL study of 217 treatment-naïve participants, 88% of those treated 
with lopinavir/ritonavir (LPV/r) plus lamivudine (3TC) and 84% of the LPV/r plus two- 
NRTI arm had HIV-1 RNA <50 copies/mL at week 48; the two-drug strategy was non-
inferior to the three-drug comparator, regardless of baseline HIV-1 RNA. The efficacy of 
LPV/r plus 3TC in GARDEL surpassed the results from other experimental dual ART 
regimens. 
 
Viral resistance during two-drug ART failure is linked to mutations associated with the 
ARVs that are being used. The main mutation associated with 3TC failure is M184V/I. 
The mutations linked to DTG are less well defined as a result of the low viral failures. 
 
 
Table 2.1 Studies of two-drug ART 
 
Trial 
Sample Size 
Design 
Outcome 
ACTG 5142 [2] 
(N=757) 
LPV/r + 2NRTIs vs 
EFV + 2NRTs vs 
LPV/r + EFV 
LPV/r + EFV 
associated with 
NNRTI resistance and 
lipid abnormalities 
PROGRESS [3] 
(N=206) 
LPV/r + RAL vs LPV/r 
+ TDF/FTC 
LPV/r + RAL was 
non-inferior but mean 
baseline HIV-1 RNA 
was low (~18,000 
copies/mL) 
ACTG 5262 [4] 
(N=112) 
DRV/r + RAL single 
arm 
Increased virologic 
failure if baseline HIV-
1 RNA > 100,000 
copies/mL 
SPARTAN[5] 
(N=94) 
ATV + RAL BID vs 
ATV/r +TDF/FTC 
ATV + RAL was 
associated with 
increased virologic 
failure and jaundice 
RADAR [6] 
(N=85) 
DRV/r + RAL vs 
DRV/r + TDF/FTC 
More failure with 
DRV/r + RAL 
NEAT [7] 
(N=805) 
DRV/r + RAL vs 
DRV/r + TDF/FTC 
Non-inferior overall; 
Higher virologic failure 
when baseline HIV-1 
RNA was >100,000 
copies/mL or CD4+ < 
200 cells/mm3. 
GARDEL [1] 
(N=217) 
(N=217) 
LPV/r + 3TC vs LPV/r 
+ 2NRTIs 
LPV/r + 3TC non-
inferior regardless of 
baseline HIV-1 RNA 
MODERN [8] 
(N=797) 
MVC + TDF/FTC vs 
MVC + DRV/r 
MVC + DRV/r inferior 
 


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2.2 
Rationale 
Dolutegravir (DTG) plus lamivudine (3TC) is a potential two-drug regimen. Desired 
attributes of a two-drug regimen include excellent efficacy regardless of baseline HIV-1 
RNA, reliable long-term safety and tolerability, a resistance profile that preserves options 
for second-line therapy, potential for co-formulation into a single tablet, and relatively low 
cost. To realize the potentially dramatic impact of two-drug ART in resource-limited 
settings, the ideal two-drug regimen will need to be compatible with tuberculosis (TB) 
therapy, and safe in populations with high rates of opportunistic infections and immune 
reconstitution inflammatory syndrome. Such a regimen will also need to recapitulate 
other benefits of triple ART including efficacy in different anatomic compartments and 
control of systemic immune activation and inflammation.  
Despite its virologic efficacy in GARDEL, LPV/r plus 3TC is not an acceptable two-drug 
regimen since LPV/r is associated with dyslipidemia, lipodystrophy, insulin resistance, 
and treatment-limiting drug interactions including with rifampin, a key drug for TB 
treatment. Additional trials are studying darunavir/ritonavir plus 3TC (or emtricitabine 
[FTC]), but this regimen also has the drawbacks of gastrointestinal side effects, elevated 
lipids, and drug-drug interactions with ritonavir. In contrast, DTG plus 3TC has the 
potential to be an acceptable two-drug ART regimen. 
Dolutegravir (DTG) 
DTG is a highly potent integrase strand transfer inhibitor (INSTI). In a phase I study, 
monotherapy with DTG 50mg once-daily for 10 days resulted in a mean plasma HIV-1 
RNA decline of 2.46 log10 copies/mL and 7/10 (70%) of the participants achieved HIV-1 
RNA <50 copies/mL [9]. DTG is now approved for both treatment-naïve and treatment-
experienced HIV-1-infected individuals. DTG has a high barrier against resistance with 
no mutations emerging in large clinical trials of treatment-naïve individuals [10-12]. 
Multiple mutations in the major INSTI resistance pathways (positions 143, 148 and 155), 
or in the 148 pathway plus other INSTI mutations, are needed for significant loss of 
activity to occur [13, 14]. This is a higher resistance barrier than raltegravir and 
elvitegravir [15]. DTG selects the R263K mutation, which confers low-level resistance 
while simultaneously compromising viral fitness [16, 17]. However, in a study of ART-
experienced integrase-naïve HIV-infected adults, minority condon changes in a subject 
suggested evolving resistance in the presence of R263K during continued DTG 
exposure [18]. Other mutations described in association with DTG (e.g., G118R and 
H51Y) also decrease viral replicative fitness [19], which may explain the relative rarity of 
DTG-related mutations in clinical trials. The reduced replicative fitness of viruses 
selected by DTG is consistent with findings suggesting that integrase mutations selected 
by DTG may attenuate the emergence of resistance to some reverse transcriptase 
inhibitors including lamivudine [16]. Transmitted resistance to DTG has not been 
reported to date.  
Virologic failure and emergence of INSTI resistance during DTG exposure has been 
associated with non-adherence [18]. The metabolic, renal, bone, and drug interaction 
profiles of DTG are favorable. The cerebrospinal fluid (CSF) concentrations of DTG 
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ng/mL) and are similar to unbound DTG concentrations in plasma [20]. Consistent with 
this, DTG-containing three-drug ART effectively suppresses CSF HIV-1 RNA.  
 
Pharmacogenetics of DTG  
Dolutegravir undergoes hepatic metabolism by uridine diphosphate (UDP) 
glucuronosyltransferases (UGT) 1A1. Frequent polymorphisms in UGT1A1 affect hepatic 
expression of UGT1A1. The most frequent genetic variant that affects UGT1A1 function 
is a dinucleotide TAn repeat polymorphism (rs8175347) in a TATAA element in the 
UGT1A1 promoter. This varies from 5 to 8 TA repeats. In all populations, TA6 (UGT1A1 
*1) and TA7 (UGT1A1 *28) are most frequent, while TA5 (UGT1A1 *36) and TA8 
(UGT1A1 *37) are infrequent or absent [21-23]. The UGT1A1 *28 allele is a causative 
genetic variant of Gilbert syndrome, a form of mild unconjugated hyperbilirubinemia that 
affects ~5% of individuals of European ancestry [24]). The TA8 repeat (UGT1A1 *37) 
appears to cause even slower transcription than TA7, while TA5 (UGT1A1 *36) appears 
to cause even faster transcription than TA6. Genome-wide association studies [25-27] 
have consistently associated a nearby single nucleotide polymorphism, rs887829 
(UGT1A1 *80), with indirect hyperbilirubinemia in the general population. The rs887829 
T allele is in almost complete linkage disequilibrium with TA7 and TA8, while rs887829 C 
is in almost complete linkage disequilibrium with TA5 and TA6 (r2 ~ 0.99) [22]. Thus, 
either rs887829 or rs8175347 may be used to interrogate UGT1A1 expression. In a 
study of 88 volunteers, UGT1A1 loss-of-function genotypes were associated with 
significantly increased plasma dolutegravir clearance, plasma area-under-the-
concentration-time-curve (AUC) values, and maximal plasma concentrations [28]. 
Homozygosity for the rs887829 T loss-of-function allele varies in frequency by 
race/ethnicity, and is present in ~19% of African Americans, ~8% of European 
Americans, and ~16% of Hispanic Americans. UGTIA1 polymorphisms are not known to 
exert significant impact on response to DTG hence pre-screening is not needed.  
 
Lamivudine (3TC) 
3TC is a potent ARV drug with an outstanding safety and tolerability record and low in 
vitro and in vivo mitochondrial toxicity. The M184V/I mutation confers resistance to 3TC 
and FTC; while also reducing the viral replicative capacity. Transmitted resistance to 
3TC is well described, although rarely observed at a population genotyping level as a 
result of the poor viral fitness of M184V/I viruses, and the clinical impact is variable.  
 
DTG plus 3TC  
A small pilot study of DTG plus 3TC in treatment-naïve individuals (PADDLE) is ongoing 
in Argentina [29] and demonstrates preliminary virologic activity [Pedro Cahn, personal 
communication], but the study is inadequate to estimate the virologic efficacy of DTG 
plus 3TC and determine whether a phase III study of this combination is warranted. 
PADDLE was designed to include only 20 participants with baseline HIV-1 RNA 
≤100,000 copies/mL and CD4+ count ≥200 cells/mm3. As such, there is an urgent need 
to evaluate DTG plus 3TC in a larger, more representative population of treatment-naïve 
HIV-1-infected individuals.  
 
To better understand the ideal population and consequences of DTG plus 3TC dual 
therapy, it will be important to evaluate whether variables such as UGT1A1 
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3TC, particularly in individuals with high pre-treatment viremia. Minority variants have 
been associated with reduced response to NNRTI and CCR5 antagonists [30-35] while 
studies of the effects of INSTI [36-38] and NRTI [39-42] resistant minority variants have 
produced mixed results. In the ACTG A5262 study, only one of the five participants with 
raltegravir resistance during darunavir/ritonavir plus raltegravir failure had evidence of 
baseline minority variants bearing a raltegravir resistance mutation [38]. There is no 
evidence that PI resistant minority variants have any clinical consequence [39, 43]. 
 
An important consideration in the use of a DTG plus 3TC regimen is the development of 
resistance mutations (i.e., M184V/I) that confer resistance to 3TC as these may be more 
clinically significant than in a triple-therapy regimen where the presence of a M184V/I 
mutation can increase susceptibility to zidovudine (ZDV) and TDF [44]. Current 
guidelines and a recent meta-analysis [45, 46] support the clinical equivalence of 3TC 
and FTC in terms of efficacy and safety. Some data however suggest a lower rate of 
M184V/I resistance mutations when FTC is used [47-49] potentially related to the greater 
potency or longer half-life of FTC compared to 3TC [50-52]. Importantly, the use of 3TC 
is supported by World Health Organization (WHO) guidelines and many countries have 
turned to its use because of significant cost savings. Identifying emergence of M184V/I 
in the setting of this clinical trial could have significant policy implications internationally.  
 
Potential impact of DTG plus 3TC 
The two main potential benefits of DTG plus 3TC are reduced adverse effects and lower 
cost. Despite the established efficacy of triple ART, cumulative exposure to some of the 
constituent NRTIs have been associated with adverse effects that may be avoided with 
dual therapy. Tenofovir disoproxil fumarate (TDF) has well-established deleterious bone 
and renal effects [53-56], and there are continued concerns about possible 
cardiovascular adverse effects of abacavir [57]. Tenofovir alafenamide (TAF) is a potent 
tenofovir prodrug that achieves approximately 90% lower plasma levels of tenofovir than 
TDF, hence improved renal and bone profiles. TAF also achieves 5 fold higher cellular 
levels of tenofovir diphosphate compared to TDF [58, 59]. It is unknown whether 
concentrating tenofovir diphosphate in cells will predispose to untoward effects such as 
reduced telomerase activity [60, 61]. The combination of DTG and 3TC is expected to 
have a favorable safety and metabolic profile [10-12]. Given the large number of 
individuals on life-long ART, even small reductions in side effects could have a 
tremendous impact globally. 
 
Another potential benefit of two-drug ART is lower cost of therapy, which may improve 
access to ART, particularly in resource-limited settings. A major driver of the reduced 
cost of DTG plus 3TC is availability of generic 3TC. ViiV Healthcare has submitted an 
abbreviated New Drug Application (NDA) to the Food and Drug Administration (FDA) for 
the generic version of DTG. If approved, this would allow provision of DTG to PEPFAR-
supported countries and dramatically enhance availability of a DTG plus 3TC regimen 
globally. Based on pricing listed in the RED BOOK and applicable MEDICAID discounts, 
the cost of DTG plus generic 3TC is approximately 60% of the cost of branded 
DTG/3TC/abacavir (Triumeq, ViiV Healthcare, Research Triangle Park, NC). This 
potential cost saving from DTG plus 3TC is much greater than what is expected from 
another DTG-based two-drug combination (DTG plus rilpivirine) since rilpivirine is not 
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increase as the 19 million people who are currently unaware of their HIV infection 
globally get diagnosed and seek care [62].  
 
 
3.0 
STUDY DESIGN 
 
A5353 is a phase II, single-arm, open-label, pilot study designed to estimate the efficacy 
of DTG plus 3TC as initial combination ART in HIV-1-infected treatment-naive 
participants. Participants with plasma HIV-1 RNA ≥1000 copies/mL and <500,000 
copies/mL obtained within 90 days prior to study entry are eligible. Participants are 
ineligible if the screening HIV PR/RT and integrase genotype or any previous genotype 
shows any RT, any integrase, or major protease resistance mutation according to the 
2014 International Antiviral Society (IAS)-USA drug resistance mutations list. There is no 
CD4+ cell count restriction.  
 
A total of 120 participants will be enrolled and followed for 52 weeks. The study will 
enroll ≥25% (i.e., at least 30 participants) with screening HIV-1 RNA >100,000 to 
<500,000 copies/mL and will aim to enroll ≥20% women.  
 
All participants will undergo routine monitoring including plasma HIV-1 RNA, CD4+ cell 
counts, hematology, chemistry, and urinalysis. All participants will also undergo UGT1A1 
genotyping. Adherence to all study drugs will be monitored by self-report and phone call 
reminders.  
 
Integrase genotyping will be performed in all participants at screening to assess drug 
resistance. Since integrase genotyping is not standard of care, it will be provided by the 
study. Population-based sequencing of entire protease (PR) and partial reverse 
transcriptase (RT) will be performed at screening through standard of care if results are 
not available through pre-treatment resistance testing. Population-based sequencing of 
entire protease, partial RT, and integrase will be performed in participants with confirmed 
virologic failure. 
 
Plasma samples will be stored for future studies to determine the impact of adherence, 
drug-resistant minority variants and DTG exposure on responses to DTG plus 3TC.  
 
Participants with suspected virologic failure (defined in section 6.2.3) or HIV-1 RNA of 
50-200 copies/mL at weeks 24 or 48 will have a confirmatory HIV-1 RNA obtained within 
7 to 28 days after the initial sample was drawn. A plasma sample will be collected at the 
confirmation visit and sent for real-time population-based integrase, PR, and RT 
sequencing if virologic failure is confirmed. 
 
To allow for confirmation if there is a suspected failure at week 48, all participants will 
receive therapy and be followed until week 52. Only those participants with HIV-1 RNA 
levels >50 copies/mL at week 48 will have a plasma HIV-1 RNA measurement (and 
other laboratory evaluations) at week 52. Participants who experience confirmed 
virologic failure or treatment-limiting adverse effects may be switched to another ART 
regimen by their HIV care provider, in consultation with the study team and guided by 
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Participants who modify or permanently discontinue the study regimen or miss doses are 
expected to stay on study and will be followed to contribute to the intent-to-treat analysis.  
 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Men and women ≥18 years of age. 
 
4.1.2 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 
RNA viral load. 
 
NOTE: The term “licensed” refers to a US FDA-approved kit, which is required for 
all IND studies.  
 
WHO and CDC (Centers for Disease Control and Prevention) guidelines 
mandate that confirmation of the initial test result must use a test that is different 
from the one used for the initial assessment. A reactive initial rapid test should be 
confirmed by either another type of rapid assay or an E/CIA that is based on a 
different antigen preparation and/or different test principle (e.g., indirect versus 
competitive), or a Western blot or a plasma HIV-1 RNA viral load. 
 
4.1.3 Plasma HIV-1 RNA ≥1000 copies/mL and <500,000 copies/mL obtained within 
90 days prior to study entry using any FDA-approved assay by any US laboratory 
that has a CLIA certification or its equivalent. 
4.1.4 No evidence of any RT, any integrase, or major protease resistance mutation 
(according to the 2014 IAS-USA drug resistance mutations list, available at 
https://www.iasusa.org/sites/default/files/tam/22-3-642.pdf) based on pre-ARV 
treatment genotype performed any time prior to study entry.  
 
NOTE: Integrase genotyping must be performed at screening and is provided by 
the study. RT and PR genotyping should be performed at screening as part of 
routine clinical care if not previously performed. 
4.1.5 ARV treatment drug-naive (defined as no previous ARV treatment at any time 
prior to study entry, with the exception of successful post-exposure prophylaxis 
(PEP) or pre-exposure prophylaxis (PrEP).  
NOTE: Participants who were diagnosed with HIV while on PrEP or within a year 
of PrEP (unless documented seronegative in the interim) are not eligible. 


 
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4.1.6 The following laboratory values obtained within 45 days prior to study entry by 
any US laboratory that has a CLIA certification or its equivalent:  
• 
ANC ≥750/mm3 
• 
Hemoglobin ≥10.0 g/dL   
• 
Platelets ≥50,000/mm3  
• 
Calculated creatinine clearance (CrCl) ≥50 mL/min, as estimated by the 
Cockcroft-Gault equation 
• 
AST <5 x ULN (upper limit of normal)  
• 
ALT <5x ULN 
• 
Total bilirubin <1.5 x ULN 
 
4.1.7 Hepatitis B surface antigen negative within 45 days prior to study entry 
performed by a CLIA-certified laboratory.  
 
4.1.8 For women with reproductive potential, negative serum or urine pregnancy test at 
screening and within 48 hours prior to study entry (by any US clinic or laboratory 
that has a CLIA certification or its equivalent, or is using a point of care 
(POC)/CLIA-waived test). Reproductive potential is defined as women who have 
not been postmenopausal for at least 24 consecutive months, i.e., who have had 
menses within the preceding 24 months, or have not undergone surgical 
sterilization (e.g., hysterectomy, bilateral oophorectomy, salpingectomy, tubal 
ligation or tubal micro-inserts). The urine test must have a sensitivity of ≤50 
mIU/mL.  
 
NOTE: Women who report 12 months of amenorrhea and have a follicle-
stimulating hormone (FSH) level in the menopausal range should be considered 
as NOT having reproductive potential.  
 
4.1.9 If participating in sexual activity that could lead to pregnancy, female participants 
with reproductive potential must use one form of contraceptive as listed below 
while receiving protocol-specified medications and for 30 days after stopping the 
medications. At least one of the following methods must be used appropriately: 
• 
Condoms (male or female) with or without a spermicidal agent. Condoms are 
recommended because their appropriate use is the only contraception 
method effective for preventing HIV transmission. 
 
NOTE: In the setting of condom failure, emergency contraception (plan B) is an 
appropriate backup method of contraception. 
 
• 
Diaphragm or cervical cap with spermicide. 
• 
Intrauterine device.  
• 
Hormone-based contraceptive.  
 
4.1.10 Ability and willingness of participant or legal representative to provide informed 
consent. 
 


 
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4.2 
Exclusion Criteria 
 
4.2.1 Serious illness requiring systemic treatment and/or hospitalization 
 
 
NOTE: Participant is eligible if the participant completes therapy 7 days prior to 
study entry or is clinically stable on therapy in the opinion of the site investigator 
for 7 days prior to study entry.  
 
NOTE: Participants with oral candidiasis, vaginal candidiasis, mucocutaneous 
herpes simplex, and other minor illnesses (as judged by the site investigator) are 
eligible.  
 
4.2.2 Treatment within 30 days prior to study entry with immune modulators  such as 
systemic steroids, interleukins, interferons, granulocyte colony-stimulating factor 
(G-CSF), erythropoietin, or any investigational therapy.  
 
NOTE: Participants receiving stable physiologic glucocorticoid doses (defined as 
prednisone ≤15 mg/day or equivalent as a stable or tapering dose) are eligible. 
Participants receiving corticosteroids for acute therapy for PCP or asthma 
exacerbation, or receiving a short course (defined as ≤2 weeks of pharmacologic 
glucocorticoid therapy) are eligible. 
 
4.2.3 Pregnancy or breastfeeding. 
4.2.4 Requirement for any medication that is prohibited with a study medication (see 
Section 5.4). 
4.2.5 Known allergy/sensitivity to any of the study drugs or their formulations.  
4.2.6 Active drug or alcohol use or dependence that may interfere with adherence to 
study requirements, in the opinion of the site investigator. 
4.2.7  Active hepatitis C virus (HCV) treatment or anticipated need for treatment within 
study period.  
 
NOTE: HCV infection alone is not exclusionary.  
4.2.8  Unstable liver disease (as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent 
jaundice), known biliary abnormalities (with the exception of Gilbert’s syndrome 
or asymptomatic gallstones). 
4.2.9 Severe hepatic impairment (Class C) as determined by Child-Pugh classification. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 


 
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approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support 
Center (RSC). The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all of the required documents have been received.  
 
Site-specific informed consent forms (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. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, 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 ICF(s) 
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.  
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant (or, when necessary, the legal 
representative if the participant is under guardianship) will be asked to read and 
sign the approved protocol consent form.  
 
For participants from whom a signed informed consent has been obtained, an 
ACTG Screening Checklist must be entered through the Data Management 
Center (DMC) Participant Enrollment System.  
 
4.3.2 Participant Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database.  
 
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures.  
 


 
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4.4 
Coenrollment Guidelines  
 
• 
US sites are encouraged to co-enroll participants in A5128, “Plan for Obtaining 
Informed Consent to Use Stored Human Biological Materials (HBM) for Currently 
Unspecified Analyses.”  
• 
Coenrollment in A5128 does not require permission from the A5353 protocol chairs.  
• 
For specific questions and approval for coenrollment in other studies, sites should 
first check the PSWP or contact the protocol team via email as described in the 
Study Management section. 
 
 
5.0 
STUDY TREATMENT  
 
5.1 
Regimens, Administration, and Duration 
 
Study treatment is defined as dolutegravir (DTG) and lamivudine (3TC), both of which 
will be provided through the study. 
 
5.1.1 Regimen 
 
Participants will receive:  
 
Dolutegravir (DTG) 50mg PO daily plus 
 
Lamivudine (3TC) 300mg PO daily. 
 
Participants should begin study treatment within 72 hours after entry and 
continue on study treatment for a maximum of 52 weeks. 
 
Participants should return remaining medication at each study visit. 
 
5.1.2 Administration 
 
Dolutegravir will be administered orally as one 50 mg tablet daily, with or without 
food. 
 
Dolutegravir should be taken at least 2 hours before or 6 hours after taking 
calcium, iron, or magnesium containing antacids or laxatives, sucralfate, oral 
supplements containing iron or calcium, or buffered medications. Alternatively, 
dolutegravir and supplements containing calcium or iron can be taken together 
with food. 
 
Lamivudine will be administered orally as one 300 mg tablet daily, with or without 
food. 
 
5.1.3 Duration 
 
Participants will take study medications for 52 weeks. 


 
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5.2 
Study Product Formulation and Preparation 
 
5.2.1 Dolutegravir (DTG, Tivicay ®) 50 mg tablets. Store at 25°C (77°F); excursions 
permitted to 15°C - 30°C (59°-86°F) [See USP Controlled Room Temperature].     
 
5.2.2 Lamivudine (3TC, Epivir ®) 300 mg tablets. Store at 25°C (77°F); excursions 
permitted to15°C - 30°C (59°-86°F) [See USP Controlled Room Temperature].         
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Supply/Distribution 
 
Dolutegravir will be supplied by ViiV Healthcare Ltd. 
 
Lamivudine will be supplied by ViiV Healthcare Ltd. 
 
Study products will be available through the NIAID Clinical Research Products 
Management Center (CRPMC). The site pharmacist can obtain study products 
for this protocol by following the instructions in the manual Pharmacy Guidelines 
and Instructions for DAIDS Clinical Trials Networks, in the section Study Product 
Management Responsibilities. 
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. All unused study 
products must be returned to the NIAID CRPMC (or as otherwise directed by the 
sponsor) after the study is completed or terminated. The procedures to be 
followed are provided in the manual Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks in the section Study Product Management 
Responsibilities.  
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the updated ACTG Precautionary and 
Prohibited Medications Database located at: 
http://tprc.pharm.buffalo.edu/home/di_search/.  
 
5.4.1 Required Medications 
 
Prophylaxis for those who are at risk of opportunistic infections is strongly 
recommended. Investigators should refer to the current version of the U.S. Public 


 
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Health Service/Infectious Diseases Society of America “Guidelines for Preventing 
Opportunistic Infections Among HIV-Infected Persons.”  
 
5.4.2 Prohibited Medications 
 
The following are prohibited while the participant is on study drugs: 
• 
Systemic cytotoxic chemotherapy  
NOTE: Topical 5FU and treatments for human papilloma virus disease are 
allowed. 
• 
Dofetilide is prohibited with DTG as DTG may inhibit its renal tubular 
secretion resulting in increased dofetilide concentrations and potential for 
toxicity. 
• 
There are no prohibited medications with 3TC. 
 
5.5 
Adherence Assessment 
 
Adherence to the study drugs DTG and 3TC will be monitored by self-report. Sites will 
provide adherence reinforcement according to local standard practice and phone call 
reminders between visits and whenever poor adherence is suspected. Participants with 
poor adherence will be provided counseling by the site. 
 


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Events 
 
Evaluation 
Pre-Treatment 
Entry (Day 0) 
On-Treatment Evaluations 
Visit To 
Confirm 
HIV-1 RNA 
Premature 
Treatment 
Discontinuation 
and 
Premature Study 
Discontinuation 
Evaluations 
Day/Week 
Screening 
(-45 Days) 
 
Week 2 
Week 4 
 
Week  8 
 
Week  12 
 
Week 16 
 
Week  20 
 
Week 24 
 
Week 32 
Week 40 
Week 48 
 
Week 52 
Visit Window 
 
± 3 
Days 
 
± 7 Days 
 
± 14 Days 
 
7-28 Days 
After Initial 
Sample 
Documentation of 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/ Medication 
History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted Physical 
Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Blood Chemistries 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Creatinine 
Clearance 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Liver Function Tests 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Fasting Lipids 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Hepatitis B Surface 
Antigen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C 
Antibody1 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Evaluation 
Pre-Treatment 
Entry (Day 0) 
On-Treatment Evaluations 
Visit To 
Confirm 
HIV-1 RNA 
Premature 
Treatment 
Discontinuation 
and 
Premature Study 
Discontinuation 
Evaluations 
Day/Week 
Screening 
(-45 Days) 
 
Week 2 
Week 4 
 
Week  8 
 
Week  12 
 
Week 16 
 
Week  20 
 
Week 24 
 
Week 32 
Week 40 
Week 48 
 
Week 52 
Visit Window 
 
± 3 
Days 
 
± 7 Days 
 
± 14 Days 
 
7-28 Days 
After Initial 
Sample 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Pregnancy Test 
X 
X 
Whenever pregnancy suspected 
CD4+ Cell Count 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Plasma HIV-1 RNA 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
HIV Genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
X3 
X 
 
Stored Plasma for 
Minority Viral 
Variants 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
Stored Plasma for  
Random DTG Levels 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
Stored Blood for 
Pharmacogenomics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Call 
Reminder 
 
 
Weeks 1 (± 3 days) , 6 and 10  (±7 days) and whenever non-adherence is suspected 
Adherence 
Questionnaire 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study 
Drug 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
1. Only required in participants with no prior positive hepatitis C antibody.  
2. Screening HIV RNA within 90 days of entry. 
3. Only required if virologic failure suspected or HIV RNA >50 copies/mL at week 48 visit. These evaluations are identical to the Visit to Confirm HIV-1 RNA.


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening 
Screening evaluations to determine eligibility must be completed within 45 days 
prior to study entry, unless otherwise specified. The site may use documentation 
of HIV infection and the HIV resistance genotype obtained any time prior to study 
entry provided test results are available prior to study entry.  
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a screening log and entered into the ACTG database.  
 
6.2.2 Entry Evaluations 
 
Entry evaluations must occur at least 24 hours after screening evaluations and 
be completed prior to the initiation of study medications. Participants should 
begin study treatment within 72 hours after entry. 
 
6.2.3 Post-Entry Evaluations 
 
On-Treatment Evaluations 
The visit window for evaluations at week 2 is ±3 days after treatment initiation. 
The visit window for evaluations at weeks 4 to 24 is ±7 days after treatment 
initiation. The visit window for subsequent study visits is ± 14 days. 
 
Virologic failure is defined as follows: 
• 
Weeks 16 or 20: 
o 
Confirmed plasma HIV-1 RNA >400 copies/mL,  
• 
Week 24 or later: 
o 
Confirmed value >200 copies/mL 
 
Visit to Confirm HIV-1 RNA  
A confirmatory plasma HIV-1 RNA measurement will be done within 7-28 days of 
the initial sample when a participant has any of the following: 
• 
Suspected virologic failure, OR  
• 
HIV-1 RNA 50-200 copies/mL at week 24, OR 
• 
HIV-1 RNA 50-200 copies/mL at week 48 
 
If the initial sample was collected during a treatment interruption, sites are 
encouraged to address toxicity or adherence issues before taking the 
confirmatory sample, if possible, within the allowed window. If the visit for HIV-1 
confirmation coincides with a regularly scheduled visit, the evaluations should be 
combined.  
 


 
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If virologic failure is confirmed, sites must email the protocol core team at 
actg.corea5353@fstrf.org. Management of ART will be left to the discretion of the 
site investigator. If stopping study treatment, the participant will complete the 
Premature Treatment Discontinuation evaluations and continue to be followed on 
study/off study treatment per Section 6.2.4. 
 
Study Completion Evaluations 
Week 52 evaluations will be completed as the participant’s final on-study visit. 
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Registered Participants Who Do Not Start Study Treatment 
Participants who do not begin study treatment within 7 days after study entry will 
be discontinued from the study, and will be replaced. No evaluations beyond the 
entry visit are required. All CRFs must be completed and keyed for the period up 
to and including week 0.  
 
Premature Treatment Discontinuation Evaluations  
Participants who discontinue the study treatment prior to the week 52 visit will    
have the Premature Treatment Discontinuation evaluations done within 14 days 
after stopping study drugs, or as soon as possible thereafter.  
 
Participants who prematurely discontinue study treatment will be encouraged to 
continue on study/off study treatment and receive all study evaluations per the 
schedule of events, with the exception of plasma storage and adherence 
questionnaires, through completion of the study. 
 
Premature Study Discontinuation Evaluations  
Participants who prematurely discontinue from the study prior to the week 52 visit 
will have the Premature Study Discontinuation evaluations performed within 14 
days after discontinuing the study as per Section 6.1. 
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
Web site for information about what must be included in the source document: 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/sourced
ocappndx.pdf 
 
All stated evaluations are to be recorded on the case report form (CRF) and keyed into 
the database unless otherwise specified. This includes events that meet the International 
Conference on Harmonisation (ICH) definitions for a serious adverse event: 
• 
Results in death 
• 
Life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 


 
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• 
Results in persistent or significant disability/incapacity  
• 
Congenital anomaly/birth defect 
• 
Other important medical event (may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the events listed above).  
 
To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), Version 2.0, November 2014, which can be found on the DAIDS RSC 
Web site: http://rsc.tech-res.com/safetyandpharmacovigilance/.   
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.2 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the CRF. 
 
6.3.2 Medical History 
 
The medical history must include all diagnoses identified by the ACTG criteria for 
clinical events and other diagnoses. In addition to reporting all diagnoses within 
the past 30 days, the following diagnoses should be reported regardless of when 
the diagnosis was made: 
• 
AIDS-defining conditions 
• 
Bone fractures (verbal history accepted) 
• 
Coronary heart disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis 
• 
Chronic hepatitis B 
• 
Chronic hepatitis C 
 
Any allergies to any medications and their formulations must also be 
documented.  
 
6.3.3 Medication History 
 
A medication history must be present including start and stop dates. The table 
below lists the medications that must be included in the history.  
 
Medication Category 
Complete History or Timeframe 
Record in CRFs 
Antiretroviral therapy 
Complete history 
Yes 
Immune-based therapy 
Within 30 days prior to entry 
Yes 
Prescription drugs for 
treatment of opportunistic 
infections  
Within 30 days prior to entry 
Yes 


 
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Medication Category 
Complete History or Timeframe 
Record in CRFs 
Other prescription drugs, 
including hormonal 
contraceptives 
Within 30 days prior to entry 
Yes 
Non-prescription drugs  
Within 30 days prior to entry 
No 
Complementary and 
alternative medicines 
Within 30 days prior to entry 
No 
 
6.3.4 Clinical Assessments 
 
Complete Physical Exam 
A complete physical examination performed at study entry is to include at a 
minimum an examination of the skin, head, mouth, and neck; auscultation of the 
chest; cardiac exam; abdominal exam; examination of the lower extremities for 
edema. The complete physical exam will also include signs and symptoms, 
diagnoses, height, weight, and vital signs (temperature, pulse, respiration rate, 
and blood pressure). 
 
Targeted Physical Exam 
A targeted physical examination is to be driven by any previously identified or 
new signs or symptoms and diagnoses that the participant has experienced since 
the last visit. This examination includes weight and vital signs (temperature, 
pulse, respiration rate, and blood pressure). 
 
Signs and Symptoms 
At entry, record all signs/symptoms occurring within 30 days prior to entry. After 
entry, record all Grade ≥2 rash and all other Grade ≥3 signs and symptoms. Any 
signs or symptoms that lead to a change in study treatment, regardless of grade, 
must be recorded.  
 
Diagnoses 
Record all diagnoses identified by the ACTG criteria for clinical events and other 
diseases. Refer to the study CRFs for the appropriate appendix used for current 
ACTG criteria. 
 
Concomitant Medications 
Record any new or discontinued prescription medications including lipid-lowering 
agents, contraceptives, systemic steroids, other immune modulatory drugs, 
investigational drugs, and study-prohibited medications taken since the last study 
visit, including actual or estimated start dates and stop dates. 
 
Study Treatment Modifications 
During the study, all study drug modifications (DTG and/or 3TC) including 
participant-initiated and/or protocol-mandated interruptions, modifications, and 
permanent discontinuation of treatment will be recorded on the CRFs at each 


 
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visit. Participant-initiated and protocol-mandated interruptions include both 
inadvertent and deliberate interruptions of study drugs for a period of >3 days. 
The protocol core team (actg.corea5353@fstrf.org) must be notified of the 
addition of any ARV drug or permanent discontinuation of any study medication. 
 
6.3.5 Laboratory Evaluations 
 
At screening and entry, record all protocol-required laboratory values, regardless 
of grade, on the CRFs. For post-entry assessments, record all grades of 
creatinine and fasting lipid values and all other Grade ≥3 laboratory values. All 
laboratory toxicities that lead to a change in treatment, regardless of grade, must 
be recorded.  
 
All grade 3 or higher laboratory values, any laboratory value that led to a change 
in treatment or that met ICH, EAE, or SAE guidelines are defined by the protocol 
as reportable events that will require more detailed event reporting. 
 
Hematology 
Hemoglobin, hematocrit, white blood cell count (WBC), differential WBC, ANC, 
and platelet count. 
  
Blood Chemistries 
Blood urea nitrogen (BUN), creatinine, electrolytes (sodium, potassium, chloride, 
and CO2/bicarbonate), and glucose. 
 
Creatinine Clearance (CrCl)  
CrCl should be calculated using Cockcroft-Gault method. A program for 
calculating CrCl is available on the DMC website at: http://www.fstrf.org./ All 
values will be recorded in the CRFs. 
 
Liver Function Tests 
Total bilirubin, direct bilirubin, AST (SGOT), ALT (SGPT), and alkaline 
phosphatase. 
 
Fasting Lipids 
Total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides  
 
NOTE: Participants must fast for 8 hours prior to this test. Fasting is defined as 
no food or drink, except for sips of water with medications. If a participant is not 
fasting at the time of the visit, the sample should be drawn and labeled non-
fasting. The date and time of the participant’s last food or drink will not be 
recorded on the CRF. 
 
Hepatitis B Surface Antigen  
Documentation of hepatitis B surface antigen negative status within 45 days prior 
to study entry. This will not be recorded on the CRF. 
 


 
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Hepatitis C Antibody 
Only required in participants with no prior positive hepatitis C antibody.  
 
Urinalysis 
Dipstick or microscopic exam may be done; if dipstick results are abnormal, 
microscopic exam is required.  
 
Pregnancy Test 
All women of reproductive potential must have a negative serum or urine beta-
human chorionic gonadotropin (β-HCG) pregnancy test result at screening and 
within 48 hours prior to study entry and any time thereafter when pregnancy is 
suspected. The urine test must have a sensitivity ≤50 mIU/mL.  
 
6.3.6 Immunologic Studies 
 
Refer to the A5353 Lab Processing Chart (LPC) for collection, processing and 
shipping instructions.  
 
CD4+ Cell Count 
Evaluations for CD4+ cell counts and percentages should be performed at the 
same laboratory, if possible, for all on-study evaluations. The laboratory must 
have CLIA certification, or equivalent, and be certified for protocol testing by the 
DAIDS Immunology Quality Assurance (IQA) Program. 
 
Because of the diurnal variation in CD4+ cell counts, determinations for individual 
participants should be obtained consistently in either the morning or the 
afternoon throughout the study if possible. 
 
6.3.7 Virologic Studies 
 
Refer to the A5353 LPC for collection, processing and shipping instructions. 
 
Plasma HIV-1 RNA 
Screening HIV-1 RNA must be performed within 90 days prior to study entry 
using any FDA-approved assay by a laboratory that possesses a CLIA 
certification or equivalent. Entry and post-entry plasma HIV-1 RNA quantification 
will be measured in real time using the Abbott Realtime assay at Quest 
Diagnostics-Baltimore. 
 
HIV Genotype 
Genotypic resistance testing may be performed any time prior to study entry and 
results must be available prior to study entry. For the screening genotype, 
previous results verifiable by reports from a local CLIA-certified laboratory are 
acceptable as long as the results are available at entry. In the unlikely event that 
the candidate has more than one prior genotype, consult with the protocol team 
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Integrase genotyping must be performed at screening and will be provided by the 
study through Quest Diagnostics-Baltimore since screening for integrase 
resistance before ART initiation is not standard of care.  
 
RT and PR genotyping should be performed at screening as part of routine 
clinical care if not previously performed. 
 
When a participant is suspected to have virologic failure or has HIV-1 RNA of 50-
200 copies/mL at weeks 24 or 48, a plasma sample for real-time genotyping will 
be collected 7 to 28 days from the initial sample. The specimen collected for 
genotyping at this visit will be sent as per the instructions in the LPC for 
resistance testing if virologic failure is confirmed. Real-time results will be shared 
with sites.  
 
6.3.8  Stored Plasma for Minority Viral Variants 
 
Plasma samples will be stored for possible evaluation of the impact of minority 
variants and on responses to DTG plus 3TC. Individual participant results will not 
be shared with sites.  
 
6.3.9 Stored Plasma for Random DTG Levels  
 
Plasma samples will be stored for evaluation of random-timed DTG levels. 
Individual participant results will not be shared with sites. The time and date of 
the last three doses of DTG, and the time and date the plasma samples were 
obtained will be documented. 
 
6.3.10 Stored Blood for Pharmacogenomics  
 
At entry, a single whole blood sample will be obtained from all participants for 
human genotyping of UGT1A1 and other selected polymorphisms relevant to the 
study drugs. If blood for pharmacogenomics is not obtained at entry, it may be 
obtained at any subsequent study visit. 
 
6.3.11 Phone Call Reminders 
 
Study staff will contact participants by telephone between visits to provide 
adherence reinforcement. Phone call reminders will not be recorded on the CRF. 
 
 
6.3.12 Adherence Questionnaire 
 
An adherence questionnaire will be used to document participant adherence to 
the study medications. Sites will provide adherence reinforcement, according to 
local standard practice throughout the study. Participants with poor adherence 
will be provided counseling by the site.  
 


 
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6.3.13 Dispense Study Drug 
 
Study drug will be dispensed as indicated per the Schedule of Events. 
 
 
7.0 
CLINICAL MANAGEMENT ISSUES 
 
7.1 
Toxicity Management 
 
Criteria for participant management, dose interruptions, modifications, and 
discontinuation of study treatment are delineated only for toxicities attributable to study 
drugs (i.e., DTG and 3TC). The goal is to maintain participant safety while continuing 
therapy, if possible. If any individual study drug must be interrupted or discontinued due 
to toxicity, then the entire regimen must be interrupted or discontinued. 
 
The grading system for drug toxicities is located in the DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Version 2.0, November 2014, which can 
be found on the DAIDS web site: http://rsc.tech-
res.com/safetyandpharmacovigilance/gradingtables.aspx 
 
NOTE: The protocol core team must be notified at actg.corea5353@fstrf.org regarding 
toxicities that result in regimen interruption or discontinuation. The protocol does not 
allow drug substitution for toxicity management.  
 
The general guidelines presented in sections 7.1.1 to 7.1.3 apply to toxicities that are not 
specifically discussed further below.  
 
7.1.1 Grade 1 or 2  
 
Participants who develop a Grade 1 or 2 AE or toxicity may continue DTG and 
3TC. If the participant chooses to discontinue study treatment, the site should 
complete the Premature Treatment Discontinuation evaluations, notify the A5353 
protocol core team at actg.corea5353@fstrf.org and encourage the participant to 
attend all remaining study visits. 
 
7.1.2 Grade 3 
 
Grade 3 abnormalities must be evaluated and managed by the site investigator 
according to the standard of care. It may be necessary to discontinue both study 
drugs. The A5353 protocol core team must be notified at 
actg.corea5353@fstrf.org regarding toxicities that result in a change of regimen. 
If the site investigator has compelling evidence that the AE was NOT caused by 
a study drug, dosing may continue. If study drugs are temporarily held, the 
participant should be re-evaluated closely until the AE returns to Grade <2, at 
which time study treatment may be reintroduced at the discretion of the site 
investigator or according to standard practice.  
 


 
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If the site investigator determines that a Grade 3 AE or toxicity is an isolated 
event, the site has the option of confirming the toxicity before holding study 
treatment. 
 
If the same Grade 3 AE recurs within 4 weeks of reintroducing study drugs, the 
implicated study regimen must be permanently discontinued. However, if the 
same Grade 3 AE recurs after 4 weeks, but is not thought to be related to DTG or 
3TC, the management scheme outlined above may be repeated. 
 
Participants experiencing Grade 3 AEs requiring permanent discontinuation of 
study treatment should be followed closely until resolution of the AE. The A5353 
protocol core team must be notified at actg.corea5353@fstrf.org. The participant 
should be encouraged to attend all remaining study visits and continue other 
study evaluations according to the protocol. 
 
7.1.3 Grade 4 
 
Participants who develop a Grade 4 AE or toxicity thought to be related to study 
treatment must have both DTG and 3TC temporarily held. If the site investigator 
has compelling evidence that the AE has NOT been caused by DTG or 3TC, 
dosing may resume when the AE has resolved to Grade ≤2. Notify the A5353 
protocol core team at actg.corea5353@fstrf.org. 
 
Participants experiencing Grade 4 AEs requiring permanent discontinuation of 
study treatment should be followed closely until resolution of the AE to Grade ≤2, 
and the protocol team must be consulted. The participant should be encouraged 
to attend all remaining study visits and continue other study evaluations 
according to the protocol. 
 
7.2 
Rash 
 
Mild to moderate rash is an expected adverse reaction for DTG-containing ART. 
Episodes generally occur within the first 10 weeks of treatment, rarely require 
interruptions or discontinuations of therapy, and tend to resolve within 2 to 3 weeks. A 
single case of hypersensitivity with DTG involved a profuse, purpuric, and coalescing 
leukocytoclastic vasculitis as well as clinically significant liver chemistry elevations. Other 
than this case, no other instances of serious skin reaction, including Stevens-Johnson 
Syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme have been 
reported for DTG in clinical trials. 
 
Participants with an isolated Grade 1 rash (defined as having no systemic symptoms) 
may continue study medications at the site investigator’s discretion. The participant 
should be advised to contact the site investigator immediately if there is any worsening 
of the rash, if any systemic signs or symptoms worsen, or if mucosal involvement 
develops. 
 
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study medications (and all other concurrent medication(s) suspected in the site 
investigator’s causality assessment) should be permanently discontinued for any ≥Grade 
2 rash that is associated with an increase in ALT. The participant should be advised to 
contact the site investigator immediately if rash fails to resolve (after more than 2 
weeks), if there is any worsening of the rash, if any systemic signs or allergic symptoms 
develop, or if mucosal involvement develops. 
 
Participants should permanently discontinue study medications (and all other concurrent 
medication(s) suspected in the site investigator’s causality assessment) for an isolated 
Grade 3 or 4 rash, and the participant will be followed on study/off study treatment. 
Participants should be treated as clinically appropriate and followed until resolution of 
the AE. 
 
If the etiology of the rash can be definitely diagnosed as being unrelated to study 
medications and due to a specific medical event or a concomitant non-study medication, 
routine management should be performed and documentation of the diagnosis provided. 
Study treatment should be continued. 
 
7.3 
Nausea/Vomiting 
 
Nausea/vomiting of any grade may be treated symptomatically with oral antiemetics or 
antiemetic suppositories. For Grade ≥3 nausea or vomiting thought to be secondary to 
study drugs that fails to improve on antiemetics to Grade ≤2, all study drugs must be 
held until Grade ≤2. If Grade ≥3 nausea or vomiting recurs with reinstitution of study 
drugs or persists beyond 14 days despite symptomatic management, then study 
treatment must be discontinued and the protocol team consulted. 
 
7.4 
AST/ALT Elevations 
 
All study medications may be continued for asymptomatic ≤Grade 3 AST/ALT elevations 
at the discretion of the site investigator.  
 
For symptomatic Grade 3 (fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia) or any Grade 4 elevations in AST or ALT, all 
study medications should be held and the protocol core team should be consulted 
actg.corea5353@fstrf.org. In addition, for Grade 3 ALT and bilirubin ≥2 x ULN (attempts 
should be made to fractionate the bilirubin), the study medications should be held and 
the core team consulted as this will likely result in permanent study medication 
discontinuation.  
 
Participants who develop symptomatic Grade 3 or any Grade 4 AST or ALT should be 
followed weekly until resolution to ≤Grade 2. Participants will be followed on study/off 
study treatment after study medication discontinuation.  
 
Participants with Grade 3 or 4 AST or ALT with fever, rash, or eosinophilia should stop 
all study medications and not be re-challenged. Participants should be followed weekly 
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Careful assessments should be done to rule out the use of alcohol, non-study 
medication-related toxicity, or viral hepatitis (including viral hepatitis complicated by 
immune reconstitution inflammatory syndrome) as the cause of Grade 3 or 4 AST/ ALT 
elevations. Evaluations to be considered (but are not required) include:  
• 
Viral hepatitis serology including: Hepatitis A IgM antibody, Hepatitis B Surface 
Antigen (HBsAg) and Hepatitis B Core Antibody (IgM), Hepatitis C RNA, Hepatitis E 
IgM antibody; 
• 
Cytomegalovirus IgM antibody; 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing); 
• 
Syphilis screening; 
• 
Drugs of abuse screen including alcohol; 
• 
Serum acetaminophen test (APAP adduct test); 
• 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH); 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies; 
• 
Liver imaging to evaluate liver disease. 
 
7.5 
Calculated Creatinine Clearance (CrCl) 
 
3TC requires dose adjustment for CrCl <50 mL/min per the standard of care.  
 
7.6 
Allergic Reaction  
 
Participants may continue study medication for Grade 1 or 2 allergic reactions at the 
discretion of the site investigator. The participant should be advised to contact the 
investigator immediately if there is any worsening of symptoms or if further systemic 
signs or symptoms develop. Antihistamines, topical corticosteroids, or antipruritic agents 
may be prescribed at the discretion of the site investigator.  
 
Participants with ≥Grade 3 allergic reactions that are considered to be possibly or 
probably related to the study medications should permanently discontinue study 
medications and continue to be followed on study/off study treatment. Participants 
should be treated as clinically appropriate and followed until resolution of the AE. 
 
7.7 
Suicidal Ideation 
 
Participants with HIV infection may occasionally present with symptoms of depression 
and/or suicidality (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 participants being 
treated with integrase inhibitors, including DTG. Therefore, it is appropriate to monitor 
participants for suicidality before and during treatment. 
 
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and behavior or any other unusual changes in behavior. It is recommended that the 
investigator consider mental health consultation or referral for participants who 
experience signs of suicidal ideation or behavior. 
 
 
7.8 
Pregnancy 
 
Women who become pregnant while on study treatment must immediately discontinue 
study treatment and consult with their primary care physicians. Participants should have 
the Premature Treatment Discontinuation evaluations completed within 2 weeks after 
stopping study treatment.  
 
 
Participants will be encouraged to remain in the study to be followed on study/off study 
treatment until study completion and will be followed by telephone contact thereafter to 
determine the pregnancy outcome. Pregnancy-related outcomes (health of the infant) 
and any pregnancy-related complications (e.g., fetal loss/abnormalities) and obstetrical 
history must be reported on the CRF. Sites are encouraged to prospectively register 
pregnant women in the Antiretroviral Pregnancy Registry. More information is available 
at www.apregistry.com. Phone: 800-258-4263; Fax: 800-800-1052. 
 
NOTE: Pregnant participants will be considered on study until the outcome of the 
pregnancy has been obtained and reported on the CRF. 
 
 
8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Permanent Study Treatment Discontinuation 
 
• 
Drug-related toxicity requiring permanent study treatment discontinuation (see 
section 7.0) 
• 
Requirement for prohibited concomitant medications (see Section 5.4) 
• 
Pregnancy 
• 
Breastfeeding  
• 
Completion of treatment as defined in the protocol 
• 
Request by participant to terminate treatment 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
the toxicity section of the protocol 
• 
Failure by the participant to attend three consecutive clinic visits 
 
8.2 
Premature Study Discontinuation 
 
• 
Request by the participant to withdraw 
• 
Request of the primary care provider or investigator if s/he thinks the study is no 
longer in the best interest of the participant  
• 
Participant judged by the investigator to be at significant risk of failing to comply with 
the provisions of the protocol as to cause harm to self or seriously interfere with the 
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• 
At the discretion of the IRB/EC, FDA, NIAID, Office for Human Research Protections 
(OHRP), other government agencies as part of their duties, or pharmaceutical 
supporters. 
 
 
9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
General Design Issues 
 
This is single arm, open-label study to evaluate the safety and virologic efficacy of DTG 
plus 3TC in treatment-naïve HIV-1-infected participants. A total of 120 participants will 
be enrolled and followed for 52 weeks. The study will enroll ≥25% (i.e., at least 30 
participants) with screening HIV-1 RNA >100,000 copies/mL, and will aim to enroll ≥15% 
women. Efficacy of the study regimen will be assessed using FDA Snapshot definition. 
Participants who experienced study-defined virologic failure will have real-time 
population-based sequencing done on plasma sample obtained at confirmation visit.  
 
The primary efficacy outcome measure is at week 24 while the study follow-up is week 
52. Final analysis will commerce after all participants complete week 52 follow-up. 
Preliminary analysis will be conducted after all participants complete required follow-up 
for evaluation of primary efficacy outcome measure at week 24.   
 
9.2 
Outcome Measures 
 
9.2.1 Primary Outcome Measure 
 
Virologic success at week 24  
 
NOTE: virologic success is defined as HIV-1 RNA <50 copies/mL and on study 
treatment (FDA Snapshot definition). Participants with HIV-1 RNA ≥50 copies/mL 
or who discontinued study treatment or did not have HIV-1 RNA data are counted 
as non-success.  
 
9.2.2 Secondary Outcome Measures  
 
9.2.2.1 Virologic success at weeks 12 and 48 
 
9.2.2.2 Virologic failure (as defined in Section 6.2.3) 
 
NOTES:  
1. Participants are evaluated for virologic failure regardless of whether 
on study treatment.  
2. Confirmation will be determined based on any two consecutive 
evaluations meeting the virologic failure definition regardless of the 
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3. Participants discontinuing the study (for any reason, including death 
and lost to follow-up) will be considered a virologic failure if their last 
measurement meets the definition of virologic failure but no 
confirmatory measurement was obtained. All other participants’ follow-
up will be censored immediately after the last available plasma HIV-1 
RNA measurement.  
 
9.2.2.3 Plasma HIV-1 RNA level 
 
9.2.2.4 CD4+ cell count  
 
9.2.2.5 HIV-1 drug resistance mutations in participants with virologic failure 
 
9.2.2.6  Lipid values 
 
9.2.2.7 Sign/symptoms or laboratory toxicities of Grade 3 or higher, or of any 
grade which led to a permanent change or discontinuation of study treatment 
 
9.2.3 Exploratory Outcome Measures  
 
HIV-1 minority variants in participants with virologic failure 
 
9.3 
Randomization and Stratification 
 
There is no randomization or stratification in this study. 
 
Since a key secondary objective of the study is to determine if the regimen works in 
participants with high viral loads (>100,000 copies/mL) as well as in participants with 
lower viral loads (≤100,000 copies/mL). Participants with high viral loads will constitute at 
least one-fourth (1/4) of the study population. Hence, the enrollment of participants with 
screening HIV-1 RNA ≤100,000 copies/mL will be capped  at ¾ of the entire study 
population (N=90). 
 
9.4 
Sample Size and Accrual 
 
Virologic success at week 24 (HIV-1 RNA <50 copies/mL and on study treatment, using 
FDA Snapshot definition) will be estimated with a two-sided 95% confidence interval (CI) 
using exact binomial probability. With a sample size of 120 participants, if the observed 
virologic success rate is between 85% and 90%, the 95% CI will have a width of ±5.75% 
to ±6.75%. The estimated virologic success rate is based on results of dolutegravir arms 
from SPRING-2 (93% at week 24), SINGLE (92% at week 24) and FLAMINGO (90% at 
week 24), as well as the raltegravir arm from A5257 (84% at week 24). 
 
For subgroup analysis of participants with higher viral load, assuming N=30 and the 
observed virologic success rate between 85% and 90%, the 95% CI will have a width of 
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assuming N=20 and the same observed virologic success rates, the 95% CI will have a 
width of (-15.3%, +10%) to (-17.4%, +15%). 
 
It is anticipated that the study will meet its accrual target in 4 to 6 months after sites are 
enrolling. While accrual is ongoing, participants who are enrolled but never started 
treatment will be replaced. Each participant will be followed for 52 weeks. Only 
participants those with plasma HIV-1 RNA levels >50 copies/mL at week 48 visit will 
undergo confirmatory plasma HIV-1 RNA quantification at the week 52 visit.  
 
9.5 
Monitoring  
 
The team will routinely monitor accrual, baseline characteristics, toxicities and premature 
treatment and study discontinuation. The study will be reviewed by an independent 
Study Monitoring Committee (SMC) on study conduct, safety and efficacy annually. The 
first SMC review will occur 6 months after the enrollment of the 40th participant.  
 
At the interim review, to help assess regimen efficacy, the SMC will be provided with a 
two-sided 95% CI for the estimated week 24 virologic success (HIV-1 RNA <50 
copies/mL and on study treatment, FDA Snapshot definition) rate. Table below shows 
examples of observed number of success and the corresponding 95% CIs for the initial 
SMC review. 
 
Number of 
participants 
evaluated 
Observed 
number of 
virologic 
success 
Observed 
virologic 
success rate 
95% CI 
N=40 
27 
67.5% 
[51%, 81%] 
 
28 
70% 
[54%, 83%] 
 
29 
72.5% 
[56%, 85%] 
 
30 
75% 
[59%, 87%] 
 
An upper bound of the 95% CI for the virologic success rate that is smaller than 85% at 
this interim review would be consistent with a lower success rate than expected. For 
example, at the SMC review of 40 participants, if 28 participants had virologic success at 
week 24, the observed success rate is 70% with 95% CI of [54%, 83%], which excludes 
85%. In this situation, the SMC may want to consider modifying the study on the basis 
that the virologic success rate is lower than desirable.  
 
In addition, to ensure participants’ safety, virologic success at weeks 12 and 24 (at each 
increment of 20 participants) will be monitored by the team throughout accrual and 
follow-up. The team will immediately inform the SMC and may request a formal review at 
any time when the upper bound of the nominal 95% CI for the virologic success rate at 
week 12 excludes 80% or at week 24 excludes 85%.  
 
The table below shows the largest number of participants with virologic success where 
95% CI excludes the threshold at week 12 and 24, respectively, at various evaluation 


 
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times. For example, if 11 participants are observed to have virologic success at week 12 
among the first 20 participants who reached week 12, the observed virologic success 
rate is 55% with 95% CI of [32%, 77%] which excludes 80%, the team will consider 
requesting a formal SMC review prior to the initial scheduled review.  
 
Number of 
participants 
evaluated 
Week 12 
Week 24 
Largest number of 
virologic success 
where 95% CI 
exclude 80% 
95% CI 
Largest number of 
virologic success 
where 95% CI 
exclude 85% 
95% CI 
20 
11 
[32%, 77%] 
13 
[41%, 84.6%] 
40 
26 
[48%, 79%] 
28 
[54%, 83%] 
60 
41 
[55%, 79.7%] 44 
[60%, 84%] 
80 
56 
[59%, 79.7%] 60 
[64%, 84%] 
100 
71 
[61%, 79.6%] 76 
[66%, 84%] 
 
Since the monitoring procedure will evaluate the interim CI at multiple times, a simulation 
study (iteration=500) was carried out to assess the properties of the monitoring 
procedure. Table below presents the probability of at least one interim 95% CI excluding 
threshold (80% at week 12 and 85% at week 24) and triggering an unscheduled SMC 
review for various true virologic success rates at weeks 12 and 24. For example, if the 
true virologic success rate is 70% at week 12 and 82% at week 24 (lower than 
desirable), the study will have 68% of probability to observe an interim 95% CI excluding 
the threshold and trigger an unscheduled SMC review. On the contrary, if the true rate is 
85% at week 12 and 88% at week 24, the probability of triggering an unscheduled SMC 
review is only 1%.  
 
True virologic success rate 
Probability of at least 
one interim 95% CI 
excluding threshold  
Week 12 
Week 24 
65% 
79% 
0.93 
70% 
82% 
0.68 
75% 
84% 
0.34 
80% 
86% 
0.08 
85% 
88% 
0.01 
 
9.6 
Analyses 
 
9.6.1  Primary Analyses 
 
The proportion of participants with virologic success (plasma HIV-1 RNA <50 
copies/mL and while on study treatment, FDA Snapshot definition) at week 24 
will be estimated with 95% CI. Participants with last HIV-1 RNA <50 copies/mL 
while on study treatment in the analysis window (i.e., week 24 ± 6 weeks) are 


 
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counted as success. The two-sided 95% CI will be calculated using the exact 
binomial distribution. 
 
Participants who enrolled but never started study treatment will be excluded from 
all analyses.  
 
9.6.2 Secondary Analyses 
 
Virologic success at scheduled visit weeks will be analyzed using the same 
approach for the primary analysis and summaries of plasma HIV-1 RNA results 
will be provided. The cumulative proportion of participants experiencing virologic 
failure at or prior to week 48 will be estimated using the method of Kaplan and 
Meier with 95% CI calculated using the Greenwood variance. 
 
Participant-specific changes in CD4+ count and lipid measures from baseline to 
scheduled week(s) will be summarized by descriptive statistics and longitudinal 
plots. Patterns of drug resistance mutations at study entry and failure will be 
summarized for participants who experienced virologic failure.  
 
Reported signs/symptoms or laboratory toxicities will be tabulated. Premature 
treatment discontinuation will be summarized with detailed reasons provided.  
 
 
10.0 
PHARMACOLOGY PLAN 
 
See section 6.3.9. 
 
 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
Case report forms (CRF) will be provided for each participant. Participants must not be 
identified by name on any CRFs. Participants will be identified by the participant 
identification number (PID) and study identification number (SID) provided by the ACTG 
DMC upon registration. 
 
11.2 
Role of Data Management 
 
11.2.1 Instructions concerning the recording of study data on CRFs will be provided by 
the ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
11.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 


 
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11.3 
Clinical Site Monitoring and Record Availability 
 
11.3.1 Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, CRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection 
of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect sites’ regulatory files to 
ensure that regulatory requirements are being followed and sites’ pharmacies to 
review product storage and management. 
 
11.3.2 The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, CRFs) and pertinent hospital or clinic records readily available 
for inspection by the local IRB/EC, the site monitors, the FDA, the NIAID, the 
OHRP, and the industry supporter or designee for confirmation of the study data.  
 
11.4 
Expedited Adverse Event Reporting to DAIDS 
 
11.4.1 Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website at   http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
 
The DAIDS Adverse Events Reporting System (DAERS), an internet-based 
reporting system, must be used for expedited AE reporting to DAIDS. In the 
event of system outages or technical difficulties, expedited AEs may be 
submitted via the DAIDS EAE Form. For questions about DAERS, please contact 
DAIDS-ES at DAIDS-ESSupport@niaid.nih.gov. Site queries may also be sent 
from within the DAERS application itself. 
 
Sites where DAERS has not been implemented will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form. This form is 
available on the RSC website: http://rsc.tech-
res.com/safetyandpharmacovigilance/. For questions about EAE reporting, 
please contact the RSC (DAIDSRSCSafetyOffice@tech-res.com). 


 
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11.4.2 Reporting Requirements for this Study 
 
• 
The suspected unexpected serious adverse reactions (SUSAR) Reporting 
Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be used 
for this study from the time of enrollment through week 52. 
 
• 
The study agents for which expedited reporting are required are:  
• 
Dolutegravir 
• 
Lamivudine 
 
Liver Events: Any liver toxicity that results in discontinuation of study 
medications, based on liver stopping criteria in 7.4, will be reported as an EAE 
regardless of seriousness. 
 
Suicidal Ideation or Behaviors: If the participant expresses suicidal ideation or 
intent, the data will be captured as an AE on the CRF. Any suicide thought or 
attempt that qualifies as an SAE will be reported as an EAE. 
 
11.4.3 Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014, must 
be used and is available on the DAIDS RSC Web site at http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
 
11.4.4 Expedited AE Reporting Period 
 
The EAE reporting period for this study is the entire study duration for an 
individual participant (from study enrollment until study completion or 
discontinuation of the participant from study participation for any reason). 
 
After the protocol-defined AE reporting period, unless otherwise noted, only 
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 (e.g., from 
publicly available information). 
 
 
12.0 
PARTICIPANTS 
 
12.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix I) and any subsequent 
modifications will be reviewed and approved by the IRB or ethics committee responsible 
for oversight of the study. A signed consent form will be obtained from the participant or 
legal representative. The consent form will describe the purpose of the study, the 


 
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procedures to be followed, and the risks and benefits of participation. A copy of the 
consent form will be given to the participant or legal representative and this fact will be 
documented in the participant’s record. 
 
12.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, 
OHRP, other government agencies as part of their duties, or the industry supporter or 
designee.  
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
other government agencies as part of their duties to ensure that research participants 
are protected, or the industry supporter. 
 
 
13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporter prior to submission.  
 
 
14.0 
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 Centers for 
Disease Control and Prevention and the National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  


 
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15.0 
REFERENCES 
 
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nevirapine. Proc Natl Acad Sci USA 2011; 108:9202–7. 
 
31. Li JZ, Paredes R, Ribaudo HJ, et al. Low frequency HIV-1 drug resistance mutations and 
risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled 
analysis. JAMA 2011; 305:1327–35. 
 
32. Halvas EK, Wiegand A, Boltz VF, et al. Low frequency nonnucleoside reverse-
transcriptase inhibitor-resistant variants contribute to failure of efavirenz-containing 
regimens in treatment- experienced patients. J Infect Dis 2010; 201:672–80. 
 
33. Lecossier D, Shulman NS, Morand-Joubert L, et al. Detection of minority populations of 
HIV-1 expressing the K103N resistance mutation in patients failing nevirapine. J Acquir 
Immune Defic Syndr 2005; 38:37–42. 
 
34. Westby M, Lewis M, Whitcomb J, et al. Emergence of CXCR4-using human 
immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients 
following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-
using virus reservoir. J Virol 2006; 80:4909–20. 
 
35. Swenson LC, Mo T, Dong WW, et al. Deep sequencing to infer HIV-1 co-receptor usage: 
application to three clinical trials of maraviroc in treatment-experienced patients. J Infect 
Dis 2011; 203:237–45. 


 
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36. Armenia D, Vandenbroucke I, Fabeni L, et al. Study of genotypic and phenotypic HIV-1 
dynamics of integrase mutations during raltegravir treatment: a refined analysis by ultra-
deep 454 pyrosequencing. J Infect Dis 2012; 205:557–67. 
 
37. Nguyen H, Charpentier C, Nguyen N, et al. Longitudinal analysis of integrase N155H 
variants in heavily treated patients failing raltegravir- based regimens. HIV Med 2013; 
14:85–91. 
 
38. Li JZ, Chapman B, Charlebois P, et al. Comparison of illumina and 454 deep sequencing 
in participants failing raltegravir-based antiretroviral therapy. PLoS One 2014; 
9(3):e90485. doi: 10.1371/journal.pone.0090485. 
 
39. Lataillade M, Chiarella J, Yang R, et al. Prevalence and clinical significance of HIV drug 
resistance mutations by ultra-deep sequencing in antiretroviral-naive subjects in the 
CASTLE study. PLoS One 2010; 5:e10952. 
 
40. Metzner KJ, Rauch P, von Wyl V, et al. Efficient suppression of minority drug-resistant 
HIV type 1 (HIV-1) variants present at primary HIV-1 infection by ritonavir-boosted 
protease inhibitor-containing antiretroviral therapy. J Infect Dis 2010; 201:1063–71 
 
41. Stekler JD, Ellis GM, Carlsson J, et al. Prevalence and impact of minority variant drug 
resistance mutations in primary HIV-1 infection. PLoS One 2011; 6:e28952. 
 
42. Bansal V, Metzner KJ, Niederost B, et al. Minority K65R variants and early failure of 
antiretroviral therapy in HIV-1-infected Eritrean immigrant. Emerg Infect Dis 2011; 
17:1966–8. 
 
43. Simen BB, Simons JF, Hullsiek KH, et al. Low-abundance drugresistant viral variants in 
chronically HIV-infected, antiretroviral treatment-naive patients significantly impact 
treatment outcomes. J Infect Dis 2009; 199:693–701. 
 
44. Whitcomb JM, Parkin NT, et al. Broad nucleoside reverse-tanscriptase inhibitor cross-
resistance in human immunodeficiency virus type 1 clinical isolates. J Infect Dis 2003; 
188:992-1000.  
 
45. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV 
infection. Available at 
http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf?ua=1 
 
46. Ford N, Shubber Z, Hill A, Vitoria M, Doherty M, Mills EJ, Gray A. Comparative efficacy 
of lamivudine and emtricitabine: a systematic review and meta-analysis of randomized 
trials. PLoS One. 2013;8(11):e79981. 
 
47. Svicher V, Alteri C, et al. Different evolution of genotypic resistance profiles to 
emtricitabine versus lamivudine in tenofovir-containing regimens. JAIDS 2010; 55:336-
44. 
 


 
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48. McColl DJ, Margot N, Chen SS, et al. Reduced emergence of the M184V/I resistance 
mutation when antiretroviral-naïve subjects use emtricitabine versus lamivudine in 
regimens composed of two NRTIs plus the NNRTI efavirenz. HIV Clin Trials 2011; 2:61-
70.  
 
49. Marcelin AG, Charpentier C, Wirden M, et al. Resistance profiles of emtricitabine and 
lamivudine in tenofovir-containing regimens. J Antimicrob Chemother. 2012 Jun; 
7(6):1475-8 
 
50. Drogan D, Rauch P, Hoffman D, et al. The antiretroviral potency of emtricitabine is 
approximately 3-fold higher compared to lamivudine in dual human immunodeficiency 
virus type 1 infection/competition experiments in vitro. Antiviral Res 2010; 86:312-5.  
 
51. Wang LH, Begley J, St Claire J, et al. Pharmacokinetic and pharmacodynamic 
characteristics of emtricitabine support its once daily dosing for the treatment of HIV 
infection. AIDS Res Hum Retroviruses 2004; 11:1173-82. 
 
52. Grant PM, Tierney C, Budhathoki C, et al. Early virologic response to 
abacavir/lamivudine and tenofovir/emtricitabine during ACTG A5202. HIV Clin Trials 
2013; 6:284-91.  
 
53. Stellbrink HJ, Orkin C, Arribas JR, et al. Comparison of changes in bone density and 
turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 
48-week results from the ASSERT study. Clin Infect Dis 2010; 51:963-72. 
 
54. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in 
antiretroviral-naïve persons randomized to receive abacavir-lamivudine or tenofovir 
disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS 
Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis 2011; 203:1791-
801. 
 
55. Herlitz LC, Mohan S, Stokes MB, Radhakrishnan J, D'Agati VD, Markowitz GS. 
Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and 
mitochondrial abnormalities. Kidney Int  2010; 78:1171-77. 
 
56. Karras A, Lafaurie M, Furco A, et al. Tenofovir-related nephrotoxicity in human 
immunodeficiency virus-infected participants: three cases of renal failure, Fanconi 
syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis 2003; 36:1070-73. 
 
57. Palella FJ, Althoff KN, Moore R, et al. Abacavir use and risk for myocardial infarction in 
the NA-ACCORD. Abstract 749LB. Abstract 121. Conference on Retroviruses and 
Opportunistic Infection. February 23-26, 2015. Seattle, WA. 
 
58. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafunemide vs. tenofovir disoproxil fumarate in 
single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir 
Immune Defic 2014; 67(1):52-8. 
 


 
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59. Wohl D, Pozniak A, Thompson M, et al. Tenofovir alafenamide (TAF) in a single-tablet 
regimen in initial HIV-1 therapy. Abstract 113LB. Conference on Retroviruses and 
Opportunistic Infections  2015. Seattle, WA. 
 
60. Leeansyah E, Cameron PU, Solomon A, et al. Inhibition of telomerase activity by human 
immunodeficiency virus (HIV) nucleos(t)ide reverse transcriptase inhibitors: a potential 
factor contributing to HIV-associated accelerated aging. J Infect Dis 2013 Apr; 
207(7):1157-65 
 
61. Solomon A, Tennakoon S, Leeansyah E, et al. No difference in the rate of change in 
telomere length or telomerase activity in HIV-infected patients after three years of 
darunavir/ritonavir with and without nucleoside analogues in the MONET trial. PLoS One 
2014; 9(11):e109718. 
 
62.http://www.unaids.org/en/resources/presscentre/pressreleaseandstatementarchive/2014/j
uly/20140716prgapreport 
 


 
 
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DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT 
For protocol A5353 
 
FINAL Version 1.0: A Study to Evaluate Dolutegravir plus Lamivudine Dual Therapy for the 
Treatment of Naïve HIV-1-infected Participants 
 
SHORT TITLE FOR THE STUDY: (A5353) Dolutegravir plus Lamivudine in Treatment Naïve 
HIV-1-infected Participants  
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you: 
• 
are infected with HIV (the virus that causes AIDS) 
• 
have never taken any medicine for the treatment of HIV  
 
This study is sponsored by the National Institutes of Health. The doctor in charge of this study at 
this site is: (insert name of Principal Investigator). Before you decide if you want to be a part of 
this study, we want you to know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
This study is being done to see if the combination of two anti-HIV medicines, dolutegravir (DTG, 
Tivicay) and lamivudine (3TC, Epivir) taken once a day, will provide a safe, effective, and well-
tolerated treatment for HIV. DTG is a type of HIV medicine called an integrase inhibitor; 3TC is a 
type of HIV medicine called a reverse transcriptase inhibitor. DTG works by blocking integrase 
and 3TC works by blocking reverse transcriptase, two HIV proteins (enzymes). This prevents 
HIV from multiplying and lowers the viral load (amount of HIV in the blood). Both DTG and 3TC 
are currently part of Food and Drug Administration (FDA) recommended regimens along with a 
third active drug. Since some HIV medicines have side effects and are costly, there is interest in 
whether HIV can be successfully controlled with fewer than three HIV drugs.  
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you decide to take part in this research study, you will be asked to sign this consent form and 
schedule a screening visit to determine if you are eligible to enter this study. If screening visits 
determine that you are eligible and you agree to be in this study, you will take DTG and 3TC 
once a day for 52 weeks. While you are in this study, you will be seen in the clinic about 13 


 
 
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times. The study staff will tell you about how long each visit will last. During the study, you will 
get the results from any routine tests that are done during the study when they are available.  
 
Screening visit 
• 
Your HIV infection will be confirmed if there is no record available. You have another HIV 
test and may have to sign a separate consent form before having this test 
• 
You will be asked about your medical history and any medicines you have taken.  
• 
You will have a brief physical exam and be asked about your health.  
• 
You will have blood drawn for routine safety tests to check your blood count, kidney and 
liver function, to measure your HIV viral load (the amount of HIV in your blood). 
• 
You will have blood drawn to test for hepatitis B (infection caused by a virus that attacks the 
liver).  
• 
You will have blood drawn to determine your HIV integrase genotype (genetic makeup of the 
virus that will show if there is any evidence of HIV drug resistance). You will have blood 
drawn to determine your HIV protease and reverse transcriptase genotype as part of your 
routine medical care if this was not already done. 
• 
If you are a woman who could become pregnant, you will be asked to give a urine or blood 
sample to see if you are pregnant. You will not be able to enroll in this study if you are 
pregnant or breastfeeding.  
 
If you do not enroll into the study 
If you do not qualify to take part in this study or you decide not to take part in this study, we will 
still use some of your information. As part of the screening visit, some demographic (for 
example, age, gender, race), clinical (for example, disease condition, diagnosis), and laboratory 
(for example, CD4+ cell count, HIV viral load) information is being collected from you so that 
ACTG researchers may see if there are patterns or common reasons why people do not join a 
study. 
 
Entry visit 
• 
If the screening evaluations show that you are eligible for the study, you will return to the 
clinic for the entry visit.  
• 
You will have a physical exam. The study staff will check the different systems in your body 
and your vital signs such as temperature, pulse, blood pressure, and respiratory rate. 
• 
You will be asked about medicines you have taken in the past or are taking now.  
• 
You will have blood drawn for routine safety tests to check your blood count, kidney and 
liver function, and to measure your CD4+ cell count and HIV viral load. Some of your blood 
will be stored for future testing.  
• 
You will have blood drawn to test for hepatitis C (infection caused by a virus that attacks the 
liver).  
• 
You will have a fasting lipid blood test to measure the level of cholesterol in your blood. 
Fasting means no food or drink, except for sips of water with medications for 8 hours before 
the test. If you are not fasting at the time of the blood draw, your blood will still be drawn. 
• 
You will be asked to provide a urine sample.  
• 
If you are a woman who could become pregnant, you will be asked to give a urine or blood 
sample to see if you are pregnant. You will not be able to enroll in this study if you are 
pregnant.  


 
 
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• 
Some of your blood will be stored to check your genetic makeup which may be useful in 
understanding your response to the study drugs. The way medication affects a person is 
often varied and depends to a certain degree on genes and variations in those genes. Blood 
will be stored with the usual protectors of identity. 
• 
You will begin taking DTG and 3TC by mouth once a day for the next 52 weeks.  
• 
There are no food restrictions with this combination so you may take these drugs with or 
without food. If you are taking some antacids, laxatives, or iron or calcium supplements 
you will need to take the DTG 2 hours before or 6 hours after these medications. 
Alternatively, you may take iron or calcium supplements at the same time as DTG if 
taken with food.  
• 
You will be given DTG and 3TC at your study visits to take home, and you will need to 
store them in a safe place at room temperature  
• 
Both DTG and 3TC will be supplied by the study. 
 
During the study visits:   
After the entry visit, your study visits will be on weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48 and 52. 
All (or some) of the following tests will be done at each visit, depending on the week you come 
to the clinic: 
• 
You will have a brief physical examination performed at each study visit. 
• 
At each study visit, you will be asked questions about any medicines you are taking now and 
about any signs or symptoms that you are experiencing and any changes in other 
medications that you have had since your last visit. 
• 
You will have blood drawn for routine safety tests to check your blood count, cholesterol 
level and kidney and liver function and to measure your CD4+ cell count.  
• 
Blood will be drawn to check your HIV viral load at each study visit. 
• 
You will have a fasting lipid blood test taken to measure the level of cholesterol in your 
blood. 
• 
You will have a urine sample collected. 
• 
If you are a woman who could become pregnant, you will have a pregnancy test whenever 
pregnancy is suspected. 
• 
The study staff will contact you between some of your study visits to remind you of your 
appointment and to take your study medications. 
• 
You will be asked about how well you take the study medicines at each study visit. The 
study staff will give you information and encouragement to help you take your medications 
as prescribed. 
• 
Some of your blood will be stored to check the level of study drugs in your blood. Blood will 
be stored with the usual protectors of identity. You will not be told the results of these tests. 
 
Confirmation of Viral Load 
You will be asked to return to the clinic to have blood drawn if your HIV viral load gets too high 
and it is suspected that the study drugs might be failing to fight your HIV. You will have a brief 
physical exam and be asked about how well you have been taking your study medications. You 
will have blood drawn to measure your viral load and to do HIV-1 genotype resistance testing if 
virologic failure is confirmed. Your study doctor will talk to you about the plan for future 
treatment. This visit may be combined with another study-scheduled visit. 
 


 
 
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Pregnancy 
If you are a woman and you become pregnant, you will have to stop taking the study drug but 
we will ask you to stay in the study to be followed on study/off treatment until study completion. 
If you do not wish to continue to be followed on study/off treatment, the study staff will ask your 
permission to contact you regarding the outcome of your pregnancy. Your pregnancy will be 
reported to the Antiretroviral Pregnancy Registry, an international database that collects 
information about pregnancies in women taking anti-HIV drugs. These reports will not use your 
name or other information that could be used to identify you. 
 
Premature Treatment/Study Discontinuation 
If you stop taking the study drug before the study-defined treatment period, you will be asked to 
return to the clinic to complete some evaluations: 
• 
You will have a brief physical exam and be asked about any medicines you have been 
taking. 
• 
You will be asked about how well you took the study medicines. 
• 
You will have blood drawn for routine safety tests to check your blood count, liver and 
kidney function, CD4+cell count, and viral load. 
• 
You will be asked to provide a urine sample.  
• 
Some of your blood will be stored for future testing. 
 
Other Information  
As stated above, some of your blood will be stored for study-required testing which is part of 
your participation in this study. If you agree to be in this study, you are also agreeing to have 
blood stored for study-required tests. 
 
If you agree, some of your blood that is left over after all required study testing is done may be 
stored (with usual protectors of identity) and used for future ACTG-approved HIV-related 
research.  
 
Please indicate below “yes” or “no” and initial and date whether you approve the use of these 
extra stored samples for future testing. Note that you can withdraw your consent for research on 
stored specimens at any time you want and the specimens will be discarded. Your refusal or 
withdrawal of consent for the storage of these samples will not affect your study participation 
since storage of leftover samples is not a requirement for the study. 
 
______________________ Yes, I agree.      ____________________ No, I do not agree. 
 
 
 


 
 
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A5353 Study Visits 
The study staff can answer any questions you have about individual study visits, the evaluations 
that will occur, or how long each visit will be. The table below can be used as a quick reference.  
 
Study Schedule 
Evaluation or test 
Screen 
 
Entry 
Post-Entry Visits 
Confirm 
virologic 
failure 
Early 
discontinuation 
On treatment 
(Weeks 2, 4, 
8, 12, 16, 20, 
24, 32, 40, 48  
End of 
treatment 
(Week 52) 
Consent 
 
 
 
 
 
 
Complete physical 
examination 
 
 
 
 
 
 
Brief physical 
examination 
 
 
 
 
 
 
Medical/medication 
history 
 
 
 
 
 
 
Blood sample 
collection and 
laboratory testing 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
Stored blood samples 
 
 
 
    
 
 
 
Phone call reminder 
 
 
Between 
study visits 
 
 
 
Adherence 
questionnaire 
 
 
 
 
 
 
Approximate amount 
of blood  
30 mL 
30 mL  
15 to 25 
mL/visit 
30 mL 
22 mL 
25 mL 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 120 people (men and women) will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 52 weeks.  
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
The study is stopped or cancelled. 


 
 
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• 
A Study Monitoring Committee (SMC) recommends that the study be stopped early (An 
SMC is an outside group of experts who monitor the study). 
• 
Your doctor thinks the study is no longer in your best interest. 
• 
The site investigator thinks that you are at significant risk of failing to comply with the 
requirements of the protocol.  
• 
Your primary care physician requests you be taken off the study. 
 
The study doctor may also need to take you off the study drug without your permission if: 
• 
Continuing the study medicine may be harmful to you. 
• 
You need a treatment that you may not take while on the study. 
• 
You become pregnant or are breastfeeding. 
• 
Your viral load worsens. 
• 
You are not able to take the study medicine as required by the study. 
• 
You miss three consecutive clinic visits. 
 
If you must stop taking the study drug before the study is over, the study doctor will ask you to 
continue to be part of the study and return for some study visits and procedures. 
 
If I have to permanently stop taking study drugs through the study, or once I leave the study, 
how can I get study drugs? 
 
If you must permanently stop taking DTG and 3TC before the study is over, the study staff will 
talk with you about other treatment options. After you have finished the study, you will not be 
able to get DTG or 3TC through the study. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Risks of Social Harm 
Although the study site will make every effort to protect your privacy and confidentiality, it is 
possible that others could find out that you are participating in this study and that social harm 
may result (because you could become labeled as being infected with HIV). For example, you 
could be treated unfairly or discriminated against by family members, friends, and/or the 
community. Poor adherence (failing to take HIV medications as prescribed) can increase the 
risk of drug resistance, HIV treatment failure, and a risk of HIV transmission to others. 
 
Risks of Drawing Blood 
Drawing blood may cause some discomfort, lightheadedness, bleeding, swelling, or bruising 
where the needle enters the body, and in rare cases, fainting, or infection. 
 
Risks of Study Drugs 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. It is very important 
that you tell your study doctor of any changes in your medical condition while taking part in the 
study. At any time during the study, if you believe you are experiencing any of these side 
effects, you have the right to ask questions on possible and /or known risks.  


 
 
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There is a risk of serious and/or life threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and you must ask approval for taking any 
new medication while you are on the study. 
 
Use of Combination Antiretroviral Drugs 
Immune Reconstitution Syndrome:  
In some people with advanced HIV infection, symptoms from other infections or certain 
diseases may occur soon after starting combination anti-HIV treatment but can also occur later. 
Some of these symptoms may be life threatening. If you start having new symptoms, or notice 
that existing symptoms are getting worse after starting your antiretroviral therapy, tell your 
healthcare provider right away. 
 
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 
 
Integrase Inhibitor  
Dolutegravir, (DTG, Tivicay®) 
 
The following serious and potentially life-threatening side effects have been associated with the 
use of dolutegravir. These include allergic reactions and liver problems.  
 
Contact your health care provider right away if you develop a rash while taking dolutegravir, 
especially if it’s associated with any of the following symptoms: 
• 
Fever 
• 
General ill feeling 
• 
Extreme tiredness 
• 
Muscle or joint aches 
• 
Blisters or sores in your mouth 
• 
Blisters or peeling skin 
• 
Redness or swelling of your eyes 
• 
Swelling of your mouth, face, lips, or tongue 
• 
Trouble breathing 
 
Contact your health care provider right away if you have any of the following symptoms that 
could be signs of liver problems: 
• 
Yellowing of your skin or whites of your eyes (jaundice) 
• 
Dark or tea-colored urine 
• 
Pale-colored bowel movements 
• 
Nausea or vomiting 
• 
Loss of appetite 
• 
Pain, aching, or tenderness on your right side below your ribs 


 
 
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People with pre-existing history of depression or other psychiatric illness may be at greater risk 
for suicidal thoughts, or attempts, which may lead to death. If your psychiatric condition 
worsens, or if you develop suicidal thoughts, call your healthcare provider right away.  
 
Other side effects include: 
• 
Changes in liver test results, more common in people with hepatitis B or C 
• 
Trouble sleeping 
• 
Tiredness 
• 
Headache 
 
Nucleoside Analogue 
Lactic acidosis (elevated lactic acid levels in the blood) and severe hepatomegaly (enlarged 
liver) with steatosis (fatty liver) that may result in liver failure, other complications or death have 
been reported with the use of antiretroviral nucleoside analogues alone or in combination. The 
liver complications and death have been seen more often in women on these drug regimens. 
Some nonspecific symptoms that might indicate lactic acidosis include: unexplained weight loss, 
stomach discomfort, nausea, vomiting, fatigue, cramps, muscle pain, weakness, dizziness and 
shortness of breath.  
 
Lamivudine (3TC, Epivir®) 
The following side effects have also been associated with use of lamivudine: 
• 
Headache 
• 
Feeling tired  
• 
Dizziness 
• 
Numbness, tingling, and pain in the hands or feet  
• 
Depression 
• 
Trouble sleeping 
• 
Rash 
• 
Upset stomach, vomiting, nausea, loose or watery stools  
• 
Pancreatitis (inflammation of the pancreas), which may cause death. If you develop  
• 
pancreatitis, you may have one or more of the following: stomach pain, nausea, and      
vomiting.  
• 
Abnormal pancreatic and liver function blood tests 
 
If you are infected with both Hepatitis B and HIV, you should be aware that your liver function 
tests may increase, and symptoms associated with hepatitis (an acute inflammation of the liver) 
may worsen if lamivudine is stopped. Although most of these cases have resolved without 
treatment, some deaths have been reported. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
It is not known if drug combinations in this study harm unborn babies. If you are a woman and 
having sex that could lead to pregnancy, you must agree not to become pregnant. 
 


 
 
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If you are a woman participating in sexual activity that could lead to pregnancy, you and/or your 
male partner must use one form of birth control that you discuss with the study staff. You must 
start one method of birth control before you start taking the study drugs, while you are taking the 
study drugs, and for 30 days after stopping study drugs.  
• 
Condoms (male or female) with or without a spermicidal agent. Condoms are recommended 
because their appropriate use is the only contraceptive method effective for preventing HIV 
transmission.  
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) 
• 
Hormone-based contraceptive 
 
If you can become pregnant, you must have a pregnancy test before you enter this study and 
before you start taking DTG and 3TC. The test must show that you are not pregnant. Pregnancy 
tests will also be performed whenever pregnancy is suspected. If you think you may be 
pregnant at any time during the study, tell your study staff right away. Pregnancy will result in 
immediate discontinuation of the study drugs.  
 
BREASTFEEDING 
It is unknown whether the study drugs pass through breast milk and may cause harm to your 
infant. You must not breastfeed while you are in this study. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you but no guarantee can be 
made. Your health may be watched more closely than usual while you are on the study, which 
may help you to feel better. It is also possible however that you may receive no benefit from 
being in this study. Information learned from this study may help others who have HIV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study, you have the choice of: 
• 
Treatment with FDA-approved HIV prescription drugs available to you.  
• 
Treatment with HIV experimental drugs, if you qualify.  
• 
No HIV treatment. 
 
Please talk to your doctor about these and other treatment choices available to you and the 
risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the U.S. Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 


 
 
A5353 (08/14/15) 
 
 
FINAL Version 1.0 
 
APPENDIX I (Cont'd) 
Page 10 of 12 
 
participation. Also, any publication of this study will not use your name or identify you 
personally.  
 
People who may review your records include the ACTG, Office for Human Research 
Protections, FDA, your site’s institutional review board (a committee that makes sure that your 
rights and safety are protected while in the study), National Institutes of Health (NIH), study 
staff, study monitors, and other government agencies as part of their duties, and the 
pharmaceutical company supporting this study and its designees. Having a Certificate of 
Confidentiality does not prevent you from releasing information about yourself and your 
participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov. This Web site will 
not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.  
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study drugs (DTG and 3TC), the study visits, physical 
examinations, laboratory tests or other tests required by the study. You or your insurance 
company, or your health care system will be responsible for the costs of your regular medical 
care as well as for the costs of drugs not given by the study.  
 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases, it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study.  
 
 
WILL I RECEIVE ANY PAYMENT? 
 
Compensation for participating in this study will be at site’s discretion. 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of taking part in this study, you will be given treatment right away 
for your injuries and be referred for further treatment, if necessary. However, you or your 
insurance company may have to pay for this care. There is no program for compensation either 
through this institution or the NIH. You will not be giving up any of your legal rights by signing 
this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. The care that you would normally receive will not be affected if 


 
 
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APPENDIX I (Cont'd) 
Page 11 of 12 
 
you decide not to take part. Your decision will not affect other studies done by NIH in which you 
may be taking part, and will not lead to any penalty or loss of benefits that you have the right to 
expect.  
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or decision to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
• 
name of the investigator or other study staff 
• 
telephone number of above  
 
For questions about your rights as a research participant, contact: 
 
• 
name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
telephone number of above 
 


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APPENDIX I (Cont'd) 
Page 12 of 12 
SIGNATURE PAGE ACTG Study A5353 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
_________________________________ 
___________________________________ 
Participant’s Legal Representative (print) 
Legal Representative’s Signature and Date 
(As appropriate) 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 

SAP_000.pdf: 
ACTG A5353 
 
A Study to Evaluate Dolutegravir plus Lamivudine Dual Therapy for the 
Treatment of Naïve HIV-1-infected Participants 
 
Statistical Analysis Plan – Final 
 
Version 1.0 
 
9/28/2016 
 
ClinicalTrials.gov ID: NCT02582684 
 
 
This is SAP Version 1.0 with names of authors, names of publication writing team 
members, and analysis timeline redacted. 
 
 


Table of Contents 
1 
Introduction ................................................................................................................................................ 4 
2 
Study schema, hypotheses and objectives ................................................................................................ 4 
2.1 
Study schema .................................................................................................................................... 4 
2.2 
Hypothesis ......................................................................................................................................... 4 
2.3 
Primary Objective .............................................................................................................................. 5 
2.4 
Secondary Objectives ....................................................................................................................... 5 
3 
General analysis considerations ................................................................................................................ 6 
3.1 
Timing of Primary Analyses .............................................................................................................. 6 
3.2 
Study visit windows ........................................................................................................................... 6 
3.3 
Handling Multiple Observations ........................................................................................................ 6 
3.4 
Listings of Data in Reports ................................................................................................................ 6 
3.5 
Definition of Baseline......................................................................................................................... 6 
3.6 
Period of Follow-up ........................................................................................................................... 6 
3.7 
Validation of Programs ...................................................................................................................... 7 
4 
Study population ........................................................................................................................................ 7 
4.1 
Screening [Not for interim analysis] .................................................................................................. 7 
4.2 
Accrual and eligibility violations ......................................................................................................... 7 
4.3 
Baseline characteristics..................................................................................................................... 7 
5 
Study and treatment status ........................................................................................................................ 8 
5.1 
Study status ....................................................................................................................................... 8 
5.2 
Currency of Follow-Up (Interim Only) ................................................................................................ 9 
5.3 
Treatment Status ............................................................................................................................... 9 
6 
Pregnancy .................................................................................................................................................. 9 
7 
Adherence to study treatment .................................................................................................................. 10 
8 
Data completeness .................................................................................................................................. 10 
9 
Safety ....................................................................................................................................................... 10 
9.1 
Adverse Event Reporting Requirements ......................................................................................... 10 
9.2 
Summaries of Post-Entry Adverse Events ...................................................................................... 11 
10 
Primary Outcome Measure ................................................................................................................. 11 
10.1 
Virologic success at week 24 .......................................................................................................... 11 
11 
Secondary Outcome Measures ........................................................................................................... 13 


11.1 
Comparison of efficacy in participants with baseline HIV-1 RNA ≤ 100,000 vs. > 100,000 
copies/mL .................................................................................................................................................... 13 
Proportion of participants with virologic success at week 24 between participants with baseline HIV-1 RNA 
≤ 100,000 vs. > 100,000 copies/mL will be compared using Fisher’s exact test. ....................................... 13 
11.2 
Virologic success at weeks 12 and 48 [Not done for interim analysis] ........................................... 13 
11.3 
Virologic failure ................................................................................................................................ 13 
11.4 
Plasma HIV-1 RNA level < 50 and < 200 copies/mL ...................................................................... 14 
11.5 
CD4+ cell count ............................................................................................................................... 14 
11.6 
HIV-1 drug resistance mutations in participants with virologic failure ............................................. 14 
11.7 
Lipid and creatinine values [Not done for interim analysis] ............................................................. 14 
11.8 
Sign/symptoms (including Grade 2 rash) or laboratory toxicities of Grade 3 or higher, or of any 
grade which led to a permanent change in or discontinuation of study treatment ...................................... 15 
12 
Exploratory Outcome Measure [Not done for interim analysis] .......................................................... 15 
12.1 
HIV-1 minority variants in participants with virologic failure ............................................................ 15 
 
 
 


1 
Introduction 
 
This document describes the proposed content for the primary statistical analysis of ACTG A5353. This 
document focuses on analyses that address the key safety and efficacy outcome measures, including those 
needed to address the study’s primary and secondary objectives.  A subset of these analyses will form the 
basis of reports provided to the ACTG Study Monitoring Committee (SMC) while the study is ongoing. This 
analysis plan thus includes the key analyses which might lead to modification or termination of the study, 
and hence also form the core of any presentation or publication used to disseminate the primary conclusions 
of the study. It is, however, recognized that this analysis plan may be modified by the study team as new 
information becomes available outside of the study, or to reflect recommendations made by the SMC. In 
addition, some analyses, tables, or figures may be omitted at interim analyses if there are insufficient data to 
warrant analysis or at the request of the SMC. 
2 
Study schema, hypotheses and objectives 
2.1 
Study schema 
DESIGN 
This is a phase II, single-arm, open-label, pilot study of dolutegravir 
(DTG) plus lamivudine (3TC). 
All participants will undergo routine monitoring including plasma HIV-
1 RNA levels, CD4+ cell count, hematology, chemistry, and 
urinalysis. 
Population-based protease (PR), reverse transcriptase (RT), and 
integrase genotyping will be done at the time of confirmed virologic 
failure. Plasma samples will be stored for potential future studies to 
assess the impact of adherence, drug-resistant minority viral variants, 
and DTG exposure on virologic and CD4+ cell count responses to 
DTG plus 3TC. All participants will also undergo UGT1A1 genotyping. 
DURATION 
52 weeks 
SAMPLE SIZE 
120 participants 
POPULATION 
HIV-1 infected, antiretroviral (ARV) naïve men and women, 18 years 
and older, with plasma HIV-1 RNA ≥1,000 copies/mL and <500,000 
copies/mL, and with no evidence of a major PR mutation, any RT or 
any integrase mutations as defined by the 2014 International Antiviral 
Society (IAS)-USA drug resistance mutations list. At least 25% 
(N=30) of the participants will have screening HIV-1 RNA >100,000 
copies/mL. The study will aim to enroll ≥20% women. 
REGIMEN 
DTG 50 mg once a day (QD) plus 3TC 300 mg QD for 52 weeks 
 
2.2 
Hypothesis 
In treatment-naive participants, dual therapy with DTG plus 3TC is efficacious and well tolerated. 


2.3 
Primary Objective 
To estimate the virologic success rate at week 24 after initiating DTG plus 3TC. 
2.4 
Secondary Objectives 
 
To compare the efficacy of DTG plus 3TC in participants with baseline HIV-1 RNA ≤ 100,000 versus 
> 100,000 copies/mL. 
 
To estimate the virologic success rate of DTG plus 3TC therapy at weeks 12 and 48. 
 
To describe emergent integrase and RT resistance in participants with virologic failure. 
 
To evaluate the safety and tolerability of DTG plus 3TC. 
 
To evaluate changes in CD4+ cell counts and serum lipids. 
 
To store plasma samples for future studies of the impact of drug-resistant minority viral variants on 
response to DTG plus 3TC. 
 
To describe the relationships between functional genetic variants in selected UGT1A1 and other 
human genes relevant to the study drugs and responses (virologic and immunologic) as well as 
adverse events observed with DTG plus 3TC. 
 
To store random-timed plasma samples that may be used to characterize associations between 
plasma DTG exposure, adherence, responses (virologic and immunologic) as well as adverse 
events observed with DTG plus 3TC. 
 
 
 


3 
General analysis considerations 
Unless otherwise specified, data will be summarized overall and by screening HIV-1 RNA strata (≤ 
100,000 vs. > 100,000 copies/mL). Throughout this document, “study entry” is defined as the visit date of a 
participant’s entry visit captured on the study initiation case report form (ADM0010). Annotations in square 
brackets ([xxx]) will provide the source table/view names and in cases, target fields. 
3.1 
Timing of Primary Analyses 
The primary efficacy outcome measure is at week 24 while the study follow-up is week 52. Primary analysis 
will be conducted after all participants complete required follow-up for evaluation of primary efficacy 
outcome measure at week 24. Secondary analysis will commerce after all participants complete week 52 
follow-up. 
3.2 
Study visit windows 
For longitudinal outcomes, with the exception of the week 2 visit, analysis windows around each study visit 
will be defined as non-overlapping intervals spanning the entire period of follow-up starting and ending half-
way between each successive study visit at which a given evaluation is expected. For example, for clinic 
visits and HIV-1 RNA evaluations, the week 12 window will span the period from >10 to 14 weeks after 
enrollment, the week 24 visit window will span the period from >22 to 28 weeks, etc. The exception with 
respect to the week 2 visit window is that this visit window will span the entire period from after the start of 
treatment to week 3. In all cases, week 0 will include evaluations up to and including the date of study entry. 
The start time for calculation of study week will be the date of study entry (variable onstdt in status dataset).  
 
3.3 
Handling Multiple Observations 
Unless otherwise specified, in the event of multiple evaluations in a visit window, the evaluation taken 
closest to the center of the week window (the actual scheduled study week) will be used.  
Exception: multiple HIV-1 RNA evaluations in week 24 and 48 windows will be handled as per section 10. 
3.4 
Listings of Data in Reports 
Listings of data by individual study participants are described below to facilitate the interpretation of the 
study results.  To help protect confidentiality of data, the content of these lists will be limited and will not 
include dates, participants’ ACTG identifier numbers or other combinations of information that might identify 
an individual participant (except that these may be included in the confidential closed reports prepared for 
SMC review). 
3.5 
Definition of Baseline 
Baseline observations are defined as the last observations prior to the date of first dose of study treatment, 
unless otherwise specified in the protocol. 
3.6 
Period of Follow-up 
Per protocol section 6.2.3, week 24 evaluation and confirmation evaluation, if warranted, will serve as the 
evaluations for the study’s primary endpoint. Study follow-up will continue until the week 52 evaluation to 
complete study evaluation for secondary endpoints.  


3.7 
Validation of Programs 
All programs creating treatment codes, derived datasets, formats, and primary analyses will be validated in 
accordance with SOP PROG.10066 and PROG.10067. All user options files will be validated in accordance 
with SOP PROG.10071. 
The primary analyses will be additionally validated through independent coding. 
4 
Study population 
4.1 
Screening [Not for interim analysis] 
Table: number (%) screened by site and month/year   
Table: number (%) screened by screening HIV-1 RNA  
Table: number (%) screened by sex 
Table: number (%) screened by screening status (enrolled, not enrolled with detailed reason for not 
enrolled)  
 
Note: clearly state in the report that there may be multiple screen number for any one participant and there 
may be more than one reason for any screen failure.   
4.2 
Accrual and eligibility violations 
Table: number (%) enrolled by site and month/year   
Table: number (%) enrolled by screening HIV-1 RNA  
Table: number (%) enrolled by sex 
 
Note: the dates of first and last enrollments will be provided in a footnote to the table. 
List: Description of violations of eligibility criteria and details of exclusion from analyses, screening RNA 
category, site, and length of follow-up prior to exclusion due to violation [STATUS, ANSTAB].  
 
Note: Participants who are registered and later found to be ineligible will be excluded from all analyses. 
Information on how long they have been followed on the study will be provided in the list. 
Note: Participants who are registered but do not attend their entry visit (as determined from ADM0010 and 
ADM0050) will be excluded from all analyses. 
 
4.3 
Baseline characteristics 
Purpose: to describe the characteristics (demographic, health status and other key characteristics) of 
enrolled participants at study entry.  
Selected baseline characteristics will be analyzed as continuous, categorical, or both, as appropriate. Tables 
will provide the number of participants, number of missing data points, median (Q1-Q3), mean, standard 
deviation, P10 and P90, minimum and maximum for continuous variables (with transformations as 
appropriate) and number (%) for categorical variables. In the calculation of percentages, participants with 
missing data will not be included in the denominator. 
All categorical variables will have missing categories if data for a particular participant is missing. For 
interim analysis, since data comes in at different speeds depending on the CRF, there will also be a 
category available showing that the form containing the specific data has not yet been entered. This 
category will be denoted “Missing Form”. 
 


Demographic Information 
a. Age on day of study entry (years): N, N missing, mean, standard deviation, median, 1st and 3rd 
quartiles, 10th and 90th percentiles, minimum and maximum; number (%) by age group (18-29, 30-
39, 40-49, 50-59, 60+ years, rounded down) [PATIENT]. 
b. Sex: Number (%) by category (male/female) [PATIENT]. 
Note: Per protocol, the study aims to enroll at least 20% women. 
c. Self-reported race/ethnicity: number (%) by category [PATIENT]. 
 
Health Status 
a. Screening HIV-1 RNA level: number (%) by category (> 100,000 copies/mL or ≤ 100,000 copies/mL) 
[ANSTAB]. 
Note: Per protocol, the study aims to enroll at least 25% of participants with screening HIV-1 RNA > 
100,000 copies/mL. 
b. Baseline HIV-1 RNA level (copies/ml) and corresponding results for log10 copies/ml: N, median, 1st 
and 3rd quartiles, 10th and 90th percentiles, minimum and maximum; number (%) by category 
(<1,000, 1,000-9,999, 10,000-99,999, 100,000-200,000, >200,000) [RNALDMS]. 
Note: Baseline is the closest value prior to date of first dose of study treatment and after screening. 
c. Baseline CD4+ count: N, N missing, mean, standard deviation, median, 1st and 3rd quartiles, 10th 
and 90th percentiles, minimum and maximum; number (%) by category (< 200, 200- 349, 350-499, 
500-649, 650-799, ≥ 800) [LBW0054]. 
Note: Baseline is the closest value prior to date of first dose of study treatment and after screening. 
d. Baseline CD8+ count: N, N missing, mean, standard deviation, median, 1st and 3rd quartiles, 10th 
and 90th percentiles [LBW0054]. 
Note: Baseline is the closest value prior to date of first dose of study treatment and after screening. 
e. Baseline CD4:CD8 ratio: N, N missing, mean, standard deviation, median, 1st and 3rd quartiles, 10th 
and 90th percentiles, minimum and maximum. 
f. 
IV drug use: number (%) by category (never, currently, previously) [CASE]. 
g. Hepatitis C status: number (%) by category (positive, negative, indeterminate) [SR0009]. 
h. PEP or PrEP history: number (%) by category (yes, no) [HXW0171]. 
i. 
Screening resistance genotype obtained: number (%) by category (yes, no) [LBW0115]. 
5 
Study and treatment status  
Purpose: To summarize the extent of follow-up and reasons for premature study treatment and study 
discontinuation 
A CONSORT diagram will be provided at final analysis only summarizing key components of study follow-up 
and treatment status of participants, including number enrolled, starting treatment (with reasons why did not 
start treatment), complete study on study treatment, complete study off study treatment, off study 
prematurely with reason. 
5.1 
Study status 
Table: number (%) of the following categories: 
a. Complete study per protocol [STATUS] 
b. On study with subcategories of < 24 weeks on study and ≥ 24 weeks on study (interim and primary 
analysis only) [STATUS] 
c. Died [STATUS] 
d. Prematurely discontinued study for reasons other than death (with subcategories showing reason 
using coded reason). The premature study discontinuation date will be date of last participant 
contact. [STATUS, F1601] 
 


List of participants off study prematurely: site, week of study, screening RNA category, coded and specified 
reason, week of last clinic visit, week of last participant contact, and whether participants off study prior to 
reaching the study’s primary endpoint (week 24) or virologic failure [STATUS, ADM0050, F1601]. 
Table: Time (weeks) from study entry to last visit at which contact with the participant was reported: mean, 
standard deviation, median, 10th and 90th percentiles, minimum, maximum [STATUS, ADM0050]. 
Note: A footnote to this table will provide number of participants for whom last visit with contact did not 
involve the participant attending a study clinic. 
 
5.2 
Currency of Follow-Up (Interim Only) 
Table: Time (weeks) from last clinic visit to the date of data download: median, 1st and 3rd quartiles, 10th and 
90th percentiles, minimum, maximum; and number (%) by category of 0-4, 4-8, 8-12, and >12 weeks 
[STATUS & AMD0050]. 
Note: Participants who have died or discontinued study follow-up will be excluded; the number of 
participants and length of time on study before death or discontinuation of study follow-up will be included in 
a footnote. 
 
5.3 
Treatment Status 
Table: number (%) for categories as follows: 
a. Completed study treatment per protocol [F1601/TXT0004/F4003] 
b. On study treatment with subcategories of < 24 weeks on study treatment and ≥ 24 weeks on study 
treatment (interim and primary analysis only) [STATUS] 
c. Prematurely discontinued study treatment (with subcategories showing reasons) [TXT0004/F4003] 
 
Study treatment discontinuation is defined as permanent discontinuation of DTG or 3TC more than 14 days 
prior to protocol completion, death, premature study discontinuation, or the addition of an antiretroviral drug 
to the regimen for greater than one day. Analysis will be based on TXT0004 with cross-reference to 
F4003/F1601 as appropriate.  
List of participants off study treatment prematurely: site, week of study treatment, coded and specified 
reason off study treatment [F4003, STATUS].  
Table: Number (%) of days after study entry to study treatment initiation [STATUS].  
List: Participants that initiated DTG + 3TC more than 3 days after study entry with length of time to treatment 
initiation and detailed reason for delay [ADM0020]. 
Table: Number (%) of treatment interruption (Yes/no) with subcategories of duration of treatment interruption 
(days, 3-<14, 14+) [TXT0004] 
List: Participant-initiated and/or protocol-mandated treatment interruption for > 3 days detailed reason 
[TXT0004] 
6 
Pregnancy 
List: Pregnancies, study week of pregnancy test (if available), study week of pregnancy outcome, pregnancy 
outcome, delivery circumstances, ART during the entire course of the pregnancy from pregnancy report to 


two weeks after outcome, for live births: birth weight, gestational age by LMP, any congenital abnormalities 
[EVW0180]. 
7 
Adherence to study treatment 
Purpose: to summarize how compliant participants were with study treatment.  
Table: percentage of missed dose based on 4-day recall [QL0757]: median, 1st and 3rd quartile, 10th and 90th 
percentiles, minimum, maximum. The percentage of missed dose is calculated across both study drugs as 
follows: (ds1ago1 + ds1ago2 + ds1ago3 +ds1ago4 + ds2ago1 + ds2ago2 + ds2ago3 +ds2ago4)/ 
((dosnum1+dosnum2)*4).  
Note: if answer to Question 1 is No, then the percentage of missed dose will not be calculated.  
8 
Data completeness 
Purpose: to summarize how compliant participants were with visits, study-defined evaluations, and CRFs 
and laboratory data are being recorded in the database in a timely fashion. Data completeness will not be 
presented by stratum.   
Table: Summary of missed visits and reasons for missed visits, if missing data is an issue. 
 
Tables: Data availability for the following key study tests, measurements, and specimens: HIV-1 RNA 
[RNALDMS], CD4+ cell count [LBW0054], CD8+ cell count [LBW0054], self-reported adherence form 
completion [QL0757], whole blood storage for pharmacogenomics [L_ALIQ], stored plasma for minority viral 
variants [L_ALIQ], total fasting cholesterol [F2861], and serum creatinine [LBW0144]. The weeks at which 
each measurement is expected are detailed in the visit and evaluation schedule in section 3.4 above. Each 
table will include study week, participants expected to have data entered, observed visits among those 
expected, and the number of complete observations of the measurement of interest. 
 
9 
Safety 
9.1 
Adverse Event Reporting Requirements 
Protocol section 6.3 states the following reporting requirements:  
Signs and Symptoms 
Grade ≥ 2 rash and all other grade ≥3, any signs and symptom lead to a change in treatment 
regardless of grade [EVW0314]. 
 
Diagnoses 
All diagnoses identified by the ACTG criteria for clinical events and other diseases [EVW0314]. 
Laboratory Evaluations 
Grade ≥ 3 or any laboratory toxicities that lead to a change in treatment, regardless of grade 
[EVW0314].  
Note: Creatinine and fasting lipid values are required to be reported regardless of grade are not 
considered adverse events unless they are Grade ≥ 3 or lead to a change in treatment. 
 


9.2 
Summaries of Post-Entry Adverse Events 
Table: Summary of adverse events [EVW0314] presented by MedDRA preferred term (PT) according to 
primary system organ class (SOC) and grade giving the number (%) of participants reporting at least one 
event (PT) and the number (%) of participants reporting at least one event within each SOC. Participants will 
be counted only once (at the highest reported grade for the PT, SOC, and overall totals. 
Table: Summary of adverse events [EVW0314] by type (sign/symptom, diagnosis, laboratory measurement, 
and death) giving the number (%) of participants within each category and overall. 
List: Listing of all adverse events [EVW0314] by participant (publicid). The listing will detail the participant, 
scheduled study week of the event, the type of event (sign/symptom, diagnosis, laboratory measurement, 
and death), the specific name of the event, whether the event was resolved, the event grade, and whether 
the event was related to study treatment. Associated events will be indented to the associated primary 
events.  
List: narrative of all deaths including weeks on study at time of death, week of last study evaluation, baseline 
and most recent HIV-1 RNA and CD4 count, weeks since the last dose of study treatment, weeks since the 
last dose of other ART treatment (if applicable), last ART regimen, and site’s reports of primary cause of 
death (text, categorization and diagnosis), and site’s determination of relatedness to study treatment. 
 
10 
Primary Outcome Measure 
10.1 Virologic success at week 24 
Primary efficacy outcome of the study is virologic success at week 24. Virologic success is defined as HIV-1 
RNA < 50 copies/mL and on study treatment (FDA Snapshot definition: Human immunodeficiency virus-1 
infection: developing antiretroviral drugs for treatment guidance for industry, November 2015).  
The virologic success at week 24 will be tabulated as below: 
Virologic Success  
N (%) 
       HIV-1 RNA < 50 copies/mL 
N 
Virologic Non-success 
N (%) 
       HIV-1 RNA ≥ 50 copies/mL 
N  
       Discontinued study drug for lack of efficacy 
N 
       Discontinued study drug for other reasons; HIV-1 RNA ≥ 
50 copies/mL 
N  
       Discontinued study drug for other reasons; HIV-1 RNA < 
50 copies/mL 
N  
No Virologic Data at Week 24 window 
N (%) 
       Discontinued study/study drug due to AE or Death 
N 
       Discontinued study/study drug for Other Reasons 
N  
       On study but missing data in window 
N  


 
Table: Primary outcome measure evaluability N(%): Evaluable vs. HIV-1 RNA pending. [For interim 
analysis only] 
Table: Proportion of participants with virologic success and 95% CI. 
 
Notes: 
 
The primary outcome window at week 24 is defined as week 22-28, i.e., 155-196 days, inclusive. The 
window is defined based on the guidance “Window size is one-half the duration of time between study 
visits”.  
 
 
For interim analysis: 
 
o 
Evaluable participants are those with week 24 visit (ADM0020 visit form and/or HIV-1 RNA 
results in database) or those who discontinued the study prior to the visit window.  
 
o 
Participants with premature study discontinuation will be evaluated for primary outcome 
measure regardless whether their potential on-study follow-up would reach week 24 by data 
retrieval date.  
 
 
Snapshot analysis follows a Virology First hierarchy. Because this is primarily a virologic endpoint, the 
hierarchy for assessing row and column percentages is HIV-1 RNA < 50 copies/mL or HIV RNA ≥ 50 
copies/mL, first, for any given window followed by reasons for No Virologic Data in the window. 
 
 
Data in the window 
o 
Virologic outcome should be determined by the last available measurement while the participant 
is on treatment and continued on study within the time window. 
o 
Participants who had changes in ART will be counted as virologic non-success. 
 
 
No data in the window 
o 
Discontinued study due to Adverse Event or Death.  
 
Any participant who discontinues because of an AE or death before the window should 
be classified as Discontinued due to AE or Death, regardless of the HIV-1 RNA result, 
even if the HIV-1 RNA < 50 copies/mL at the time of discontinuation.  
 
If a participant has an HIV-1 RNA in the time window and also discontinues after the 
viral load was tested in the time window, the viral load data should be used to classify 
the participant’s response. 
o 
Discontinued study for Other Reasons 
 
If a participant discontinues the study before the window because of lack of efficacy 
then the participant should be included in the HIV-1 RNA ≥ 50 copies/mL row and not in 
the Discontinued for Other Reasons row.  
 
For participants who discontinued for Other Reasons, it is important to realize that in the 
Virology First hierarchy only participants who have achieved virologic suppression can 
be counted as Discontinued for Other Reasons. Example, if a participant discontinues 
because of the withdrew of consent and the HIV-1 RNA at the time of discontinuation 
was ≥ 50 copies/mL, then s/he should be categorized as HIV RNA ≥ 50 copies/mL and 
not Discontinued for Other Reasons. 
o 
On study but missing data in window 
 
Only participants remaining on study but with missing virologic data should be classified 
as this category.  
 
 
Dataset for Snapshot approach should contain, at minimum, the following information: 
o 
PATID 


o 
Study day and date of last study treatment 
o 
Virologic outcome based on the Snapshot approach (i.e., HIV-1 RNA < 50 copies/mL, HIV-1 
RNA ≥ 50 copies/mL, Discontinued due to AE or death, Discontinued for Other Reasons, On 
study but missing data during window) 
o 
HIV-1 RNA measurement and the corresponding study day and date used to determine the 
above virologic outcome if the measurement was not missing 
o 
Study day and date when the participant switched to non-study treatment because of lack or 
loss of virologic suppression (VF), if applicable 
o 
Study day and date for permanent study discontinuation, reason for discontinuation, and last on 
study treatment HIV-1 RNA measurement before discontinuation for the participants who 
discontinued study treatment 
 
11 Secondary Outcome Measures 
11.1 Comparison of efficacy in participants with baseline HIV-1 RNA ≤ 100,000 vs. > 100,000 
copies/mL 
Proportion of participants with virologic success at week 24 between participants with baseline HIV-1 RNA 
≤ 100,000 vs. > 100,000 copies/mL will be compared using Fisher’s exact test. 
 
11.2 Virologic success at weeks 12 and 48 [Not done for interim analysis] 
The analysis of virologic success at weeks 12 and 48 will follow the same approach for virologic success at 
week 24 (section 12.1). 
Notes: 
 
The outcome window at week 12 is defined as week 10-14, i.e., 71-98 days.   
 
The outcome window at week 48 is defined as week 44-52, i.e., 309-364 days.  Since week 52 is the 
final study visit, the window will be the latter of (last day of study follow-up and 364 days).  
 
11.3 Virologic failure 
Virologic failure is defined as follows (in protocol section 6.2.3): 
 
Weeks 16 or 20: 
 
o 
confirmed plasma HIV-1 RNA > 400 copies/mL 
 
Week 24 or later: 
 
o 
confirmed plasma HIV-1 RNA > 200 copies/mL 
Notes: 
 
Participants are evaluated for virologic failure regardless of whether on study treatment. 
 
Confirmation will be determined based on any two consecutive evaluations meeting the virologic failure 
definition regardless of the time between them. 
 
Participants discontinuing the study (for any reason, including death and lost to follow-up) will be 
considered a virologic failure if their last measurement meets the definition of virologic failure but no 
confirmatory measurement was obtained. All other participants’ follow-up will be censored immediately 
after the last available plasma HIV-1 RNA measurement. 
 
 
Table: N (%) of virologic failures and by subcategories of prior to week 16, after week 16 and prior to week 
24, and after week 24.  
 
Table: Frequency of days from date of initial VF measurement to date of confirmation measurement (< 7 
days, ≥7-≤28 days, > 28 days, lost to follow-up) 


 
Table: Kaplan-Meier estimates of the cumulative probability of VF overall with 95% confidence intervals 
estimated with Greenwood’s variance at weeks 24 and 48. 
 
Figure: Kaplan-Meier curve 
 
 
11.4 Plasma HIV-1 RNA level < 50 and < 200 copies/mL 
Three analyses will be performed with alternative considerations of missing data, treatment discontinuation 
and loss to follow-up: 
 
ITT, pure virologic missing=ignored. The numerator will include participants with HIV-1 RNA < 50 (200) 
copies/mL; the denominator will include all participants with an HIV-1 RNA evaluation at the given week.  
 
ITT missing/off study/off treatment=failure. The numerator will include participant with HIV-1 RNA < 50 
(200) copies/mL and still on initial treatment; the denominator will include all participants with potential 
for the given week of follow-up based on the date of registration. 
 
AT, purely virologic missing=ignored. The numerator will include participants with HIV-1 RNA < 50 (200) 
copies/mL and still on initial treatment; the denominator will include participants on initial treatment with 
an HIV-1 RNA evaluation at the given week.  
 
Note: at interim analyses, only ITT, pure virologic missing=ignored approach will be used. 
Table: proportions of participants with HIV-1 RNA < 50 (200) copies/mL at each study week with exact 95% 
confidence intervals.   
Figure: Plot of the proportions of participants with HIV-1 RNA < 50 (200) copies/mL at each study week with 
exact 95% confidence intervals. 
11.5 CD4+ cell count 
Table: Mean (95% confidence interval), standard deviation, min, max, median, 25th and 75th percentile of 
CD4+ T-cell counts at all scheduled study weeks. 
Table: Mean (95% confidence interval), standard deviation, min, max, median, 25th and 75th percentile of 
CD4+ T-cell count changes from baseline at all scheduled study weeks. 
Figure: Plot of the mean CD4 T-cell count at each study week with 95% confidence intervals. 
Figure: Plot of the mean CD4 T-cell count change at each study week with 95% confidence intervals. 
 
11.6 HIV-1 drug resistance mutations in participants with virologic failure 
List: HIV-1 drug resistance mutations by participants 
 
11.7 Lipid and creatinine values [Not done for interim analysis] 
Table: Mean (95% confidence interval), standard deviation, min, max, median, 25th and 75th percentile of  
creatinine, total cholesterol (fasting), triglycerides, LDL cholesterol (fasting), HDL cholesterol (fasting), and 
glucose (fasting) at all scheduled study weeks. 
Table: Mean (95% confidence interval), standard deviation, min, max, median, 25th and 75th percentile of 
creatinine, total cholesterol (fasting), triglycerides, LDL cholesterol (fasting), HDL cholesterol (fasting), and 
glucose (fasting) changes from baseline at all scheduled study weeks. 


Figure: Plot of the mean creatinine, total cholesterol (fasting), triglycerides, LDL cholesterol (fasting), HDL 
cholesterol (fasting), and glucose (fasting) at each study week with 95% confidence intervals. 
 
11.8 Sign/symptoms (including Grade 2 rash) or laboratory toxicities of Grade 3 or higher, or of any 
grade which led to a permanent change in or discontinuation of study treatment 
Table: Summary of Grade 2 rash and other adverse events Grade 3 or higher, or of any grade which led to a 
permanent change in or discontinuation of study treatment with onset date on or after the initiation of study 
treatment [EVW0314] by type (sign/symptom, diagnosis, laboratory measurement, and death) giving the 
number (%) of participants within each category and overall. 
List: Listing of all signs/symptoms (including Grade 2 rash) or laboratory toxicities of grade 3 or higher or 
which led to permanent change in or discontinuation of study treatment [EVW0314], including participant 
(publicid), scheduled study week of the event, the type of event (sign/symptom, laboratory measurement), 
the specific name of the event, whether the event was resolved, the event grade, and whether the event was 
related to study treatment. Associated events will be indented to the associated primary events. 
12 Exploratory Outcome Measure [Not done for interim analysis] 
12.1 HIV-1 minority variants in participants with virologic failure 
List: HIV-1 minority variants by participants.