Clinical trial NCT02519777
Conditions: HIV Infections
Keywords: HIV-Associated Neurocognitive Disorder
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2016-04-21; Completion date: 2021-01-05
Enrollment: 191 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
People infected with HIV often have cognitive dysfunction even if they are on antiretroviral therapy (ART) and have undetectable viral loads. The study evaluated if the addition of maraviroc (MVC) and dolutegravir (DTG) (which are two antiretroviral \[ARV\] medications) to participants' existing ART regimens improved participants' neurocognitive performance.

Detailed description:
HIV-infected people often have cognitive dysfunction (HIV-associated neurocognitive disorder, or HAND), which includes asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD), even if they are on ART and have undetectable viral loads. In this study, researchers evaluated the effectiveness of adding MVC and DTG to the current ART regimen of HIV-infected people with undetectable (\<50 copies/mL) plasma HIV-1 RNA who had neurocognitive impairment and who had been on stable ART for at least 6 months prior to study entry. The purpose of this study was to evaluate if the addition of MVC and DTG to participants' existing ART regimens improved participants' neurocognitive performance.

Participants were randomly assigned to one of three arms. All participants remained on their existing ART regimens; they took their assigned study drugs in addition to their ART regimen. Study visits occurred at entry and Weeks 2, 4, 12, 24, 48, 72, and 96. Visits may have included physical examinations, blood collection, neurocognitive testing, pregnancy testing, and questionnaires. Some participants may have had an optional lumbar puncture procedure at study entry and Week 48. Participants returned for refills of study drugs on Weeks 36, 60, and 84.

Arms: arm 1: In addition to their existing ART regimens, participants in Arm A received placebo for MVC and placebo for DTG. arm 2: In addition to their existing ART regimens, participants in Arm B received DTG and placebo for MVC. arm 3: In addition to their existing ART regimens, participants in Arm C received MVC and DTG
Interventions: intervention 1: Placebo for maraviroc (MVC) intervention 2: Placebo for dolutegravir (DTG) intervention 3: Dolutegravir (DTG) intervention 4: Maraviroc (MVC)
Intervention descriptions: intervention 1: Administered orally as one 150 mg tablet BID OR two 300 mg tablet BID OR one 300 mg tablet BID depending upon background ARV regimen intervention 2: Administered orally as one 50 mg tablet BID OR one 50 mg tablet QD depending upon background ARV regimen intervention 3: Administered orally as one 50 mg tablet BID OR one 50 mg tablet QD depending upon background ARV regimen intervention 4: Administered orally as one 150 mg tablet BID OR two 300 mg tablet BID OR one 300 mg tablet BID depending upon background ARV regimen

Protocol documents:
Prot_ICF_000.pdf: 
 
 
 
 
 
A5324 
 
 
A Randomized, Double-Blinded, Placebo-Controlled Trial Comparing 
Antiretroviral Intensification with Maraviroc and Dolutegravir with No 
Intensification or Intensification with Dolutegravir Alone for the Treatment of 
Cognitive Impairment in HIV 
 
 
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# 126,854 
 
 
The ACTG Neurology  
Collaborative Science Group:  
 
 
Scott Letendre, MD, Chair 
 
 
Protocol Chair:  
Kevin Robertson, PhD 
 
 
 
Protocol Co-Chair: 
Serena Spudich, MD 
 
Protocol Vice-Chair:  
Scott Letendre, MD  
 
 
DAIDS Clinical Representative: 
 
 
Beverly L. Alston-Smith, MD 
 
Clinical Trials Specialist: 
Jhoanna C. Roa, MD 
 
 
 
 
 
 
 
 
Final Version 2.0 
August 25, 2017 
 
 


A5324 
Final Version 2.0 
 
 
08/25/17 
 
 
A Randomized, Double-Blinded, Placebo-Controlled Trial Comparing 
Antiretroviral Intensification with Maraviroc and Dolutegravir with No 
Intensification or Intensification with Dolutegravir Alone for the Treatment of 
Cognitive Impairment in HIV 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all 
applicable protocol-related documents. I agree to conduct this study in compliance with 
United States (US) Health and Human Service regulations (45 CFR 46); applicable U.S. 
Food and Drug Administration regulations; standards of the International Conference on 
Harmonization Guideline for Good Clinical Practice (E6); Institutional Review 
Board/Ethics Committee determinations; all applicable in-country, state, and local laws 
and regulations; and other applicable requirements (e.g., US National Institutes of Health, 
Division of AIDS) and institutional policies. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
Name/Title 
 
 
 


A5324 
Final Version 2.0 
 
 
08/25/17 
 
 
 
CONTENTS 
Page 
 
SITES PARTICIPATING IN THE STUDY .................................................................................... 5 
PROTOCOL TEAM ROSTER ..................................................................................................... 6 
STUDY MANAGEMENT ........................................................................................................... 10 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 13 
SCHEMA .................................................................................................................................. 14 
1.0 
HYPOTHESES AND STUDY OBJECTIVES.................................................................. 15 
1.1 
Hypotheses ........................................................................................................ 15 
1.2 
Primary Objectives ............................................................................................. 15 
1.3 
Secondary Objectives ........................................................................................ 15 
2.0 
INTRODUCTION ........................................................................................................... 16 
2.1 
Background/Rationale ........................................................................................ 16 
3.0 
STUDY DESIGN ........................................................................................................... 24 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ............................................... 25 
4.1 
Inclusion Criteria ................................................................................................ 25 
4.2 
Exclusion Criteria ............................................................................................... 27 
4.3 
Study Enrollment Procedures............................................................................. 29 
4.4 
Coenrollment Guidelines .................................................................................... 30 
5.0 
STUDY TREATMENT ................................................................................................... 31 
5.1 
Regimens, Administration, and Duration ............................................................ 31 
5.2 
Study Product Formulation and Preparation ....................................................... 32 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 33 
5.4 
Concomitant Medications ................................................................................... 33 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 34 
6.1 
Schedule of Evaluations ................................................................................... 34 
6.2 
Timing of Evaluations ......................................................................................... 36 
6.3 
Instructions for Evaluations ................................................................................ 37 
7.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 46 
7.1 
Toxicity Management ......................................................................................... 46 
7.2 
Additional Considerations for Participants Infected with Hepatitis B 
Virus (HBV) ........................................................................................................ 51 
7.3 
Pregnancy.......................................................................................................... 51 
7.4 
Breastfeeding ..................................................................................................... 52 
7.5 
Unblinding .......................................................................................................... 52 
7.6 
Antiretroviral Therapy Changes ...................................................................... 52 


 
A5324 
Final Version 2.0 
 
CONTENTS (Cont'd)  
08/25/17 
 
 
Page 
 
8.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 52 
8.1 
Premature Treatment Discontinuation ................................................................ 52 
8.2 
Premature Study Discontinuation ....................................................................... 53 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 53 
9.1 
General Design Issues ....................................................................................... 53 
9.2 
Outcome Measures .......................................................................................... 54 
9.3 
Randomization and Stratification ........................................................................ 55 
9.4 
Sample Size and Accrual ................................................................................... 56 
9.5 
Monitoring .......................................................................................................... 58 
9.6 
Analyses ............................................................................................................ 59 
10.0 
PHARMACOLOGY PLAN .............................................................................................. 61 
10.1 
Pharmacology Objectives .................................................................................. 61 
10.2 
Pharmacology Study Design .............................................................................. 62 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis .............................. 63 
10.4 
Anticipated Outcomes ........................................................................................ 63 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 63 
11.1 
Records to Be Kept ............................................................................................ 63 
11.2 
Role of Data Management ................................................................................. 63 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 64 
11.4 
Expedited Adverse Event Reporting to DAIDS ................................................... 64 
12.0 
PARTICIPANTS ............................................................................................................ 65 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 65 
12.2 
Participant Confidentiality ................................................................................. 66 
12.3 
Study Discontinuation ........................................................................................ 66 
13.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 66 
14.0 
BIOHAZARD CONTAINMENT ...................................................................................... 66 
15.0 
REFERENCES .............................................................................................................. 67 
APPENDIX I:  SAMPLE INFORMED CONSENT 


 
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SITES PARTICIPATING IN THE STUDY 
 
A5324 is a multicenter study and will be opened only at US and select non-US AIDS Clinical 
Trials Group (ACTG) clinical research sites (CRSs). Refer to the Site tab on the protocol’s 
web page on the ACTG Member website for the list of eligible non-US CRSs.


 
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PROTOCOL TEAM ROSTER 
 
Chair 
Kevin Robertson, PhD 
Department of Neurology 
School of Medicine 
University of North Carolina  
2127 Physicians Office Building 
170 Manning Drive 
Chapel Hill, NC 27599-7025 
Phone: 919-966-5549 
FAX: 919-966-2922  
E-Mail: kevinr@neurology.unc.edu 
 
Co-Chair 
Serena Spudich, MD 
Neurology 
Yale University School of Medicine  
Cornell CRS 
P.O. Box 208018 
15 York Street 
New Haven, CT 06520 
Phone: 650-400-1222 
FAX: 203-737-2704 
E-Mail: serena.spudich@yale.edu 
 
Vice Chair 
Scott Letendre, MD 
UCSD Antiviral Research Center 
220 Dickinson Street, Suite A 
San Diego, CA 92103 
Phone: 619-543-8080 
FAX: 619-298-0177 
E-Mail: sletendre@ucsd.edu 
 
DAIDS Clinical Representative  
Beverly L. Alston-Smith, MD 
Complications and Co-Infectious 
Research Branch  
TRP, DAIDS, NIAID, NIH 
5601 Fishers Lane, 9F50 
Rockville, MD  20852 
Phone: 301-435-3773 
FAX: 301-480-4522 
E-Mail: balston@niaid.nih.gov  
Clinical Trials Specialist 
Jhoanna C. Roa, MD 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3196 
FAX: 301-628-3302 
E-Mail: jroa@s-3.com 
 
Statisticians 
Huichao Chen, PhD 
Statistical & Data Analysis Center  
Harvard School of Public Health  
FXB Building, Room 607  
651 Huntington Avenue  
Boston, MA 02115-6017 
Phone: 617-432-0040 
FAX: 617-432-2843 
E-Mail: hchen@sdac.harvard.edu  
 
Ashley McKhann, MS 
Statistical & Data Analysis Center  
Harvard School of Public Health  
FXB Building, Room 604B  
651 Huntington Avenue  
Boston, MA 02115-6017 
Phone: 617-432-7986 
FAX: 617-432-2843 
E-Mail: amckhann@sdac.harvard.edu 
 
Data Manager 
Dave Rusin, MT (ASCP), CCRP 
Frontier Science & Technology Research 
Foundation, Inc.  
4033 Maple Road  
Amherst, NY  14226-1056 
Phone: 716-834-0900 x7333  
FAX: 716-834-8432 
E-Mail: rusin.david@fstrf.org 
 


 
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PROTOCOL TEAM ROSTER (Cont’d) 
08/25/17 
 
DAIDS Pharmacist 
Nayri Khairalla, PharmD, BS 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane, 9D35 
Rockville, MD 20852 
Phone: 301-761-6659 
FAX: 240-627-3112 
E-Mail: nayri.khairalla@nih.gov   
 
Immunologist 
Peter Hunt, MD 
University of California 
San Francisco AIDS CRS 
SFGH Building 80, Ward 84 
995 Potrero Avenue 
San Francisco, CA 94110 
Phone: 415-476-4082 Ext. 345 
FAX: 415-476-6953 
E-Mail: phunt@php.ucsf.edu 
 
Pharmacologists 
Qing Ma, PhD 
NYS Center of Excellence in Bioinformatics 
and Life Sciences 
University of Buffalo 
701 Ellicott Street 
Buffalo, NY 14203 
Phone: 716-881-7500 
FAX: 716-645-2886 
E-Mail: qingma@buffalo.edu 
 
Gene Morse, PharmD 
Translational Pharmacology Research Core 
NYS Center of Excellence in Bioinformatics 
and Life Sciences 
University of Buffalo 
701 Ellicott Street 
Buffalo, NY 14203 
Phone: 716-881-7464 
FAX: 716-645-3635 
E-Mail: emorse@buffalo.edu 
 
Virologist 
Robert W. Coombs, MD, PhD 
University of Washington Retrovirology 
Laboratory  
Research and Training Building, 7th floor  
325 9th Avenue  
Seattle, WA  98104 
Phone: 206-897-5205 
FAX: 206-897-5203 
E-Mail: bcoombs@u.washington.edu 
 
Investigators 
Thomas Campbell, MD 
University of Colorado Hospital CRS 
Division of Infectious Diseases 
Mail Stop B-168, Room P15-11001 
12700 E. 19th Avenue 
Aurora, CO 80045 
Phone: 303-724-4929 
FAX: 303-724-4926 
E-Mail: thomas.campbell@ucdenver.edu 
 
Eric Daar, MD 
Los Angeles Biomedical Research Institute 
Harbor-UCLA Medical Center CRS 
1124 West Carson Street, Building N-24 
Torrance, CA 90502 
Phone: 310-222-2467 
FAX: 310-533-0447 
E-Mail: edaar@labiomed.org 
 
Christina Marra, MD 
Department of Neurology 
University of Washington  
Harborview Medical Center 
Box 359775 
325 9th Avenue 
Seattle, WA 98104-2499 
Phone: 206-897-5400 
FAX: 206-897-5401 
E-Mail: cmarra@u.washington.edu 
 


 
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PROTOCOL TEAM ROSTER (Cont’d) 
08/25/17 
 
Investigators (cont’d) 
Aaron McMurtray, MD, PhD  
Department of Neurology  
Harbor-UCLA Medical Center  
1000 West Carson Street  
Torrance, CA 90509  
Phone: 310-222-3897  
E-Mail: amcmurtray@hotmail.com 
 
NIMH Representative 
Deborah Ann Colosi, PhD 
Division of AIDS Research 
National Institute of Mental Health/NIH  
6001 Executive Boulevard 
NSC 6115D-9619 
Bethesda, MD 20892  
Phone: 301-443-8542 
E-Mail: Deborah.Colosi@nih.gov 
 
NINDS Representative 
May Wong, PhD  
NeuroAIDS & Infectious Diseases  
National Institute of Neurological Disorders 
and Stroke/NIH 
6001 Executive Boulevard 
Neuroscience Center, Room 2113  
Bethesda, MD  20892-9521  
Phone: 301-496-1431  
FAX: 301-402-2060  
E-Mail: wongm@ninds.nih.gov  
 
Field Representative 
Baiba Berzins, MPH 
Division of Infectious Diseases 
Feinberg School of Medicine 
Northwestern University  
645 N. Michigan Avenue, Suite 900 
Chicago, IL 60611 
Phone: 312-695-5012 
FAX: 312-695-5088 
E-Mail: baiba@northwestern.edu 
 
Laboratory Technologist 
Robin DiFrancesco, MT (ASCP), MBA 
Translational Pharmacology Research 
Core 
NYS Center of Excellence in 
Bioinformatics and Life Sciences 
701 Ellicott Street 
Buffalo, NY 14203 
Phone: 716-881-7465  
FAX: 716-849-6890 
E-Mail: rda@buffalo.edu  
 
Community Scientific Subcommittee (CSS) 
Representative 
Larry N. Lyle, DO, MS 
University of California, San Diego 
AntiViral Research Center CRS 
3719 Louisiana Street 
San Diego, CA 92104-3212 
Phone: 619-368-3408 
FAX: 619-299-4775 
E-Mail: lyledo2004@yahoo.com  
 
International Site Specialist 
Mary Allegra Cermak, MFA 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3312 
FAX: 301-628-3302 
E-Mail: acermak@s-3.com  
 
Industry Representative  
Belinda Ha, PhD 
ViiVHealthcare Ltd. 
Five Moore Drive 
Research Triangle Park, NC 27709 
Phone: 919-483-8284 
FAX: 919-483-8999 
E-Mail: belinda.f.ha@gsk.com 
 


 
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PROTOCOL TEAM ROSTER (Cont’d) 
08/25/17 
 
Laboratory Data Manager 
Andee Fox, MPH 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7276 
E-Mail: fox@fstrf.org 
 
 
 
 
 
 
 
 
 


 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5324@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5324@fstrf.org. A 
response should generally be received within 24 hours (Monday-Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5324 e-mail group. 
Include the protocol number in the e-mail subject line.  
• 
Send an e-mail message to actg.user.support@fstrf.org  
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact the Core team.  
• 
Send an e-mail message to actg.coreA5324@fstrf.org. Include the protocol number, 
patient identification number (PID), and a brief relevant history. 
 
Immunology 
For questions specifically related to immunologic tests, contact the protocol immunologist. Send 
an e-mail message to actg.coreA5324@fstrf.org (ATTN: Peter Hunt). 
 
Pharmacology 
For questions specifically related to pharmacologic laboratory tests, contact the protocol 
pharmacologists. Send an e-mail message to actg.coreA5324@fstrf.org (ATTN: Qing Ma and 
Gene Morse). 
 
Virology 
For questions specifically related to virologic laboratory tests, contact the protocol virologist. 
Send an e-mail message to actg.coreA5324@fstrf.org (ATTN: Robert Coombs). 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, case report forms 
(CRF), the CRF schedule of events, randomization/registration, and other data 
management issues, contact the data manager. CRFs can be downloaded from the 
FSTRF website at www.frontierscience.org.  
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Dave 
Rusin (rusin.david@fstrf.org) directly.  
• 
For other questions, send an e-mail message to actg.coreA5324@fstrf.org (ATTN: 
Dave Rusin).  
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration  
For randomization/participant registration questions or problems and study identification 
number SID lists.  
• 
Send an e-mail message to rando.support@fstrf.org or call the DMC Randomization 
Desk at 716-834-0900, extension 7301.   


 
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Computer and Screen Problems  
Contact the SDAC/DMC programmers. 
• 
Send an e-mail message to actg.user.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 e-
mail message to actg.coreA5324@fstrf.org (ATTN: Jhoanna Roa). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send an email message to ACTGNCC@s-3.com 
(ATTN: Diane Delgado). Electronic copies can be downloaded from the ACTG website at 
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 e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation, contact the clinical trials specialist at 
jroa@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, call 
Nayri Khairalla, protocol pharmacist, at 301-761-6659.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
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.  
 
Telephone Calls 
Sites are responsible for documenting any phone calls made to A5324 team members. 
• 
Send an e-mail to actg.coreA5324@fstrf.org. 
 


 
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Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 


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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
ADL 
 
activities of daily living 
ANI  
 
asymptomatic neurocognitive impairment 
BDI-II  
Beck Depression Inventory II 
BMI 
 
body mass index 
CLIA  
Clinical Laboratory Improvement Amendments 
CPE 
 
CNS Penetration Effectiveness  
CSF 
 
cerebrospinal fluid 
DTG 
 
dolutegravir or Tivicay 
HAD 
 
HIV-associated dementia  
HAND  
HIV-associated neurocognitive disorder 
HTLV-1 
human T-lymphotropic virus type 1 
HVLT-R 
Hopkins Verbal Learning Test Revised 
IHDS  
International HIV Dementia Scale 
IP-10  
interferon gamma-induced protein 10 
LAR 
 
legally authorized representative 
LP 
 
lumbar puncture  
LPS 
 
lipopolysaccharide  
LTR 
 
long terminal repeat sequences 
MCP-1  
monocyte chemoattractant protein-1 
MND   
mild neurocognitive disorder 
MVC  
maraviroc or Selzentry 
NFL 
 
neurofilament light chain  
PHQ-9  
Patient Health Questionnaire-9 
PML 
 
progressive multifocal leukoencephalopathy 
RLS 
 
resource limited settings 
 
RPR 
 
rapid plasma reagin 
TB 
 
tuberculosis 
TBI 
 
traumatic brain injury 
VF 
 
virologic failure 
VDRL  
venereal disease research laboratory 
WAT  
Word Accentuation Test 
WRAT-4 
Wide Range Achievement Test 4  
 


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SCHEMA 
 
 
A5324 
 
A Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral 
Intensification with Maraviroc and Dolutegravir with No Intensification or Intensification with 
Dolutegravir Alone for the Treatment of Cognitive Impairment in HIV  
 
 
DESIGN 
This is a phase IV randomized, double-blinded, placebo-controlled study 
to assess the efficacy of adding maraviroc (MVC) and dolutegravir (DTG) 
to the current antiretroviral therapy (ART) of HIV-infected individuals with 
undetectable (<50 copies/mL) plasma HIV-1 RNA, who have mild to 
moderate neurocognitive impairment, with a primary outcome of 
improvement in neurocognitive performance.  
 
 
DURATION 
96 weeks 
 
 
SAMPLE SIZE 
186 participants 
 
 
POPULATION  
Participants will have HIV-associated neurocognitive disorder (HAND) as 
defined by the Frascati criteria, plasma HIV-1 RNA <50 copies/mL within 
90 days prior to entry, and no more than one plasma HIV-1 RNA ≥50 and 
<200 copies/mL in the past 6 months prior to entry with a subsequent 
plasma HIV-1 RNA <50 copies/mL, and on stable ART for at least 6 
months prior to entry with no plans to change treatment. 
 
 
STRATIFICATION  
Participants will be randomized in a stratified manner. Stratification 
variables will be CD4+ nadir (≤100 vs. >100 cells/mm3), and HAND 
severity (asymptomatic neurocognitive impairment [ANI] vs. mild 
neurocognitive disorder [MND] / HIV-associated dementia [HAD]). 
 
 
REGIMEN 
At entry participants will be randomized to one of the following: 
 
Arm A: Add to their existing ART: placebo for MVC and placebo for DTG 
 
Arm B: Add to their existing ART: DTG and placebo for MVC  
 
Arm C: Add to their existing ART: MVC and DTG 
 
 


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1.0 
HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Hypotheses 
 
1.1.1 Primary 
 
In HIV-1-infected participants with suppressed plasma viremia and at least mild 
neurocognitive impairment, improved neurocognition and increased functional 
capacity over 48 weeks will be seen with addition of maraviroc (MVC) plus 
dolutegravir (DTG) (Arm C) compared to DTG only (Arm B) and compared to 
placebos (Arm A). Addition of DTG only (Arm B) compared to placebos (Arm A) 
will result in improved neurocognition over 48 weeks and increased functional 
capacity.   
 
1.1.2 Secondary 
 
Changes in peripheral blood and cerebrospinal fluid (CSF) biomarkers will 
parallel improvement in neurocognitive performance following addition of DTG 
alone or MVC and DTG.  
 
1.2 
Primary Objectives 
 
 
1.2.1 To determine whether intensification with MVC and DTG (Arm C) will improve 
neurocognitive functioning at week 48 in participants who have at least mild 
neurocognitive impairment, are on a stable antiretroviral therapy (ART) regimen, 
and have plasma HIV-1 RNA <50 copies/mL, over DTG plus placebo for MVC 
(Arm B) and over placebo of both drugs (Arm A). 
 
1.2.2 To determine whether DTG with placebo for MVC (Arm B) will improve 
neurocognitive functioning at week 48 over placebo of both drugs (Arm A). 
 
1.3  
Secondary Objectives 
 
1.3.1 To determine the safety and tolerability of MVC and DTG when added to a stable 
ART regimen. The safety and tolerability measures will include time to 
discontinuation of any study medication due to adverse events (AEs), proportion 
of Grade 3 or Grade 4 clinical AEs, proportion of Grade 3 or Grade 4 laboratory 
abnormalities, and summaries of all treatment-related AEs.  
 
1.3.2 To determine whether intensification with MVC and DTG will improve 
neurocognitive functioning at weeks 24, 72, and 96. 
 
1.3.3 To determine whether functional status improves at week 48 after intensification 
with MVC and DTG (Arm C) to a greater extent than when intensified with DTG 
and placebo for MVC (Arm B) or placebo of both drugs (Arm A). 
 
1.3.4 To assess the effect of adding MVC and DTG on biomarkers in peripheral 
blood and CSF. 


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1.3.5 To assess the association between serum and CSF biomarkers, 
neuropsychological performance, and DTG and MVC pharmacokinetics (PK) 
throughout the course of the study. 
 
1.3.6 To assess whether the addition of DTG alone (Arm B) or DTG and MVC (Arm C)  
is associated with maintenance of plasma HIV-1 RNA <50 copies/mL. 
 
1.3.7 To assess changes in blood CD4+/CD8+ counts after intensification with DTG 
and MVC (Arm C), DTG alone (Arm B) or placebos (Arm A). 
 
1.3.8 To determine associations between peripheral blood immunologic markers 
(s100β, soluble CD14) and changes in neurocognitive function at week 48. 
 
1.3.9 To determine the relationship between changes in CCR5 ligand levels (MIP-1b) 
and inflammatory marker changes in both peripheral blood and CSF.  
 
1.3.10 To determine the effect of DTG intensification on residual viremia, cellular HIV-1 
RNA expression, total cellular HIV-1 DNA, and 2 long terminal repeat sequences 
(LTR) DNA, and to determine whether these virologic changes are associated 
with week 48 neurocognitive function. 
 
 
2.0 
INTRODUCTION 
 
2.1 
Background/Rationale 
 
Despite effective suppression of plasma HIV-1 RNA below levels of detection with highly 
active antiretroviral therapy (HAART), HIV-infected persons often have cognitive 
dysfunction (HIV-associated neurocognitive disorder, or HAND), which includes 
asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) and 
HIV-associated dementia (HAD). For example, in the ACTG Longitudinal Linked 
Randomized Trials (ALLRT) study, 458 (39%) of 1160 individuals receiving HAART had 
mild and 304 (26%) had mild-to-moderate neurocognitive impairment [1]. Similarly, in the 
CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study, 40% to 52% of 
the 1555 participants were neuropsychologically impaired, including 42% 
neurocognitive impairment in those without other significant causes for impairment and 
who had undetectable plasma viral load [2]. The CHARTER study also documented the 
association between immune system functioning and neurocognitive impairment, with 
lower CD4+ lymphocyte nadirs predicting increased neurocognitive impairment. A study 
by Simioni et al. [3] found in participants who had undetectable plasma HIV-1 RNA 
(<50 copies/mL) on HAART and no cognitive complaints, 60% had ANI, 4% had MND, 
and none had HAD. Among those with cognitive complaints, 24% had ANI, 52% had 
MND and 8% had HAND.  
 
International studies have provided estimates of neurocognitive impairment and 
examined the effects of ART on neurological and neurocognitive functioning in 
HIV. Two prior relevant ACTG studies, the international neurological study (A5199, 


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“International Neurological Study: A Stand Alone Study for Participants of 
A5175”) and the international neurocognitive normative study (A5271, “Collection 
of Comparison Neurocognitive Data in Resource-Limited Settings”) found 
substantial prevalence of neurocognitive impairment at baseline in HIV+ ART-
naïve participants in diverse resource-limited settings (RLS). With ART, there were 
significant overall reductions in neurocognitive impairment over time [4, 5, 6, 7]. 
 
These and other studies demonstrate that neurocognitive impairment is common among 
HIV-1-infected persons, despite effective ART. There have been several past clinical 
trials in HAND of potential promising agents, including selegeline, nimodipine, and 
minocycline, all unsuccessful [8, 9, 10]. There are no current guidelines for the treatment 
of HAND. 
 
Cognitive impairment of treated individuals may be due to several, non-mutually 
exclusive factors including irreversible injury that occurred prior to ART, persistent 
production of HIV-1 RNA in the central nervous system (CNS) compartment [11], 
toxicities of ART [12, 13], or persistent CNS inflammation [14]. In support of the latter 
hypothesis, several studies have demonstrated elevated markers of immune activation 
in the CSF of participants with undetectable plasma HIV-1 RNA on ART [15]. Thus, 
control of plasma viral replication to <50 copies/mL may not be sufficient to prevent or 
reverse cognitive impairment. Controversy remains as to whether HAART that better 
penetrates into the CNS is important in treating or preventing HAND. Such treatment 
may reduce residual low-level viral replication within the CNS, and potentially reduce 
consequent pathologic CNS immune activation. 
 
A CNS Penetration Effectiveness (CPE) method ranks available antiretroviral (ARV)  
penetration into the CNS based on several factors [16]. The 2010 revision of the CPE 
scale ranks CNS penetration on a 4-point scale, where 1 is the lowest and 4 is the 
highest relative CNS penetrance; for example, tenofovir (TDF) is ranked 1 and 
emtricitabine (FTC) is ranked 3 (Table 1). MVC is ranked at 3. Initial data on CSF 
penetration of DTG are promising. The median DTG concentrations in CSF were 18 
ng/mL (range, 4-23 ng/mL) at week 2 and 13 ng/mL (4-18 ng/mL) at week 16. Ratios 
of DTG CSF to total plasma concentration were similar to the unbound fraction of 
DTG in plasma [17]. Higher CNS penetration of ART is associated with lower CSF HIV-
1 RNA in cross-sectional analyses [18, 19] and results in greater decreases in CSF HIV-
1 RNA in longitudinal analyses [13, 20], but has not conclusively been shown to improve 
neuropsychological performance in cognitively impaired individuals. Although the 
existing observational data are provocative, a change in clinical practice and treatment 
guidelines will require randomized controlled trials that carefully evaluate the risk as well 
as potential benefits of targeting or augmenting the CPE of ART for indivuduals with 
mild cognitive impairment.  


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Table 1. CNS Penetration-Effectiveness Ranks [19] 
CLASS 
4 
3 
2 
1 
NRTIs  
(nucleoside reverse 
transcriptase inhibitors) 
Zidovudine (ZDV) 
Abacavir (ABC) 
Emtricitabine 
(FTC) 
Didanosine (ddI) 
Lamivudine (3TC) 
Stavudine (d4T) 
Tenofovir (TDF) 
Zalcitabine (ddC) 
NNRTIs  
(nonnucleoside reverse 
transcriptase inhibitors) 
Nevirapine (NVP) Delavirdine (DLV) 
Efavirenz (EFV) 
Etravirine (ETR) 
 
PIs  
(protease inhibitors) 
Indinavir/ Ritonavir 
(IDV/r) 
Darunavir/ 
Ritonavir (DRV/r) 
Fosamprenavir/ 
Ritonavir (FPV/r) 
Indinavir (IDV) 
Lopinavir/ 
Ritonavir (LPV/r) 
Atazanavir (ATV) 
Atazanavir/ 
Ritonavir (ATV/r) 
Fosamprenavir 
(FPV) 
Nelfinavir (NFV) 
Ritonavir (RTV) 
Saquinavir (SQV) 
Saquinavir/ 
Ritonavir (SQV/r) 
Tipranavir/ 
Ritonavir (TPV/r) 
Entry Inhibitors 
 
Maraviroc (MVC) 
 
Enfuvirtide (ENF) 
Integrase Inhibitors 
Dolutegravir 
(DTG) 
Raltegravir (RAL) 
 
 
 
We propose to assess the efficacy of adding the C-C chemokine receptor type 5 
(CCR5) antagonist MVC (Class 3 CPE) and the integrase inhibitor DTG (Class 4 CPE) 
to the current ART of persons with undetectable (<50 copies/mL) plasma HIV-1 RNA 
who have mild-to-moderate neurocognitive impairment with a primary outcome of 
improvement in neurocognitive performance. We have chosen a three-arm design 
comparing: (Arm A) placebos for MVC and DTG, (Arm B) DTG active drug and MVC 
placebo, and (Arm C) MVC and DTG active drugs. This design will allow us to determine 
the neurocognitive effects of  each drug combination (all pairwise comparisons, arm B 
versus arm A, arm C versus arm A, and arm C versus arm B). MVC was chosen for this 
study because: 1) its concentrations in CSF consistently exceed the 50% inhibitory 
concentration for CCR5-using (R5) strains of HIV [21, 22]; 2) the primary target cells for 
HIV in the nervous system, microglia, express predominantly CCR5 but not C-X-C 
chemokine receptor type 4 (CXCR4); 3) inhibition of CCR5 may decrease migration of 
lymphocytes into the CNS thereby diminishing inflammation in the CNS compartment 
[23]; and 4) it is well tolerated. DTG was chosen for this study because: 1) its 
concentrations in CSF also consistently exceed the 50% inhibitory concentration for wild-
type HIV; 2) it is a member of a novel drug class that has reliable antiviral activity in 
integrase inhibitor-naïve individuals; and 3) it is well tolerated. Since eligible 
participants will have plasma HIV-1 RNA levels <50 copies/mL, performance of tropism 
and resistance assays will not be possible at the time of study screening; however, this 
testing can be applied to virological failures during the study, should the need arise. The 
potential novel properties of MVC on the CNS justify using it in this setting, along with 
the fact that all intensified participants will receive DTG, which is an active drug. While 
it is possible to assess proviral DNA tropism, this will not be done prospectively since the 
clinical relevance of the findings is unknown. However, depending upon the results of 
this study, consideration can be given to performing these assays retrospectively on 
stored peripheral blood mononuclear cells. In designing the intervention, DTG was 


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chosen as the single additional drug (Arm B) because in addition to having the favorable 
properties outlined above, it is expected to be an active agent in all enrolled 
participants, which is limited to those who are integrase inhibitor naïve. Because MVC 
does not have activity against CXCR4-using viruses, and there is one study suggesting 
that MVC may promote rather than suppress peripheral immune activation, we will not 
evaluate MVC as a single additional agent. 
 
The study design is also well suited to assess the effects of intensification with an 
integrase inhibitor alone or in combination with an entry inhibitor on residual viremia, 
cellular HIV-1 RNA expression and 2-LTR circle formation, using specimens through 
week 12, as well as the relationship between these indicators of low-level HIV 
replication and neurocognitive function at 48 weeks. The design would allow us to 
confirm (or refute) the findings of Hatano et al., who performed a randomized, 
double-blind, placebo-controlled trial of raltegravir intensification [24]. The trial 
found that 2 weeks of raltegravir increased the number of 2-LTR circles by more 
than five-fold, compared with placebo, indicating that low-level HIV replication had 
been present prior to raltegravir intensification and supporting that intensification 
with an integrase inhibitor may better suppress it. 
 
Rationale for 96-Week Follow-up 
Including an assessment at 96 weeks in A5324 is important for several reasons: 
 
First, if a neurocognitive benefit is observed, understanding the durability of the 
improvement and potential long-term toxicities will be important. For this reason, many 
clinical trials follow participants until 96 weeks and sometimes longer to assess both 
long-term efficacy and safety. 
 
Second, compared with ARV-induced changes in HIV-1 RNA levels and CD4+ T-cell 
counts, the dynamics of neurocognitive improvement in people with HAND are much 
slower. For instance, Cysique et al. [20] showed that neurocognitive functioning 
continues to improve every 12 weeks after initiating ART. After 48 weeks of ART, the 
modeled regression line of neurocognitive change still had an upward slope, indicating 
that functioning was continuing to improve. Importantly, participants in this analysis had 
detectable HIV-1 RNA levels in blood before changing ART. This long-term improvement 
in neurocognitive scores was also seen in A5199, and persisted to 96 weeks of follow-
up. Participants in A5324 will have undetectable HIV-1 RNA levels in blood prior to 
augmenting their ART and may have even slower improvement in neurocognitive 
functioning. 
 
Third, maximum ARV effectiveness in the CNS does not occur until approximately 18 
months of treatment. Specifically, in the NIH-funded CHARTER cohort, the proportion 
of treated participants who had detectable HIV-1 RNA levels in CSF declined over this 
time frame. In this analysis, recursive partitioning identified informative threshold values 
in the duration of the current ART: <7.2 months: 19.6% detectable HIV-1 RNA in CSF; 
7.2 to 18.8 months: 16.6%; 18.8 to 57.4 months: 8.1% (S. Letendre, personal 
communication, 2014). While multiple factors may explain this finding, evaluating 
participants for longer than 18 months is needed to assess the effects of maximum viral 
suppression. 


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MVC (Selzentry) 
MVC, in combination with other potent ARV drugs, is approved for suppressing R5 HIV-1 
in treatment-naïve and experienced individuals. In the MERIT trial, MVC 300 mg once a 
day (QD) or 300 mg twice a day (BID) was compared to efavirenz (EFV) 600 mg QD, 
each in combination with Lamivudine (3TC)/zidovudine (ZDV) (300/150 mg BID, 
Combivir). The MVC 600 mg QD arm failed to meet predefined criteria for non-inferiority 
to EFV and was prematurely discontinued at week 16. At week 48, MVC 300 mg BID 
failed to show non-inferiority to EFV for the primary endpoint of plasma HIV-1 RNA <50 
copies/mL (65.3% vs. 69.3%), although there was no difference in the proportion who 
achieved plasma HIV-1 RNA <400 copies/mL [25]. In the MERIT-ES study [26], data 
were reanalyzed after Enhanced Sensitivity Tropism Assay (TrofileES) was used to 
discriminate participants with exclusive R5 HIV-1 from those with X4 or dual/mixed 
strains with improved precision (sensitivity of approximately 0.3%) compared to the 
earlier Trofile assay. This re-analysis, using intent-to-treat (ITT), demonstrated similar 
suppression of R5 HIV (68% plasma HIV RNA <50 copies/mL) with EFV or MVC. There 
were fewer instances of rash, neurologic symptoms, and lipid changes in the MVC 
group. These results were confirmed at week 96 (59% vs. 62% suppressed), although, 
in general, more participants discontinued EFV due to AEs while more discontinued 
MVC due to virologic failure (VF) [27]. There was a greater mean increase in CD4+ T-
cell count with MVC compared to EFV. Early failure of MVC appears due to outgrowth of 
pre-existing X4 or dual/mixed variants under selective drug pressure and later failure 
due to resistance of R5 variants.  
 
In MOTIVATE, treatment-experienced individuals without detectable CXCR4-using 
virus were randomized to optimized background ARV regimen with or without QD or BID 
dosing of MVC. In this case, approximately 50% of participants in the QD arm and 63% 
of participants in the BID arm had evidence of non-R5 strains at the time of failure with 
no apparent immunologic consequences [28, 29]. On the other hand, MVC resistance 
occurred in approximately one-third of participants who failed with R5-tropic HIV [29, 
30]. The mechanisms of MVC resistance are not completely understood, but selection of 
mutations in the viral envelope gp120 molecule may allow HIV-1 to regain activity 
despite CCR5 inhibition with MVC [31].  
 
DTG (Tivicay) 
DTG is an integrase inhibitor approved for use in combination with other antiretrovirals in 
treatment-naïve and experienced HIV-1-infected adults and children aged 12 years and 
older and weighing at least 40 kg. The recommended dose of DTG in treatment naïve or 
treatment-experienced, integrase-naïve individuals is 50 mg QD, but when 
coadministered with potent UGT1A/CYP3A inducers such as EFV, 
fosamprenavir/ritonavir (FPV/r), tipranavir/ritonavir (TPV/r), or rifampin (RIF), a dose 
adjustment of DTG to 50 mg BID is needed in these individuals. The recommended 
dose of DTG in integrase-experienced individuals with certain integrase-associated 
resistance substitutions (L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, 
G163E/K/Q/R/S, or G193E/R) or clinically suspected integrase resistance is 50 mg BID. 
Additionally, in these individuals, alternative combinations that do not include metabolic 
inducers should be considered when possible.   
 


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DTG is metabolized by the UGT1A1 metabolic pathway with minor CYP3A4, UGT1A3, 
and UGT1A9 components. DTG has a terminal half-life of approximately 14 hours and 
an apparent clearance (CL/F) of 1.0 L/h based on population PK analyses. Following 
oral administration of DTG, peak plasma concentrations were observed 2 to 3 hours 
postdose. DTG tablets may be taken with or without food.   
 
In vitro, DTG did not inhibit or induce cytochrome P450 enzymes. DTG is therefore not 
expected to affect the PK of drugs that are substrates of CYP450. DTG should not be 
used with etravirine (ETR) without coadministration of atazanavir/ritonavir (ATZ/r), 
darunavir/ritonavir (DRV/r), or lopinavir/ritonavir (LPV/r, Kaletra). Coadministration with 
nevirapine (NVP) should be avoided because there are insufficient data to make dosing 
recommendations. Coadministration with metabolic inducers such as oxcarbazepine, 
phenytoin, phenobarbital, carbamazepine, and St. John’s wort  should be avoided 
because there are insufficient data to make dosing recommendations. DTG should be 
taken 2 hours before or 6 hours after taking cation-containing antacids or laxatives, 
sucralfate, oral iron supplements, oral calcium supplements, or buffered medications.    
 
In vitro, DTG inhibited the renal organic cation transporter, OCT2 (IC50 = 1.93 μM). In 
vivo, DTG inhibits tubular secretion of creatinine by inhibiting OCT2. Thus, 
coadministration of DTG with dofetilide is contraindicated due to the potential for 
increased dofetilide plasma concentrations and the risk for serious and/or life-
threatening events. In addition, monitoring of glucose levels is recommended when 
starting or stopping DTG and metformin together, as a dose adjustment may be needed 
for metformin.   
 
DTG is highly protein-bound (approximately 99%) based on in vitro data, and in healthy 
individuals, DTG has a mean unbound fraction of approximately 0.23% [32].  
 
The efficacy of DTG in HIV-1-infected treatment naïve individuals was based on 48-
week data from two randomized, international, multicenter, double-blind, active-
controlled trials, SPRING 2 (ING113086) and SINGLE (ING114467). In SPRING 2, 822 
participants were randomized and received either DTG 50 mg QD or raltegravir (RAL) 
400 mg BID, both in combination with fixed-dose dual nucleoside reverse transcriptase 
inhibitor (NRTI) backbone (either abacavir[ABC]/3TC or TDF/FTC) [33]. At 48 weeks, the 
proportion of participants with HIV-1 RNA <50 copies/mL was 88% in the DTG group 
compared with 85% in the RAL group (adjusted difference 2·5%; 95% confidence 
interval (CI) –2·2 to 7·1). The median increase from baseline to week 48 in CD4+ cell 
count was 230 cells/mm3 in both groups. The most common (≥10%) AEs (all grades) for 
DTG vs. RAL groups were nausea (14% vs. 13%), headache (12% vs 12%), 
nasopharyngitis (11% vs 12%), and diarrhea (11% in each group). Few participants 
had drug-related serious AEs (3 [<1%] vs. 5 [1%]), and few discontinued due to AEs (2% 
in each group). Rates of laboratory abnormalities were similar between treatment 
groups, and no clinically significant changes in the fasting lipid profile were noted in 
either group. Nonpathologic inhibition of the organic cation transporter, OCT2, in the 
proximal renal tubules [34] resulted in small, non-progressive increases in serum 
creatinine early in treatment with DTG (weeks 2-4) and then remained stable to week 48, 
consistent with previous findings [35]. No participants on the DTG or the RAL arm 
discontinued ART due to renal AEs. No evidence of treatment-emergent resistance was 


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observed in participants with VF on DTG, whereas among RAL-treated participants, 
one had integrase treatment-emergent resistance and four had NRTI treatment-
emergent resistance.  
 
In SINGLE, 833 participants were randomized and received either DTG 50 mg QD with 
fixed-dose ABC/3TC or fixed-dose TDF/FTC/EFV [36]. At 48 weeks, the proportion of 
participants with HIV-1 RNA <50 copies/mL was 88% on DTG compared with 81% on 
TDF/FTC/EFV (adjusted difference 7.4%; 95% confidence interval 2.5% to 12.3%; 
p=0.003). The adjusted median increase from baseline in CD4+ cell count was 267 
cells/mm3 for DTG+ABC/3TC vs. 208 cells/mm3 for TDF/FTC/EFV at 48 weeks (adjusted 
difference 59%; 95% CI, 33% to 84%). The most common (≥10%) AEs for 
DTG+ABC/3TC vs. TDF/FTC/EFV groups were dizziness (7% vs. 32%), nausea (10% 
vs. 12%), abnormal dreams (6% vs. 15%), and insomnia (10% vs. 5%). The number of 
participants who discontinued study due to AEs for DTG+ABC/3TC was 10 (2%) 
compared with 41 (10%) on TDF/FTC/EFV groups. Few participants had drug-related 
serious AEs (1 [<1%] vs. 8 [2%]). Renal AEs leading to discontinuation occurred in one 
participant on DTG+ABC/3TC and two participants on TDF/FTC/EFV. At 48 weeks, 
small increases were noted in total, low density lipoprotein (LDL) and high density 
lipoprotein (HDL) cholesterol in both groups but total cholesterol/HDL ratio remained 
stable; comparable increases in triglycerides were observed in both groups. No evidence 
of treatment-emergent resistance was observed in participants with VF on DTG, 
whereas among TDF/FTC/EFV-treated participants, four had nonnucleoside reverse 
transcriptase inhibitor (NNRTI) treatment-emergent resistance and one had major NRTI 
treatment-emergent resistance.  
 
DTG in CSF 
The  distribution and antiviral activity of DTG in CSF has been studied in 13 treatment-
naïve participants on a stable regimen of DTG+ABC/3TC through 16 weeks [17]. 
Median change from baseline to week 16 in CSF (N=11) and plasma (N=12) HIV-1 RNA 
were -3.42 log10 and -3.04 log10 copies/mL, respectively. Nine of eleven (82%) 
participants had both plasma and CSF HIV-1 RNA <50 copies/mL and 10/11 (91%) 
participants had CSF HIV-1 RNA <2 copies/mL. At 16 weeks, the median (range) DTG 
concentration in CSF was 13.2 (3.7-18.3) ng/mL with CSF:plasma DTG concentration 
ratio of 0.41 (0.3-2.04). These data indicate that DTG therapeutic concentrations were 
achieved in CSF, with DTG CSF concentrations exceeding the in vitro 50% inhibitory 
concentration for wild-type viruses in peripheral blood mononuclear cells (0.2 ng/mL) 
[37] and decreases in CSF HIV-1 RNA levels were similar to decreases in plasma HIV-1 
RNA levels. 
 
Biomarkers 
The search for clinically relevant biomarkers for HAND is another important, and largely 
unmet, need of the field. Many biomarkers have been investigated but an extensive 
panel is beyond the scope of this project. Instead, the project will measure a concise 
panel of biomarkers and store fluid to enable more in-depth investigations in the future. 
 
• 
Peripheral blood 
As evaluations for this study will involve neuropsychological testing and 
classification of participants prior to and following randomization, we propose to 


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additionally investigate the possible correlation between HAND diagnosis, 
neuropsychological test results, and biomarkers of CNS injury. S100β is a 
calcium-binding protein produced by astrocytes that is elevated in the serum in 
the context of traumatic brain injury, brain ischemia and hemorrhage, active CNS 
lupus erythematosis, and Human T-lymphotropic virus Type 1 (HTLV-1)-
associated tropical spastic paraparesis (but not asymptomatic HTLV-1 infection) 
[38, 39, 40, 41]. Glial activation with elevated CSF expression of S100β has 
been identified in individuals infected with HIV-1 [42], and higher CSF S100β is 
associated with neurocognitive impairment in people infected with HIV-1 [43, 44]. 
No studies have investigated the relationship between serum S100β and brain 
injury in HIV. We propose to use the opportunity afforded by the detailed 
neuropsychological characterization of enrolled participants to assess whether 
S100β might be a peripheral blood biomarker for HIV-associated CNS 
disease/HAND. In addition to S100β, we will measure the serum concentration of 
the soluble form of the receptor for bacterial lipopolysaccharide (LPS), CD14, 
based on the theory of microbial translocation-associated immune activation in 
HIV disease [45]. In vitro and animal model studies suggest that LPS may lead to 
neurological injury by augmenting trafficking of infected and activated monocytes 
across the blood-brain barrier [46]. Human studies have also linked LPS and 
soluble CD14 to HAND [47].  
 
sCD163 is a soluble marker of monocyte/macrophage activation that has been 
associated with surrogate markers of cardiovascular disease [48] and 
neurocognitive dysfunction in treated HIV infection [49]. D-dimer is a coagulation 
marker that is increased in inflammatory states including treated HIV infection 
and strongly predicts all-cause mortality in this setting [50]. MIP-1b is a natural 
CCR5 ligand, which has been shown to increase at least 2-fold in plasma during 
MVC intensification [51] due to blockade of ligand-receptor complex 
internalization. The extent of MIP-1b elevation during MVC intensification is thus 
a reasonable surrogate marker for the degree to which MVC is preventing natural 
signaling through CCR5 in vivo. 
 
• 
CSF 
In the subset of participants who agree to undergo an optional lumbar puncture 
(LP) for CSF collection, we will assess CSF concentrations of selected 
biomarkers. CSF concentrations of neopterin, monocyte chemoattractant protein-
1 (MCP-1), and Interferon gamma-induced protein 10 (IP-10) are increased in 
people infected with HIV-1 and are indicators of macrophage activation, 
monocyte-derived macrophage chemotaxis, and lymphocyte chemotaxis [14, 52, 
53, 54, 55, 56, 57, 58]. Neurofilament light chain (NFL) is a sensitive biomarker 
of axonal injury that can be assayed in CSF (and peripheral blood) [59, 60, 61, 
62, 63]. 
 
While these example biomarkers in plasma and CSF are of current interest, there 
are often substantial changes over time with the development of new more 
sensitive and specific biomarkers. As research adds to the knowledgebase in this 
area, the team will implement and assess the most scientifically rigorous and 
relevant biomarkers at study conclusion.  


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3.0 
STUDY DESIGN 
 
This is a phase IV randomized, double-blinded, placebo-controlled clinical trial. 
Participants will have at least mild HAND as defined by the Frascati criteria, plasma 
HIV-1 RNA <50 copies/mL within 90 days prior to entry, no more than one plasma HIV-1 
RNA ≥50 and <200 copies/mL in the 6 months prior to entry with a subsequent plasma 
HIV-1 RNA <50 copies/mL, and on stable ART for at least 6 months prior to entry with no 
plans to change treatment except for the allowed changes defined in sections 4.1.2 
and 4.1.3. Participants will be randomized to one of three study arms to add to their 
existing ART, placebo for MVC, and placebo for DTG (Arm A), DTG active drug and 
placebo for MVC (Arm B), or MVC and DTG active drugs (Arm C). Randomization will be 
stratified by CD4+ nadir (≤100 vs. >100 cells/mm3) and HAND severity (ANI vs. 
MND/HAD). 
 
 
Participants will be assessed at screening and then every 24 weeks for 96 weeks with a 
neurocognitive battery. The tests in the neurocognitive battery have been implemented 
successfully in multisite clinical trials, and extensive training materials within the ACTG 
exist. Appropriate country- and site-specific normative data will be used for 
comparison, and the battery is designed to adhere to the recommendations of the 
Frascati consensus [7, 64, 65]. These tests can have practice or learning effects upon 
repeated assessment; however, alternate versions of the tests will be used at each 
visit to minimize this effect. In addition, the placebo group (Arm A) will provide an 
estimate of practice effects and natural history in our analyses. A self-report assessment 
of functional ability, instrumental activities of daily living (IADLs), and psychological 
distress will be administered. In addition, an assessment of comorbidities and 
confounding factors based on the Frascati criteria will be completed at screening then 
every 24 weeks for 96 weeks and used as a covariate. Refer to the A5324 Manual of 
Operations (MOPS) for details regarding the self-report assessments and the Frascati 
criteria. 
 
There will be clinical safety evaluation and monitoring at week 2, then clinical and 
laboratory safety evaluation and monitoring at week 4, week 12, and every 24 weeks 
beginning at week 24.  
 
Blood will be collected for hematology, chemistries, CD4+/CD8+ lymphocytes, and 
quantitative plasma HIV-1 RNA, with plasma and serum collected and stored for single-
copy assay (SCA) and assessment of systemic immune and inflammation markers 
(s100β, soluble CD14 [sCD14], etc.), respectively. PBMC will be cryopreserved at the 
indicated timepoints for future T-cell and monocyte phenotypic and functional studies as 
well as HIV reservoir measures (2-LTR circles and total cell-associated HIV-1 RNA and 
DNA). 
 
A subset of consenting participants will undergo LP at entry and 48 weeks.  
 
 


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4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 HIV-1 infection, documented by: 
• 
A 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 
or plasma HIV-1 RNA viral load 
NOTE: The term “licensed” refers to a United States Food and Drug 
Administration (FDA)-approved kit, which is required for all IND 
studies, or for sites located in countries other than the United 
States, a kit that has been certified or licensed by an oversight body 
within that country and validated internally. Non-US sites are 
encouraged to use US FDA-approved methods for IND studies. 
WHO (World Health Organization) 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 (eg, indirect versus 
competitive), or a Western blot or a plasma HIV-1 RNA. 
OR 
• 
Documentation of HIV diagnosis in the medical record by a 
healthcare provider 
 
4.1.2   On current ART for at least 6 months prior to study entry with no interruption in 
treatment of ≥7 consecutive days. 
 
Note: The following ART changes are allowed: 
• 
TDF to tenofovir alafenamide fumarate (TAF)/TAF-containing fixed-
dose combination regimens  
• 
RTV to cobicistat (COBI)/COBI-containing fixed-dose combination 
regimens 
 
 
4.1.3 No plans to change ART while on study. 
Note: The following planned ART changes are allowed: 
• 
TDF to TAF/TAF-containing fixed-dose combination regimens 
• 
RTV to COBI/COBI-containing fixed-dose combination regimens 
 
4.1.4 HIV-1 plasma RNA <50 copies/mL obtained within 90 days prior to study entry  
by any FDA-approved assay at any United States laboratory that has a Clinical 
Laboratory Improvement Amendments (CLIA) certification or its equivalent, or 
at any network-approved non-US laboratory that operates in accordance 


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with Good Clinical Laboratory Practices (GCLP) and participates in 
appropriate external quality assurance programs.  
 
4.1.5 No more than one HIV-1 plasma RNA ≥50 and <200 copies/mL (only one “blip”) 
in the past 6 months with a subsequent HIV-1 plasma RNA <50 copies/mL. 
 
NOTE: There should be no plasma HIV-1 RNA >200 copies/mL within the 6 
months prior to study entry. 
 
4.1.6 HAND diagnosis (ANI, MND, or HAD) within 60 days prior to study entry.   
 
HAND is defined as at least mild impairment on neurocognitive testing (more 
than one standard deviation below appropriate normative data in two domains of 
functioning) and no severely confounding factors. 
 
4.1.7 Screening laboratory values obtained within 60 days prior to study entry by any 
US laboratory that has a CLIA certification or its equivalent, or at any 
network-approved non-US laboratory that operates in accordance with 
GCLP and participates in appropriate external quality assurance programs: 
• 
Absolute neutrophil count (ANC) ≥500/mm3 
• 
Hemoglobin ≥7.5 g/dL 
• 
Platelet count ≥40,000/mm3 
• 
Creatinine ≤2.0 x ULN 
• 
Aspartate transaminase (AST) ≤5 x ULN  
• 
Alanine transaminase (ALT) <3 x ULN 
• 
Alkaline phosphatase ≤5 x ULN 
• 
Total bilirubin <1.5 x ULN 
NOTE: If the potential participant is taking an indinavir (IDV)- or 
atazanavir (ATV)-containing regimen at the time of screening, total 
bilirubin ≤5 x ULN is acceptable. 
• 
Creatinine clearance (CrCl) ≥60 mL/min, either measured or estimated by 
Cockcroft-Gault equation   
NOTE: A calculator for estimating the CrCl can be found at 
www.fstrf.org/ACTG/ccc.html 
 
4.1.8 Females of reproductive potential (women who have not been post-menopausal 
for at least 24 consecutive months, i.e., who have had menses within the 
preceding 24 months, or women who have not undergone surgical sterilization, 
hysterectomy, or bilateral salpingectomy, or bilateral oophorectomy or tubal 
ligation) must have a negative serum or urine pregnancy test 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, or at any network-approved non-US 
laboratory or clinic that operates in accordance with GCLP and participates 


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in appropriate external quality assurance programs within 48 hours prior to 
study  entry. 
 
4.1.9 Females of reproductive potential must agree not to participate in the conception 
process (ie, active attempt to become pregnant, in vitro fertilization), and if 
participating in sexual activity that could lead to pregnancy, must use at least one 
reliable form of contraception. Female participants must use contraceptives 
while receiving study treatment and for 6 weeks after stopping study treatment. 
 
Acceptable forms of contraception include: 
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) 
• 
Hormonal contraceptive 
 
Females who are not of reproductive potential or whose male partner(s) has 
documented azoospermia are not required to use contraceptives. Any statement 
of self-reported sterility or that of her partner’s must be entered in the source 
documents.  
NOTE: Acceptable documentation of lack of reproductive potential is oral or 
written documentation from the participant. 
 
4.1.10 Men and women age ≥18 years who are able to complete the neuropsychological 
tests. 
 
4.1.11 Ability and willingness of participant or a legally authorized representative (LAR; 
see section 4.3.1.1) to provide informed consent. 
 
4.1.12 Ability and willingness to take oral study medications. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Current or past medical condition(s) that, in the opinion of the investigator, 
prevents attribution of the cause of cognitive impairment to HIV. For example: 
4.2.1.1 Major depressive disorder with psychotic features 
4.2.1.2 Traumatic Brain Injury (TBI) with a clear impact on activities of daily 
living  
4.2.1.3 Developmetal delay, intellectual deficit, and/or severe educational 
disability resulting in some dependence for activities of daily living 
4.2.1.4 Ongoing substance use with significant impact on activities of daily 
living. Difficult or impossible to determine whether cognitive or 
functional decline is due to substance use or HIV, or both 
4.2.1.5 Evidence of intoxication or withdrawal during the screening evaluation 


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4.2.1.6 CNS infections or opportunistic conditions: Brain abscess (bacterial, 
mycobacterial, fungal, or Toxoplasma), meningitis with persistent 
neurologic impairment, primary CNS lymphoma, progressive multifocal 
leukoencephalopathy (PML), or another structural brain lesion with 
neurological sequelae 
4.2.1.7 Other CNS conditions: Non-opportunistic primary or metastatic brain 
tumors, uncontrolled seizure disorder, progressive multiple sclerosis, 
stroke with neurological sequelae, or dementia due to causes other 
than HIV (eg, Alzheimer’s disease) 
4.2.1.8 Constitutional illness (eg, persistent unexplained fever, diarrhea, 
significant weight loss, disabling weakness) within 30 days of screening  
4.2.1.9 Known untreated B12 deficiency or malnutrition (body mass index [BMI] 
<18) at screening 
 
4.2.2 Evidence of current hepatitis C virus infection (HCV) (ie, HCV antibody [Ab] 
positive within 90 days prior to study entry unless also shown to be plasma HCV 
RNA negative within the same time period). 
 
4.2.3 Unstable and advanced liver disease (as defined by the presence of at least one 
of the following: ascites, encephalopathy, coagulopathy, hypoalbuminemia, 
esophageal or gastric varices, or persistent jaundice). 
 
4.2.4 Prior or current use of any CCR5 antagonist (such as MVC and cenicriviroc 
[CVC]) and integrase inhibitor (such as RAL, DTG, and elvitegravir [EVG]). 
 
4.2.5 Current use of any medication, including antiretrovirals, prohibited in the study 
(refer to the A5324 protocol-specific web page [PSWP] for the prohibited 
medications). 
 
4.2.6 Breastfeeding.  
 
4.2.7 Presence of an AIDS-defining opportunistic infection within 6 months prior to 
 
entry. 
Note: Refer to the A5324 MOPS for the list of AIDS-defining opportunistic 
infections. 
 
4.2.8 Active syphilis or treatment for syphilis within 90 days prior to study entry. 
NOTE: Active syphilis is defined as four-fold increase in serum rapid plasma 
reagin (RPR) or venereal disease research laboratory (VDRL) tests in an 
individual with past syphilis, or newly reactive serum RPR or VDRL with a 
reactive confirmatory test (enzyme immunoassays [EIA] or chemiluminescent 
assay [CIA], T. pallidum particle agglutination [TP-PA], or fluorescent 
treponemal antibody absorbed [FTA-ABS]). 


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4.2.9 Known allergy/sensitivity or any hypersensitivity to components of study 
drugs or their formulation. 
 
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) 
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 approval(s) 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 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. 
 
Sites that are registering for the first time with Version 2.0 should follow 
the protocol registration procedure for an initial registration. 
 
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 him or her. The participant (or, when necessary, the LAR [see 
section 4.3.1.1]) 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) Subject Enrollment System.  
 


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4.3.1.1  Surrogate Consent by a Legally Authorized Representative (LAR) 
 
A potential participant who lacks the capacity to provide informed 
consent due to cognitive impairment may be considered if the 
participant has a designated surrogate who can consent on his/her 
behalf. The designated surrogate is a LAR who has the ability to provide 
consent for the participant’s participation in this research protocol as 
defined in the state and/or local laws. 
 
4.3.2 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist 
found on the ACTG Member website. This checklist must be approved prior 
to any screening of participants for enrollment. 
 
4.3.3 Randomization 
 
At the entry visit, participants will be randomized according to standard ACTG 
data management procedures.  
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the protocol, an ACTG Screening 
Failure Results form must be completed and keyed into the database.  
 
4.4 
Coenrollment Guidelines  
 
• 
Sites are encouraged to coenroll 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 
A5324 protocol chairs.  
 
• 
Non-US sites are encouraged to co-enroll participants in A5243, “Plan for 
Obtaining Human Biological Samples at Non-US Clinical Research Sites for 
Currently Unspecified Genetic Analyses.” Co-enrollment in A5243 does not 
require permission from the A5324 protocol chairs. 
 
• 
Sites that have been selected to participate in the “Imaging and Inflammatory 
Biomarkers in Anti-Retroviral NeuroIntensification (SPIRIT)” study are encouraged to 
coenroll participants who are eligible. Coenrollment in the SPIRIT study does not 
require approval of the A5324 protocol chairs. 
 
• 
For specific questions and approval for coenrollment in other studies, sites should 
first check the PSWP or contact the protocol chairs via e-mail as described in the 
Study Management section. 
 
 


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5.0 
STUDY TREATMENT 
 
Study treatment is defined as maraviroc (MVC) or placebo for maraviroc, and 
dolutegravir (DTG) or placebo for dolutegravir.  
 
The study treatment will be added to the current non-study-provided ART. 
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimens 
 
Participants will be randomized (1:1:1) to one of the three (3) following 
regimens:  
• 
ARM (A): Placebo for maraviroc + Placebo for dolutegravir  
• 
ARM (B): DTG + Placebo for maraviroc 
• 
ARM (C): MVC + DTG 
 
NOTE: Participants will receive the following regimen, based on their existing 
ART therapy (see Tables A and B): 
• 
DTG OR placebo for dolutegravir 
AND  
• 
MVC OR placebo for maraviroc 
 
Table A.  
Background 
Regimen 
ARM A 
ARM B 
ARM C 
EFV + NRTI 
Placebo for dolutegravir 
 
One (50 mg Placebo) 
tablet BID 
DTG 
 
One (50 mg) tablet BID 
DTG 
 
One (50 mg) tablet BID 
Placebo for maraviroc 
 
Two (300 mg Placebo) 
tablets BID 
Placebo for maraviroc 
 
Two (300 mg Placebo) 
tablets BID 
MVC 
 
Two (300 mg) tablets BID 
 
RPV + NRTI 
Placebo for dolutegravir 
 
One (50 mg Placebo) 
tablet QD 
DTG 
 
One (50 mg) tablet QD 
DTG 
 
One (50 mg) tablet QD 
Placebo for maraviroc 
 
One (300 mg Placebo) 
tablet BID 
Placebo for maraviroc 
 
One (300 mg Placebo) 
tablet BID 
MVC 
 
One (300 mg) tablet BID 
 
 


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Table B. 
Background 
Regimen 
ARM A 
ARM B 
ARM C 
PI/r + NRTIs 
 
OR 
 
PI/r + NNRTI 
+/- NRTI 
Placebo for dolutegravir 
 
One (50 mg Placebo) 
tablet QD 
DTG 
 
One (50 mg) tablet QD 
DTG 
 
One (50 mg) tablet QD 
Placebo for maraviroc 
 
One (150 mg Placebo) 
tablet BID 
Placebo for maraviroc 
 
One (150 mg Placebo) 
tablet BID 
MVC 
 
One (150 mg) tablet BID 
 
 
Any changes to the ART regimen, other than the allowed changes in 
section 7.6, should be discussed with the A5324 core team in advance 
(actg.corea5324@fstrf.org). 
 
5.1.2 Administration and Dispensing 
 
All of the study products in the regimen should be taken with or without food. See 
section 10.2.1 for holding doses prior to the week 12 PK visit.  
 
5.1.2.1 MVC or placebo for maraviroc will be administered orally as one 150 mg 
tablet BID OR two (300 mg) tablets BID OR one 300 mg tablet BID 
depending upon background ARV regimen. 
 
5.1.2.2 DTG or placebo for dolutegravir will be administered orally as one 50 
mg tablet BID OR one 50 mg tablet QD depending upon background 
ARV regimen. 
 
5.2 
Study Product Formulation and Preparation 
 
5.2.1  MVC 150 mg tablets; 300 mg tablets. Store at room temperature 25°C (77°F); 
excursions permitted to 15°C-30°C (59°-86°F) [see USP Controlled Room 
Temperature]. 
 
5.2.2 DTG 50 mg tablets. Store at 25°C (77°F); excursions permitted to 15°C-30°C 
(59°-86°F) [see USP Controlled Room Temperature].  
 
5.2.3 Placebo for maraviroc 150 mg tablets and Placebo for maraviroc 300 mg tablets. 
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP 
Controlled Room Temperature]. 
 
5.2.4 Placebo for dolutegravir tablets. Store at 25°C (77°F); excursions permitted to 
15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. 
 


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5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
MVC and placebo for maraviroc will be supplied by ViiV Healthcare Ltd. 
 
DTG and placebo for dolutegravir will be supplied ViiV Healthcare Ltd. 
 
Study products will be available through the NIAID Clinical Research Products 
Management Center (CRPMC). The site pharmacist can obtain the 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. 
 
No other ARV therapy will be provided through the study.  
 
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. At US clinical 
research sites (CRSs), 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 Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks. At non-US 
CRSs, the site pharmacist must follow the instructions in the Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks for the 
destruction of unused study products. 
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medications’ and study agents' most recent 
package inserts, Investigator’s Brochures, 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 Drug Interactions 
Database located at http://tprc.pharm.buffalo.edu/home/di_search/.  
 
5.4.1 Prohibited Medications 
 
For a list of prohibited medications, refer to the PSWP. 
 
5.4.2 Precautionary Medications 
 
For a list of precautionary medications, refer to the PSWP. 


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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations 
 
Evaluation 
Screening Pre-
Entry  Entry 
Post-Entry Evaluations 
(Weeks) 
Confirmation  
of  VF 
Premature 
Study/Treatment 
Discontinuation 
2 
4 
12 
24 
36 
48 
60 
72 
84 
96 
Visit Windows 
 
 
 
± 1 wk 
± 2 wks 
- 4 wks, + 8 wks 
 
 
Documentation of HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Nadir CD4+ 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Neurological Exam 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Frascati HAND Rating Scale 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Neuropsychological Baseline 
Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurocognitive Batteries 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Questionnaires 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Adherence Assessment 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Study Medication 
Dispensing 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Hematology 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
Liver Function Tests 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
Chemistry 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Pregnancy Testing 
X 
 
X 
Whenever pregnancy is suspected 
 
If pregnancy is 
suspected 


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Evaluation 
Screening Pre-
Entry  Entry 
Post-Entry Evaluations 
(Weeks) 
Confirmation  
of  VF 
Premature 
Study/Treatment 
Discontinuation 
2 
4 
12 
24 
36 
48 
60 
72 
84 
96 
Visit Windows 
 
 
 
± 1 wk 
± 2 wks 
- 4 wks, + 8 wks 
 
 
HCV Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Syphilis Screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4+/CD8+ 
 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
Plasma HIV-1 RNA 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Stored Plasma 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Stored Serum 
 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
Stored Viable PBMCs 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
CSF supernatant and pellets 
(only in participants who 
undergo LP) 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
PK Studies 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
LP Safety Laboratory Tests 
(only in participants who 
will be undergoing LP) 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
LP (Optional) 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Resistance Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Tropism Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening 
Screening evaluations to determine eligibility must be completed within 60 days 
prior to study entry unless otherwise specified. 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 Failure Results form 
and entered into the ACTG database.  
 
Pre-Entry 
The screening and pre-entry visits can occur on the same day. Sites have the 
option to complete the screening and pre-entry evaluations in stages (such as 
conducting the neurocognitive battery one day then the laboratory and clinical 
evaluations on another day) if it will be easier for the site and the participant. 
 
Results of the screening and pre-entry evaluations must be received at least 24 
hours prior to entry. 
 
6.2.2 Entry Evaluations 
 
Entry evaluations must occur at least 24 hours after pre-entry unless otherwise 
specified. Participant must begin treatment within 3 days after randomization. 
 
6.2.3 Post-Entry Evaluations 
 
On-Treatment Evaluations  
Post-entry evaluations should occur following the visit windows in the Schedule 
of Evaluations (SOE), section 6.1. 
 
NOTE: The week 96 evaluations should be peformed as close to the week 96 
schedule as possible. 
 
Confirmation of VF 
For participants who have suspected VF, a confirmatory plasma HIV-1 RNA test 
and adherence assessment as per section 6.1 are to be performed within 30 
days after receipt by the site of the results of the initial HIV-1 RNA sample 
indicating suspected VF. Participants who have their first plasma HIV-1 RNA 
>200 copies/mL at their final study visit should be asked to return to the clinic for 
a confirmatory visit within 30 days of receipt of the result from their final visit. 
 
NOTE: VF is defined as confirmed HIV-1 RNA levels >200 copies/mL after study 
entry. 
 
If the confirmation of VF visit coincides with a regularly scheduled visit, the 
evaluations should be combined. 


 
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Participants who have confirmed VF will discontinue the study medications but 
will continue on study and followed through week 96. See sections 6.1 and 6.2.4 
for the procedures at premature treatment discontinuation. 
 
Samples drawn for resistance and tropism testing at the confirmation of VF visit 
should be stored. The samples should be sent to the testing laboratory following 
the guidelines in sections 6.3.19 (Resistance Testing) and 6.3.20 (Tropism 
Testing). 
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Randomized Participants Who Do Not Start Study Treatment 
All case report forms (CRFs) must be completed and keyed for the period up to 
and including the entry visit. No further follow-up is required. Participants must 
be taken off study. 
 
Premature Treatment Discontinuation Evaluations  
Participants who discontinue the study medications before the end of the study 
should have the premature treatment discontinuation evaluations done within 14 
days after stopping study medications. Participants will be followed off study 
treatment/on study. They should be encouraged to continue to attend all study 
visits and receive study evaluations as per section 6.1, with the exception of the 
adherence questionnaires, and optional lumbar puncture, through completion of 
the study. 
 
Premature Study Discontinuation Evaluations  
All participants who prematurely discontinue participation in the study should 
have the premature study discontinuation evaluations done as per section 6.1. 
Participants who prematurely discontinue participation in the study should report 
to the clinic to have the premature study discontinuation evaluations performed 
as soon as possible.  
 
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 
website for information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/sourcedocappndx.pdf. 
 
All stated evaluations are to be recorded on the 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 patient 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 AEs (DAIDS AE Grading 
Table), Version 2.1, March 2017, which can be found on the DAIDS RSC Web site: 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-
tables.   
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.1 specifies assay requirements and medical notes 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 prior to study entry, 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 C 
• 
Chronic hepatitis B 
• 
Any neurologic disease 
 
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 (except as 
otherwise indicated on the CRF). If only estimated start and stop dates are 


 
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available, these are acceptable. The table below lists the medications that must 
be included in the history and recorded on the CRFs.  
 
Medication Category 
Complete History or Timeframe 
ART 
Complete 
Immune-based therapy 
30 days prior to study entry 
Blinded study treatment 
30 days prior to study entry 
HIV-1-related vaccines 
30 days prior to study entry 
Prescription drugs for treatment of 
opportunistic infections 
30 days prior to study entry 
Prescription drugs for prophylaxis 
of opportunistic infections 
30 days prior to study entry 
Prescription drugs (other) 
30 days prior to study entry 
Alternative therapies 
30 days prior to study entry 
Dietary supplements 
30 days prior to study entry 
 
6.3.4 Nadir CD4+ 
 
The participant’s prior nadir CD4+ cell count (absolute value and date) should 
be documented when possible with a copy of the nadir CD4+ cell count report or 
participant report. If this documentation is not available or the participant is 
unable to recall, either the best available information should be used or 
recorded as missing data in the CRF.  
 
6.3.5 Clinical Assessments 
 
Complete Physical Exam 
A complete physical examination at screening is to include at a minimum an 
examination of the skin, head, mouth, and neck; auscultation of the chest; 
cardiac exam; abdominal exam; and examination of the lower extremities for 
edema. The complete physical exam will also include height, weight, signs and 
symptoms, diagnoses, and vital signs (temperature, pulse, and blood pressure). 
 
Targeted Physical Exam 
After screening, a targeted physical examination, including height (at entry and 
week 12 only), weight, and vital signs (temperature, pulse, and blood pressure) 
should be per section 6.1, along with additional assessments based upon 
previously identified findings, diagnoses, or new signs or symptoms since the last 
visit. 
 
Height 
Height in centimeters (cm) will be recorded on the CRF at the entry visit only. 
 


 
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Weight 
Weight in kilograms (kg) will be measured and recorded in the CRF at entry and 
weeks 12, 24, and 48. 
 
Signs and Symptoms 
At entry, record on the CRFs all signs/symptoms occurring within 30 days prior to 
entry. 
 
After entry, all Grade ≥3 signs/symptoms, any signs/symptoms regardless of 
grade that lead to a change in treatment, that meet EAE, SAE, or ICH guidelines, 
or are defined by the protocol as reportable events that require detailed event 
reporting. 
 
Diagnoses 
At screening, record diagnoses in the medical history per section 6.3.2. At study 
entry and thereafter, record all new diagnoses since the last study visit identified 
in the appropriate diagnoses appendix specified in the CRF. 
 
Concomitant Medications 
All current prescription medications (with start and stop dates) are to be recorded 
on the CRF. Current non-prescription medications are recorded in the source 
documents only. Alternative and traditional medications are reported as Yes/No 
on the CRF and keyed into the database. 
 
Post-entry, new and discontinued prescription concomitant medications 
must be recorded on the CRFs. 
 
Study Treatment Modifications 
At entry and weeks 4 to 96, record all study medication modifications, including 
initial doses, participant-initiated and/or protocol-mandated modifications, and 
inadvertent and deliberate interruptions of ≥3 days. Record any permanent 
discontinuation of treatment. 
 
6.3.6 Neurological Exam 
 
The neurological exam will be performed only in participants who consent to 
undergo the lumbar puncture procedure for collection of CSF. The exam will be 
performed as scheduled in section 6.1. Refer to the A5324 MOPS and the PSWP 
for specific details. 
 
6.3.7 Neuropsychological Baseline Demographic Data 
 
 
At screening, baseline demographic data, including age, educational level, and 
primary language will be collected.  
 


 
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6.3.8 Neurocognitive Batteries 
 
Neurocognitive testing will be performed as scheduled per section 6.1. This 
testing will take about an hour to complete. Refer to section 3.0 (Study Design), 
the A5324 MOPS, and the PSWP for additional information.  
 
Frascati HAND Rating 
Eligibility of the participant for the study will be based on the Frascati criteria 
for neurocognitive impairment. An assessment of relevant confounding 
factors based on medical history and participant report are recorded on the 
CRF, and are a necessary part of the HAND diagnostic criteria. Refer to the 
A5324 MOPS for description and instructions for HAND diagnoses based on the 
Frascati criteria, which is determined by the A5324 Protocol Chair. 
 
Refer to the A5324 MOPS for the Frascati HAND rating procedure for the 
post-entry visits. 
 
A5324 Neurocognitive Battery 
Based on the A5324 Neurocognitive battery administered at screening, 
participant impairment will be determined according to the Frascati criteria for 
HAND diagnoses. The tests will be administered based on CRS location as 
described below.  
 
Neurocognitive Test Battery for CRSs in the United States: 
• 
Attention/Working Memory (Symbol Search, Trail Making A) 
• 
Speed of Information Processing (Stroop Word, Stroop Color, Digit 
Symbol) 
• 
Executive Function (Trail Making B, Stroop Color/Word, Letter and 
Category Fluency) 
• 
Verbal Learning (Hopkins Verbal Learning Test Revised [HVLT-R]) 
• 
Verbal Memory (Delayed Recall – HVLT-R) 
• 
Fine Motor Skills/Complex Perceptual (Grooved Pegboard Bilateral) 
• 
Language/Premorbid Skills (Wide Range Achievement Test 4 [WRAT-
4] Reading OR Word Accentuation Test [WAT] for participants with 
Spanish as their primary language) 
 
 
 
Neurocognitive Test Battery for CRSs outside the United States: 
• 
Attention/Working Memory (Color Trails 1) 
• 
Speed of Information Processing (Digit Symbol) 
• 
Executive Function (Color Trails 2, Category Fluency) 
• 
Verbal Learning (HVLT-R) 


 
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• 
Verbal Memory (Delayed Recall – HVLT-R) 
• 
Fine Motor Skills/Complex Perceptual (Grooved Pegboard Bilateral, 
Fingertapping Bilateral); Gross Motor (Timed Gait) 
• 
International HIV Dementia Scale (IHDS) 
 
6.3.9 Questionnaires 
 
Activities of daily living (ADLs), psychological distress, and substance 
abuse will be assessed using self-report questionnaires as scheduled in 
section 6.1. The following questionnaires will be administered: 
• 
Revised Lawton and Brody Activities of Daily Living Scale 
• 
Beck Depression Inventory II (BDI-II) (CRSs in the US only) 
• 
Patient Health Questionnaire (PHQ)-9 (CRSs outside the US only) 
• 
ACTG Substance Abuse questionnaire 
 
Refer to the A5324 MOPS and PSWP for the specific information and 
instructions for completing the questionnaires. 
 
6.3.10 Adherence Assessment 
 
Adherence to all study-provided and background ART medications will be 
assessed by self-report and completed as scheduled in section 6.1.  
 
Sites will provide adherence reinforcement, according to standard practice, 
throughout the study. Participants with poor adherence (ie, less than 95%) 
will be provided counseling by the site. 
 
6.3.11 Study Medication Dispensing 
 
At study entry and thereafter, study medications will be dispensed every 12 
weeks. At weeks 36, 60, and 84, participants will return for study 
medication dispensing only. No other study evaluations will be performed. 
 
6.3.12 Laboratory Evaluations 
 
Record all protocol-required laboratory values, regardless of grade, obtained at 
screening and entry on the CRFs.  
 
After entry, record: 
• all creatinine and liver function test (LFT) values, 
AND 
• Grade ≥3 for all other laboratory values. 


 
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All laboratory values that lead to a change in study treatment, regardless of 
grade, must be recorded. 
 
Hematology 
Hemoglobin, hematocrit, white blood cell count (WBC), with differential including 
Absolute Neutrophil Count (ANC), and platelet count.  
 
Liver Function Tests (LFTs) 
Total bilirubin, AST, ALT, alkaline phosphatase. 
 
Blood Chemistries 
Electrolytes (Na+, K+, Cl-, HCO3/CO2), glucose, creatinine, phosphate, and blood 
urea nitrogen.  
 
Urinalysis 
Dipstick urinalysis with microscopic examination if dipstick urinalysis is abnormal 
or when thought necessary by the investigator. Results will be recorded on the 
CRFs. 
 
Pregnancy Test 
For women with reproductive potential: serum or urine β-HCG (urine test 
must have a sensitivity of ≤25 mIU/mL).  
 
Negative pregnancy test must be obtained within 48 hours prior to study entry for 
females of reproductive potential as defined in section 4.1.8. After entry, perform 
a pregnancy test when pregnancy is suspected. Refer to section 7.3 for 
pregnancy and pregnancy outcome reporting requirements.  
 
Serologies 
HCV Ab must be performed at the screening visit in participants without an HCV 
Ab test result within 90 days prior to study entry. 
 
Syphilis 
Screening for active syphilis will be done using nontreponemal tests (RPR or 
VDRL) with reflex confirmation with treponemal test. If screening with a 
treponemal test (EIA, CIA, TP-PA, or FTA-ABS), a nontreponemal test must also 
be performed if the treponemal test is reactive. 
 
6.3.13 Immunologic Studies 
 
CD4+/CD8+ 
During the study, CD4+/CD8+ assays must be performed as indicated in section 
6.1. For entry and post-entry evaluations, all laboratories must possess a 
CLIA certification or equivalent and must be certified for protocol testing by the 
DAIDS Immunology Quality Assurance (IQA) Program. 
 


 
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The same assay must be used across all study visits. Due to diurnal variations in 
CD4+/CD8+ counts, determinations for individual participants should be 
obtained consistently in either the morning or the afternoon throughout the study, 
if possible. 
 
NOTE: If the lab is using dual platform technology to obtain the results, each time 
a measurement is obtained, the local lab must perform a WBC and differential 
from the sample collected at the same time.  
 
6.3.14 Virologic Studies 
 
Plasma HIV-1 RNA 
Screening HIV-1 RNA must be performed within 90 days prior to study entry by a 
laboratory that possesses a CLIA certification or equivalent using any FDA-
approved assay. Eligibility will be determined based on the screening value. 
 
HIV-1 RNA on study will be performed as scheduled in section 6.1. The samples 
will be processed and shipped to the designated testing laboratory associated 
with each non-US CTU/CRS or to Quest Diagnostics for each US CTU/CRS; 
plasma HIV-1 RNA will be performed in real-time using the current approved 
assay selected by the ACTG. See the A5324 laboratory processing chart (LPC) 
for directions.  
 
6.3.15 Stored Samples    
 
EDTA blood for plasma and PBMC will be collected at the visits indicated on the 
SOE, section 6.1. Samples will be batch-tested at the end of the study. See the 
A5324 LPC for processing, storage, and shipping directions. 
 
Plasma  
Plasma will be collected and stored for single copy assay (SCA).   
 
Plasma collected at the confirmation of VF visit will be stored for resistance and 
tropism testing if VF is confirmed (see sections 6.3.19 and 6.3.20).  
 
Serum 
Serum will be collected and stored for assessment of the correlation of systemic 
immune and inflammation markers (s100β, sCD14, etc.) and 
neuropsychological test performance. 
 
Viable Peripheral Blood Mononuclear Cells (PBMCs)  
Viably cryopreserved PBMCs from whole blood collected at visits indicated on 
the SOE, section 6.1, will be stored for future T cell and monocyte phenotypic 
and functional studies, HIV reservoir measures (2-LTR circles and total cell-
associated HIV-1 RNA and DNA) and future studies. HIV reservoir measures will 
be performed on samples collected at pre-entry, entry, and weeks 2, 4, and 12.     
 


 
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CSF 
See section 6.3.18 for CSF, CSF Supernatant, and CSF Pellets storage. 
 
6.3.16 PK Studies (refer to section 10; see the A5324 LPC for processing, storage,  and 
shipping directions) 
 
At week 12, samples for MVC and DTG levels will be collected pre-dose and at 2 
and 4 hours post-dose. At weeks 24 and 48, samples will be collected pre-dose. 
 
6.3.17 Lumbar Puncture Safety Laboratory Tests 
 
Participants who agree to undergo an optional LP will need to have platelets 
and PT/INR measured within 1 week prior to the LP only if there is a known 
history of abnormalities of bleeding and coagulation, including at time of entry, or 
if the investigator has any concerns that the participant may have a heightened 
bleeding risk. For these participants that require LP safety laboratory tests to 
be performed, the following safety criteria must be met prior to the LP: 
Platelet count ≥100,000  cells/mm3 
INR ≤1.4 
 
6.3.18 Lumbar Puncture (optional) 
 
In participants who agree to undergo an optional LP, CSF will be collected at 
entry and week 48. 
 
At week 48, the CSF sample will be collected either after the observed morning 
dose or 1 hour after the trough (pre-dose) sampling. 
 
The LP will not be performed in participants with known pregnancy due to risks 
of increased discomfort or difficulty with the procedure with advanced pregnancy. 
 
CSF Storage  
CSF will be stored at week 48 to measure concentrations of MVC, DTG and 
selected biomarkers. 
 
CSF Supernatant and CSF Pellets 
The CSF supernatant will be stored at entry and week 48 for studies of soluble 
markers already noted in the protocol, as well as potential studies of additional 
soluble markers of immune activation, neural biomarkers, and intensive virologic 
assays (for example, single copy assay HIV RNA quantitation) in the future, as 
allowed by new collaborations and funding support.   
 
The CSF pellets will be stored for future potential studies, which may include 
assays such as CSF immune cellular phenotyping and quantitation and 
sequencing of CSF cell-associated HIV-1 DNA and RNA. 
 


 
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6.3.19 Resistance Testing 
 
Perform only in participants who prematurely discontinue study medications 
due to confirmed VF. The test will be performed in the designated laboratory. 
See the A5324 LPC for processing, storage, and shipping directions. 
 
If the HIV-1 RNA obtained at the confirmation of VF visit is ≥1,000 copies/mL, a 
sample should be submitted for HIV-1 resistance testing and protease and 
integrase genotype testing. 
 
6.3.20 Tropism Testing 
 
Perform only in participants who prematurely discontinue study medications 
due to confirmed VF. The test will be performed in the designated laboratory. 
See the A5324 LPC for processing, storage, and shipping directions.  
 
If the HIV-1 RNA obtained at the confirmation of VF visit is ≥1000 copies/mL, 
then a sample should be submitted for HIV-1 coreceptor tropism with reflex to 
ultradeep sequencing. If the HIV-1 RNA is <1000 copies/mL, then a sample 
should be submitted for HIV-1 coreceptor tropism, proviral DNA.  
 
 
7.0 
CLINICAL MANAGEMENT ISSUES 
 
7.1 
Toxicity Management 
 
Only toxicities related to study medications provided through this study (MVC, DTG, 
placebo for MVC, placebo for DTG) will be considered in the toxicity management 
section. The grading system is located in the Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.1, 
March 2017.   
 
For toxicities potentially attributed to one or more of the study medications, one or both 
of the study medications (or the matching placebo) may be held or permanently 
discontinued. 
 
Participants who have switched to any non-study ARV medication should be 
monitored for toxicity for that medication per standard of care and the site investigator 
should assure that no dose adjustments are needed for the study medications.  Any 
changes to the participant’s background ARV regimen must be discussed with the 
core team (actg.coreA5324@fstrf.org). 
 
7.1.1 Grade 1 or 2 
 
Participants who develop a Grade 1 or 2 AE or toxicity may continue study 
medications without alteration of the dosage at the discretion of the 
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discontinue all study medications should complete the premature treatment 
discontinuation evaluations. The site investigator should contact the core team 
(actg.coreA5324@fstrf.org), and the participant should be encouraged to 
complete follow-up protocol study evaluations. 
NOTE: If participants discontinue study medications due to Grade 1 or 2 AEs, 
this should be noted on the premature treatment discontinuation CRF as the 
reason for discontinuation. 
 
7.1.2 Grade 3 
 
If the investigator has evidence that the AE was NOT caused by study 
medications, dosing may continue. Grade 3 AE or toxicity must be evaluated and 
managed by the site investigator according to the standard of care. 
Discontinuation of one or both study medications may be necessary. 
Consultation with the core team is encouraged. The core team 
(actg.corea5324@fstrf.org) must be notified by e-mail regarding toxicities that 
result in a change in regimen. If study medication(s) are suspended the 
participant should be reevaluated weekly until the AE returns to ≤ Grade 2 or 
baseline, at which time the study medications may be reintroduced, at the 
discretion of the site investigator or according to standard practice.  
 
If the same Grade 3 AE, excluding those AEs noted in the following sections, 
recurs within 4 weeks of restarting treatment, the suspected study medication 
must be permanently discontinued. However, if the same Grade 3 AE recurs 
after 4 weeks, the management scheme outlined above may be repeated. 
 
Participants experiencing Grade 3 AEs requiring permanent discontinuation of 
one or both of the study medications should be followed weekly until resolution of 
the AE and should be encouraged to complete the premature treatment 
discontinuation evaluations and continue other study evaluations according to the 
protocol. The core team (actg.corea5324@fstrf.org) must be notified. 
 
7.1.3 Grade 4 
 
Participants who develop a Grade 4 symptomatic AE or toxicity will have all 
study medications permanently discontinued except as indicated below. 
Participants experiencing Grade 4 AEs requiring permanent discontinuation of 
all study medications should be followed weekly until resolution of the AE and 
encouraged to continue other study evaluations according to the protocol. 
Premature treatment discontinuation evaluations should be completed and 
recorded on the CRF and the core team (actg.corea5324@fstrf.org) must be 
notified. 
 
Asymptomatic Grade 4 abnormalities must be evaluated and managed by the 
site investigator according to the standard of care. Discontinuation of all study 
medications may be necessary. Consultation with the core team is encouraged. 


 
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The core team (actg.corea5324@fstrf.org) must be notified by e-mail regarding 
toxicities that result in a change in regimen. 
 
7.1.4 AST or ALT Elevations 
 
All study medications may be continued for asymptomatic ≤ Grade 3 AST/ALT 
elevations, at the discretion of the site investigator. 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 elevations.  
 
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 core team should be consulted 
(actg.corea5324@fstrf.org). In addition, for ALT ≥3 x ULN and bilirubin ≥1.5 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 
elevation should be followed weekly until resolution to ≤ Grade 2. Participants 
will be followed off study treatment, on study after study medication 
discontinuation. Refer to section 11.4.2 for the EAE reporting criteria for AST 
or ALT elevations. 
 
Participants with Grade 3 or 4 AST or ALT elevation with fever, rash or 
eosinophilia should stop all study medications and not be re-challenged. These 
individuals should be followed weekly until resolution to ≤ Grade 2 elevation and 
should be followed off study treatment, on study. 
 
In consultation with the core team, 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); 


 
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• 
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. 
 
7.1.5 Calculated Creatinine Clearance (CrCl) Decline 
 
Non-study medications should be adjusted for decline in CrCl at the discretion of 
the primary provider per the standard of care. CrCl should be calculated, using 
the Cockcroft-Gault Equation, at each post-entry visit when serum 
creatinine is measured. Refer to section 4.1.7 for the Cockcroft-Gault 
Equation calculator. 
 
MVC use is not allowed for CrCl <30 mL/min. MVC or placebo for MVC should be 
discontinued in this setting and then restarted if CrCl increases to 30 mL/min or 
above. 
 
7.1.6 Postural Hypotension 
 
If a participant develops postural hypotension of any grade, the investigator 
should contact the core team (actg.corea5324@fstrf.org).  
 
7.1.7 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 site 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.  
  
Participants with ≥ Grade 3 allergic reactions that are considered to be possibly 
or probably related to the study medications should permanently discontinue the 
putative study medication or medications and continue to be followed off study 
treatment, on study. The participant should not be re-challenged. The 
participant should be treated as clinically appropriate and followed until 
resolution of the AE.   
 
Allergic reactions that include but are not limited to severe rash or any rash with 
fever, general malaise, fatigue, muscle or joint aches, oral lesions, conjunctivitis, 
facial edema or eosinophilia should result in all study medications being stopped 
and the participant should not be re-challenged. The participant should be 
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7.1.8 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 two to three 
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. 
 
Hepatotoxicity accompanied by severe rash or systemic allergic reaction, 
including potentially life-threatening events, have been reported in individuals 
taking MVC. Severe skin and hypersensitivity reactions including SJS and TEN 
have also been reported in individuals taking MVC. 
 
Participants with an isolated Grade 1 rash 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. 
 
Participants may continue study medications for an isolated Grade 2 rash. 
However, 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. 
 
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. 
 
Participants should permanently discontinue study medications (and all other 
concurrent medication(s) suspected in the site investigators causality 
assessment) for an isolated Grade 3 or 4 rash, and the participant will be 
followed off study treatment, on study. Participants should be treated as 
clinically appropriate and followed until resolution of the AE. 
 
7.1.9 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 and/or suicidal ideation and 
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or psychiatric illness) in some patients being treated with integrase 
inhibitors, including DTG. Therefore, it is appropriate to monitor 
participants for suicidality before and during treatment.  
 
Participants should be monitored appropriately and observed closely for 
suicidal ideation 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. 
 
If the participant expresses suicidal ideation or intent, the data will be captured 
as AEs. Any suicide thought or attempts that qualifies as an EAE will be reported 
using the standard EAE mechanism (see section 11.4.2). 
 
7.2 
Additional Considerations for Participants Infected with Hepatitis B Virus (HBV) 
 
Particular diligence should be applied in initiating or maintaining effective anti-HBV 
therapy (referring to treatment guidelines such as IAS) when starting DTG-based 
therapy in HBV co-infected individuals. Liver chemistry elevations consistent with 
immune reconstitution syndrome have been observed in some HBV co-infected 
individuals at the start of DTG therapy, particularly in the setting where anti-hepatitis 
therapy was withdrawn. 
 
Clinical trial and marketed use of 3TC, FTC and TDF have shown that some individuals 
with chronic HBV disease may experience clinical or laboratory evidence of recurrent 
hepatitis upon discontinuation of 3TC, FTC or TDF, which may have more severe 
consequences in individuals with decompensated liver disease. If 3TC, FTC, or TDF is 
discontinued in participants co-infected with HBV, periodic monitoring of both liver 
chemistry tests and markers of HBV replication should be considered. 
 
7.3 
Pregnancy 
 
Pregnancy and pregnancy outcome will be recorded on the CRFs. Pregnancies 
that occur on study should be reported prospectively to The Antiretroviral 
Pregnancy Registry. More information is available at www.apregistry.com. Phone: 
800-258-4263; Fax: 800-800-1052. For studies conducted at sites outside the 
United States, report to The Antiretroviral Pregnancy Registry—Telephone: 910-
679-1598; Fax: 44-1628-789-666 or 910-256-0637. 
 
 
Pregnancy Outcomes and Reporting 
 
The core team (actg.corea5324@fstrf.org) should be notified immediately if a 
participant becomes pregnant after study entry. Study medications must be 
discontinued and the underlying ART regimen continued at the discretion of the site 
investigator. Participants will come in for a premature treatment discontinuation 
evaluation visit within 14 days after stopping study medications. Participants who 
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not have blood drawn for PK studies and stored plasma/PBMCs. They also will not have 
to complete the adherence questionnaire. 
 
If a woman has completed the study or chooses to discontinue from the study before the 
end of the pregnancy, then site staff should request permission to contact her regarding 
pregnancy outcomes at the end of pregnancy. If the information is obtained, pregnancy 
outcomes will be submitted on a CRF at the end of the pregnancy.  
 
7.4 
Breastfeeding 
 
Breastfeeding is not allowed during the study. 
 
7.5 
Unblinding 
 
 
Unblinding can be requested in the following settings: 
• 
At any time that virologic failure occurs if the primary provider is considering 
switching therapy and believes that the unblinded study medication information 
will assist in choosing the next regimen. 
• 
For an adverse event that leads to permanent discontinuation of one or both 
study medications only if the unblinded study medication information will affect 
patient management. 
 
Site should send requests for unblinding to the core team (actg.corea5324@fstrf.org). 
Unblinding procedures will follow the ACTG Standard Operating Procedure for 
Unblinding Participants, which is located on the ACTG website. At the time of the 
request, all data relevant to the medication substitution or virologic failure should have 
been entered into the ACTG database. All discussion of unblinding should be limited to 
the actg.corea5324@fstrf.org email and should be carefully worded to prevent 
unblinding the team, if possible. 
 
7.6 
Antiretroviral Therapy Changes 
 
Study participants should enter the study with the intention to continue on the 
same ART regimen. Any changes to the ART regimen, other than TDF to TAF-
based regimens and RTV to COBI-based regimens, should be discussed with the 
A5324 core team in advance (actg.corea5324@fstrf.org). New regimens should not 
include ARVs on the prohibited medications list. 
 
 
8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Premature Treatment Discontinuation 
• 
Pregnancy or breastfeeding 
• 
Drug-related toxicity (see section 7.1) 


 
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• 
Requirement for prohibited concomitant medications (see section 5.4) 
• 
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 
 
8.2 
Premature Study Discontinuation 
• 
Participant missed both week 24 and week 48 visits 
• 
Request by the participant to withdraw 
• 
Request of the primary care provider 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 
validity of the study results 
• 
At the discretion of the IRB/EC, FDA, NIAID, Office for Human Research Protections 
(OHRP), other government agencies as part of their duties, investigator, or industry 
supporter 
 
 
9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
General Design Issues 
 
A5324 is a randomized, placebo-controlled, double-blinded, phase IV clinical trial 
designed to compare changes in neurocognitive functioning at week 48 in Arm C (MVC 
and DTG) to Arm B (placebo for MVC and DTG) and Arm A (placebo for MVC and 
placebo for DTG) in participants who have at least mild neurocognitive impairment, are 
on a stable ART, and have plasma HIV-1 RNA <50 copies/mL. In addition, a comparison 
of the (Arm B: placebo for MVC and DTG) and (Arm A: placebo for MVC and placebo for 
DTG) arms will be conducted. A comparison of the safety and tolerability will be 
conducted as well. Eligible participants will be randomized to add one of the following 
to their existing ARV regimen: 
• 
Arm A: Placebo for MVC and Placebo for DTG 
• 
Arm B: DTG active drug and Placebo for MVC 
• 
Arm C: MVC and DTG active drugs 
 
All participants will be assessed at pre-entry, and then every 24 weeks for 96 weeks 
with a neurocognitive battery.  
 
Limitations of the design include the fact that changes over time will be a function of both 
intervention effects, natural history, and practice effects that are common in 
neuropsychological studies. However, randomized treatment comparisons will be valid.   
 


 
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9.2 
Outcome Measures 
 
9.2.1 Primary Outcome Measures 
 
The primary outcome is the change in normalized composite neurocognitive test 
score at week 48 from pre-entry. The normalized neurocognitive test score is 
defined as the average of z-scores on the following tests: 
 
Neurocognitive Test Battery for CRSs in the United States: 
a) Attention/Working Memory (Symbol Search Trail Making A) 
b) Speed of Information Processing (Stroop Word, Stroop Color, Digit 
Symbol) 
c) Executive Function (Trail Making B, Stroop Color/Word, Letter and 
Category Fluency) 
d) Verbal Learning (HVLT-R) 
e) Verbal Memory (Delayed Recall – HVLT-R) 
f) Fine Motor Skills/Complex Perceptual (Grooved Pegboard Bilateral) 
g) Language/Premorbid Skills (WRAT-4 Reading OR WAT for participants 
with Spanish as their primary language) 
 
Neurocognitive Test Battery for CRSs outside the United States: 
a) Attention/Working Memory (Color Trails 1) 
b) Speed of Information Processing (Digit Symbol) 
c) Executive Function (Color Trails 2, Category Fluency) 
d) Verbal Learning (HVLT-R) 
e) Verbal Memory (Delayed Recall – HVLT-R) 
f) Fine Motor Skills/Complex Perceptual (Grooved Pegboard Bilateral, 
Fingertapping Bilateral); Gross Motor (Timed Gait) 
g) IHDS 
 
For the assessment of neurocognitive impairment at baseline, weeks 24, 48, 
72, and 96, z-scores will be calculated by subtracting a demographically 
appropriate (adjusted for age, race, sex, and years of education) norm and 
dividing by a demographically appropriate standard deviation. Normative data will 
be available from Heaton et al. [65, 66] and A5271, and the best available 
normative data will be utilized. Functional change will be defined as a change on 
the IADL instrument: Best minus Now, summed across items 1-16, where 
positive changes or increments reflect better functional capacity and negative 
changes or decrements reflect poorer functional capacity. Items with a 


 
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response of 8 (not applicable) or that are missing will be excluded from the 
summation in both Best and Now. 
 
For assessment of change over time in neurocognitive impairment, z-scores 
will be calculated by subtracting the z-scores of the two time points of 
interest.  
 
In addition, based on the z-scores, Global Deficit Scores (GDS) will be computed 
for the domains, and the total battery. The GDS emphasizes impairment, reduces 
minimal learning/practice and has the advantage of reducing ‘sum to zero’ effects 
seen with counterbalancing positive and negative scores in a participant’s 
assessment. However, this approach does minimize the ability to observe subtle 
changes as scores are grouped into larger categories [67].  
 
9.2.2 Secondary Outcome Measures  
 
9.2.2.1 Treatment related AEs. 
 
9.2.2.2 Change of normalized composite neurocognitive test score at weeks 24, 
72, and 96. Change of normalized component neurocognitive test 
scores at weeks 24, 48, 72, and 96 will also be examined. 
 
9.2.2.3 Change in functional status scores based on the IADLs form at weeks 
24, 48, 72, and 96. 
 
9.2.2.4 Change from baseline of peripheral blood and CSF biomarkers at 
week 48. 
 
9.2.2.5 Plasma HIV-1 RNA less than 50 copies/mL at weeks 24, 48, and 96. 
 
9.2.2.6 CD4+ T-cell counts and changes from baseline to weeks 24, 48, and 
96. 
 
9.2.2.7 CD8+ T-cell counts and changes from baseline to weeks 24, 48, and 
96. 
 
9.2.2.8 Changes from baseline to week 48: residual viremia, cell-associated 
HIV-1 RNA/DNA/2-LTR circles and SCA, T cell and monocyte 
activation. 
 
9.3 
Randomization and Stratification 
 
Eligible participants will be randomized with equal probability to add to their existing 
ART either Arm A: placebo for MVC and placebo for DTG, or Arm B: DTG active drug 
and placebo for MVC, or Arm C: MVC and DTG active drugs. Randomization will be 
stratified by CD4+ nadir (≤100 vs. >100 cells/mm3) and HAND severity (ANI vs. 
MND/HAD). Since it is difficult to enroll participants with MND and HAD, strict balance 


 
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among the HAND stratification factors is not required. However, the distribution of HAND 
stratification factors will be closely monitored to ensure successful enrollment of 
participants with MND and HAD (≥25%). 
 
The CPE score of the current ART (before intensification) will not be used as a 
stratification factor at randomization. Instead, it will be used as a continuous covariate in 
regression models to account for CNS penetrations of different ARTs.   
 
9.4 
Sample Size and Accrual 
 
The primary outcome of this study is the 48-week change in normalized composite 
neuropsychological test score. For the primary analyses, all pairwise comparisons (ie, 
Arm B versus Arm A, Arm C versus Arm A, and Arm C versus Arm B) will be conducted 
to test for difference in the primary outcome. Based on previous results from A5235, we 
assume a standard deviation (SD) of 0.7 in the 48-week change in normalized 
neurocognitive test score.  
 
Standard 
Deviation 
Number of 
Primary 
Comparisons 
Nominal 
Power 
Sample 
Size per 
Group 
Adjusted 
Sample Size 
per Group 
Total 
Sample 
Size 
Adjusted Total 
Sample Size 
0.6 
2 
0.80 
28 
33 
84 
99 
0.85 
32 
38 
96 
114 
0.90 
36 
42 
108 
126 
0.6 
3 
0.80 
31 
36 
93 
108 
0.85 
34 
40 
102 
120 
0.90 
39 
46 
117 
138 
0.7 
2 
0.80 
38 
45 
114 
135 
0.85 
43 
51 
129 
153 
0.90 
49 
58 
147 
174 
0.7 
3 
0.80 
41 
48 
123 
144 
0.85 
46 
54 
138 
162 
0.90 
53 
62 
159 
186 
0.8 
2 
0.80 
49 
58 
147 
174 
0.85 
56 
66 
168 
198 
0.90 
64 
75 
192 
225 
0.8 
3 
0.80 
54 
64 
162 
192 
0.85 
61 
72 
183 
216 
0.90 
69 
81 
207 
243 
 
In the sample size calculation, the null hypothesis is that there is no difference in 
changes of neurocognitive functioning from baseline to week 48 across the treatment 
arms, while the alternative hypothesis is that the change of neurocognitive functioning is 
at least 0.5 higher for the (MVC and DTG) arm. The Bonferroni correction has been 
applied to account for multiple comparisons between treatments. One interim analysis of 


 
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efficacy is planned in the middle of the study and the adjusted sample sizes assume a 
15% loss to follow-up. To achieve a power of 90%, we would expect a sample size of 62 
participants per group for a total 186 participants on study. The team anticipates that 
the targeted sample size can be reached in around one year. 
 
A secondary objective of this study is to compare the changes in CSF biomarkers (eg, 
neopterin) between arms. Since CSF biomarkers are measured through optional LP 
procedures, data on CSF biomarkers will not be available for all participants in this 
study. Thus, it is of importance to provide power and sample size justification for this 
secondary objective as well. Using neopterin as an example and assuming a SD of 1.0 
from prior studies, we will need 17 participants per group to detect a mean difference of 
1.0 nmol/L with 80% power (based on a two-sample t-test). In HIV-infected individuals 
on suppressive HAART, CSF neopterin remains persistently elevated to a median 6.3 
nmol/L, while normal levels in HIV uninfected individuals are between 4.3 and 5.3 
nmol/L. Reducing the CSF neopterin by 1.0 nmol/L would lower this marker of 
macrophage immune activation to levels close to levels in HIV negative individuals. The 
figure below also shows the power curves under more conservative SD assumptions (ie, 
1.5 and 2.0).  
 
 
Figure: Power Plots for Comparing CSF Neopterin Levels at Week 48 
 


 
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9.5 
Monitoring 
 
Three types of monitoring reviews will be conducted based on reports prepared by study 
statisticians and/or data manager and/or lab data managers. They are routine monitoring 
reviews, data quality reviews, and reviews by Study Monitoring Committee (SMC) of the 
Neurology Collaborative Science Group. 
 
Routine monitoring reviews will monitor proper execution of the protocol. The study core 
team will receive monthly reports on accrual, study status, screening failures, and 
missing forms and outcomes. The accrual report will also be distributed to the whole 
protocol team. Quarterly toxicity reports and biannual data availability reports will 
be sent to the core team. 
 
The DAIDS clinical representative will review and assess EAE reports for potential 
impact on the study participant safety and protocol conduct as per DAIDS 
policies, guidance documents, and SOPs as applicable. Additionally, the DAIDS 
clinical representative will review aggregated adverse event summaries by blinded 
treatment arm prepared every 6 months by the Statistical and Data Analysis 
Center (SDAC). 
 
In addition, the team anticipates enrollment of 8 participants in each arm who  
consent to voluntary LP when the study has accrued half the required participants. If 
this is not reached, the team will focus on recruitment/enrollment efforts at the sites that 
have experience performing LPs. 
 
Data quality reviews will ensure all required samples are collected and tracked, and 
corresponding outcomes are entered in the study database. Eligibility verification will be 
checked monthly. HIV-1 RNA virology data and pregnancy will be checked every three 
months. 
 
There are three types of Neurology Collaborative Science Group SMC reviews: one 
interim analysis review, routine SMC reviews, and unexpected safety events reviews. 
The purpose of the interim analysis review is to re-evaluate sample size and to assess 
efficacy of treatment arms. This happens in the middle of the study when about 50% of 
participants are enrolled and followed-up for 48 weeks. 
 
Observed SD for the primary endpoint will be compared to the assumed value (SD=0.7) 
to determine the necessity of sample size adjustment. Also two steps will be conducted 
for monitoring efficacy. 
• 
Step 1: Pairwise comparisons will be conducted for three blinded treatment arms. 
Based on the repeated confidence intervals (RCIs) method and Bonferroni 
correction, we will use threshold p-value 0.0007 for each comparison, which 
correspond to a 99.93% CI.  
• 
Step 2: If none of the pairwise comparisons shows significance, then we will 
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predicted interval plots (PIPS) method [68, 69] will be used to see if we can stop 
the arm/study early and claim efficacy. 
 
Routine SMC reviews will assess the study progress via reviewing accrual, study status, 
screening failures, toxicity, etc. This will happen at least annually after enrolling the 
first participant as required by NIH guidelines. Unexpected safety event reviews will 
report any unexpected safety events to the Neurology Collaborative Science Group SMC 
when safety concerns are raised by the core team.  
 
NOTE: Please refer to the A5324 study monitoring plan for details of the monitoring 
process or any updates. 
 
9.6 
Analyses 
 
9.6.1 Primary Analysis 
 
The ITT principle (ie, all randomized participants will be included in the primary 
analyses) will be used for the primary analysis to compare the changes of 
neurocognitive functioning from baseline to week 48. Multiple imputation 
methods will be used to handle missing values. Sensitivity analyses will be 
conducted under different assumptions to assess the impact and informativeness 
of missing data. In addition, a per-protocol analysis will also be conducted by 
restricting the analysis to participants who adhere perfectly to the instructions in 
the study protocol. The Kolmogrov-Smirnov test will be employed to check 
whether the primary outcome is normally distributed. If the normality assumption 
is not rejected, the two-sample t-test will be used for pairwise comparisons 
between any two arms. Otherwise, the nonparametric analogue of the two-
sample t-test (ie, Wilcoxon rank-sum test) will be used as an alternative. The test 
will be stratified by CD4+ nadir (≤100 vs. >100 cells/mm3) and HAND severity 
(ANI vs. MND/HAD). All pairwise comparisons will be conducted among the three 
study arms.  
 
9.6.2 Secondary Analyses 
 
9.6.2.1 The Cox proportional hazards model will be applied to compare the time 
to discontinuation of medication due to AEs. Logistic regression models 
will be used to characterize the proportion of participants with Grade 3 
or Grade 4 clinical AEs or laboratory abnormalities. 
 
9.6.2.2 The Kruskal-Wallis test will be employed to compare changes in 
neurocognitive functioning across the three treatment arms at weeks 
24, 72, and 96. All pairwise comparisons between two treatment arms 
will be conducted based on the Wilcoxon rank-sum test. 
 
9.6.2.3 Similar to the analyses for neurocognitive functioning, changes in 
functional status scores at weeks 24, 48, 72, and 96 will also be 
compared among treatment arms using the Kruskal-Wallis test (for 


 
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overall comparisons across the three treatment arms) and the Wilcoxon 
rank-sum test (for pairwise comparisons between two treatment arms). 
 
9.6.2.4 Wilcoxon signed-rank test will be used to assess the changes from 
baseline of peripheral blood biomarkers and CSF biomarkers at week 
48. Comparisons of changes in these biomarkers between any two 
treatment arms will be conducted through Wilcoxon rank-sum test. 
 
9.6.2.5 Association between peripheral blood and CSF biomarkers and 
neuropsychological performance will be estimated at each visit using 
the Spearman correlation. 
 
9.6.2.6 For each treatment arm, the proportions of participants with HIV-1 
RNA less than 50 copies/mL and their associated 95% CIs will be 
plotted over time. Logistic regression models will be used to compare 
the odds corresponding to the proportions across the treatment arms at 
weeks 24, 48, and 96. 
 
9.6.2.7 Average CD4+/CD8+ counts and their associated 95% CIs will be 
plotted over time for each treatment arm. Changes in CD4+/CD8+ 
counts from baseline to weeks 24, 48, and 96 will be compared across 
treatments arms through Wilcoxon rank-sum test. 
 
9.6.2.8 Spearman correlation will be used to determine the association between 
changes in blood immunologic markers and changes in neurocognitive 
function from baseline to week 48. 
 
9.6.2.9 Spearman correlation will be used to explore the relationship between 
changes in CCR5 ligand levels (MIP-1β) and inflammatory markers 
changes from baseline to week 48. Scatterplots will display 
relationships. 
 
9.6.2.10 Wilcoxon rank-sum test will be used to compare Arm A and Arm B to 
assess the effect of DTG intensification on virologic changes. 
Association between the vriologic changes and changes in 
neurocognitive function from baseline to week 48 will be examined 
using the Spearman correlation. 
 
9.6.2.11 Similar to the primary analysis, the ITT principle will be used to 
compare the changes of GDS scores from baseline to week 48. All 
pairwise comparisons will be conducted among the three study 
arms.  
 
9.6.2.12 Subgroup analyses will be performed for the primary outcome in 
each participating country. In presence of significantly different 
results by country, the changes of neurocognitive functioning will 
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10.0 
PHARMACOLOGY PLAN 
 
MVC is a CCR5 co-receptor antagonist that is given twice daily. In phase II and III 
studies (MOTIVATE-1 and MOTIVATE-2), MVC demonstrated potent ARV activity and 
good tolerability in treatment-experienced participants [28, 29]. Importantly, it was 
noted, and confirmed in the phase II and III studies that MVC in combination with other 
ARV agents resulted with a significant reduction in viral load in adult participants with 
no detectable CXCR4-using plasma HIV-1 who were experiencing virologic failure on 
their current ARV regimen with  multi-resistant virus. In addition, the CD4+ cell count 
was increased to a significantly greater extent with MVC compared with placebo in these 
studies. The most frequently seen AEs in the phase II and III studies are diarrhea (8-
10%), nausea (6%), headache (2-5%), fatigue (3-4%), upper respiratory tract infection 
(4-5%), and fever (2-6%). The other common AEs (>8% incidence) include cough, 
pyrexia, rash, and dizziness. Hepatotoxicity accompanied by severe rash or systemic 
allergic reaction including potentially life-threatening events has been reported.  
 
MVC is a substrate of CYP3A and P-gp, inhibitors and inducers of these 
enzymes/transporters influence MVC pharmacokinetics (PK). A dosage of 150 mg BID is 
recommended when given with potent CYP3A inhibitors, including HIV-1 protease 
inhibitors, such as LPV/r, DRV/r, saquinavir/ritonavir (SQV/r), and ATV/r, as well as 
ketoconazole that significantly increase the Cmax and AUC of MVC, whereas 300 mg BID 
of MVC is recommended with concurrent use of NRTIs, TPV/r, NVP, DTG, and other 
drugs that are not potent CYP3A inhibitors or inducers. When MVC is coadministered 
with potent CYP3A inducers, eg, RIF, ETR and EFV, there is a significant reduction in 
MVC Cmax, AUC, and Cmin. As a result, it is recommended that when used with these 
agents, 600 mg of MVC should be given BID. 
 
Data from several studies with a small sample size, which evaluated MVC 
concentrations in CSF, suggest that MVC achieves therapeutic concentrations (EC50-
EC90) in the CSF even though MVC plasma concentrations and physiochemical 
characteristics are poor predictors of its CNS distribution [21, 70, 71, 72]. While the 
trough MVC plasma concentration ranged from 94.9 to 337 ng/mL, the mean CSF 
concentration ranged from 2.4 to 7.5 ng/mL. The mean CSF:plasma ratio was ~0.02. 
Small increases in cerebral metabolite markers of neuronal integrity were reported in 12 
participants treated with MVC, and these changes associated with MVC plasma trough 
concentrations [71].  
 
10.1 
Pharmacology Objectives 
 
10.1.1 Investigate DTG and MVC plasma concentrations and determine PK parameters 
including area-under-the curve and clearance. 
 
10.1.2 Investigate the relationship between plasma PK and CSF concentrations for DTG 
and MVC including CSF:plasma ratio. 
 


 
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10.1.3 Investigate associations between DTG and/or MVC plasma and CSF 
concentrations in a multivariate analysis including: 
a) Changes in neurocognitive testing scores. 
b) Self-reported adherence. 
c) Changes in peripheral blood and CSF biomarkers. 
 
10.2 
Pharmacology Study Design 
 
Only DTG and MVC will be measured based on the assumption that the neurocognitive 
benefits of intensification are directly related to DTG and/or MVC. 
 
10.2.1 A single abbreviated plasma PK study at week 12 in all participants including a 
pre-dose sample and observed dose. Two additional samples at 2 and 4 hours 
after the dose at week 12.  
 
If DTG/placebo for DTG is taken once daily in the evening: 
• 
At least 3 days prior to the week 12 PK visit, the evening DTG/placebo for 
DTG dose should be converted to a morning dose. Participants should 
be reminded at least 5 days prior to the week 12 PK visit to convert the 
evening DTG/placebo for DTG dose to a morning dose at least 3 days 
prior to the visit. Participants should be instructed to hold their morning 
doses of DTG/placebo for DTG and MVC/placebo for MVC on the day of 
the week 12 PK visit and the doses will be given in the clinic after the pre-
dose sample has been obtained.   
• 
If the participant does not convert DTG/placebo for DTG to morning 
dosing, there will be no observed dose of DTG/placebo for DTG. The 
participant should still hold the morning dose of MVC/placebo for MVC 
and the dose will be given in the clinic after the pre-dose sample is 
obtained. The PK sampling will remain the same. 
 
If DTG/placebo for DTG is taken twice daily: 
• 
Participants should be instructed to hold their morning doses of 
DTG/placebo for DTG and MVC/placebo for MVC on the day of the week 
12 PK visit. The doses will be given in the clinic after the pre-dose sample 
has been obtained. 
 
10.2.2 Repeated trough samples at weeks 24 and 48. 
 
Participants taking DTG/placebo for DTG once daily in the evening should be 
instructed to convert to morning dosing as described in section 10.2.1.  
Participants should also be instructed to hold their morning doses of 
DTG/placebo for DTG and MVC/placebo for MVC as described in section 10.2.1. 
The doses will be given in the clinic after the PK sample has been obtained. 
 


 
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10.2.3 CSF concentrations of MVC and DTG in participants who consent to LP (see 
section 6.3.18). 
 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
 
Using PK models derived from previous intensive PK data [73, 74], participants’ limited 
drug concentrations will be used to estimate key PK parameters (exposure, as indicated 
by area under the concentration curve, AUC and clearance, Cl/F). The population PK 
analyses incorporating plasma and CSF data will be based on nonlinear mixed effects 
models. These participant level estimates will then be used for comparison of drug 
exposure between participants with and without neurocognitive changes (with non-
parametric tests and with PK models). Pharmacodynamic analyses will evaluate the 
relationship between the model derived participant-specific estimates of PK parameters 
(AUC and Cl/F) and neurocognitive changes. 
 
10.4 
Anticipated Outcomes 
 
We anticipate that participants in A5324 will enter the study on a variety of ART 
regimens. These participants will receive the recommended doses of DTG and MVC, 
as per tables A and B in section 5.1.1, but there will be a wide range of individual 
plasma and CSF exposures based on expected interpatient variability. The proposed 
clinical pharmacology objectives will provide PK data and strengthen the multivariate 
analysis that will help identify specific covariates that are associated with the primary 
outcomes as well as provide an additional adherence confirmation.  
 
 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
CRF will be made available to sites for data entry. Participants must not be identified 
by name on any data submitted to the DMC. Participants will be identified by the 
patient identification number (PID) and study identification number (SID) provided by the 
ACTG DMC upon randomization. 
 
Participants’ background ART will be recorded at randomization on randomization logs. 
 
11.2 
Role of Data Management 
 
11.2.1 Instructions concerning entering 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 (eg, 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 supporters 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 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/clinical-research-sites/safety-
reporting/manual. 
 
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 (now part of the NIAID Clinical Research Management System) at 
CRMSsupport@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 at http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/manual. For questions about EAE reporting, please 
contact the RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
11.4.2 Reporting Requirements for this Study 
 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
 


 
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• 
The study agents for which expedited reporting are required are: 
− 
MVC and placebo for MVC  
− 
DTG and placebo for DTG 
 
• 
In addition to the EAE Reporting Category identified above, other AEs 
that must be reported in an expedited manner are: 
− 
Symptomatic or asymptotic AST/ALT and bilirubin elevations that 
result in discontinuation of study medications 
− 
Suicidal thoughts or attempts that meet the EAE reporting 
category 
 
11.4.3 Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs 
(DAIDS AE Grading Table), Version 2.1, March 2017, must be used and is 
available on the DAIDS RSC website at http://rsc.tech-res.com/clinical-
research-sites/safety-reporting/daids-grading-tables. 
 
11.4.4 Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is per the EAE manual. 
 
• 
After the protocol-defined AE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs), as defined in 
Version 2.0 of the EAE Manual, will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available 
information). 
 
 
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 legally authorized representative, ie, a person with power of attorney to consent to 
participation in a clinical trial on behalf of a participant who cannot provide informed 
consent). The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation. A copy of the consent form will be 
given to the participant or legally authorized representative, and this fact will be 
documented in the participant’s record. The IRB and site must comply with state and 
local laws regarding legally authorized representatives. 
 


 
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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, 
industry supporter, or other government agencies as part of their duties to ensure that 
research participants are protected.  
 
 
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 
 
1.  Robertson K, Smurzynski M, Parsons T, et al. The prevalence and incidence of 
neurocognitive impairment in the HAART era. AIDS 2007;21:1915-21. 
 
2.  Heaton RK, Clifford DB, Franklin DR Jr, et al.; CHARTER Group. HIV-associated 
neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER 
Study. Neurology 2010;75:2087-96.  
 
3.  Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite 
long-standing suppression of viremia. AIDS 2010;24:1243-50. 
 
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Dynamics of monocyte chemoattractant protein type one (MCP-1) and HIV viral load in 
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APPENDIX I 
 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT 
 
For protocol A5324 
A Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral 
Intensification with Maraviroc and Dolutegravir with No Intensification or Intensification with 
Dolutegravir Alone for the Treatment of Cognitive Impairment in HIV  
Final Version 2.0 dated 08/25/17 
 
 
SHORT TITLE FOR THE STUDY: Integrase and Maraviroc Intensification in Neurocognitive 
Dysfunction (InMIND), Final Version 2.0 dated 08/25/17 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are infected with the 
human immunodeficiency virus (HIV), the virus that causes AIDS. This study is sponsored by 
the National Institutes of Health (NIH). 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 tells you 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? 
 
There are now several HIV treatment options for a person with HIV infection who has not yet 
been treated. Most people who receive treatment and take their medications as directed have a 
good test result. This is usually determined by measuring the amount of HIV in the blood (viral 
load). The best response is when HIV cannot be found (undetectable) in the blood. However, it 
has recently become clear that some people with HIV who are receiving effective HIV drugs 
continue to have more health problems than people without HIV infection. Sometimes, there is 
damage to organs in the body, including bone, kidneys, and the brain. 
 
The reasons this study is being done are the following: 
• 
To see how the study drug combinations affect your ability to use your fingers and hands, 
concentrate, learn and remember, speak and write, think, solve problems and make 
decisions. 
• 
To see how well the study drug combinations lower your HIV viral load.  
• 
To see how safe the study drug combinations are, how well people are able to take the 
study drug combinations, and how well their immune systems respond to the study drugs.  


 
 
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• 
To see how well the study drug combinations get into your blood. 
 
The drugs we are testing in this study are maraviroc (MVC) and dolutegravir (DTG). Both of 
these drugs have been approved by the Food and Drug Administration (FDA) for treatment of 
HIV. MVC and DTG will be added to your current drug regimen. 
 
Some participants in the study will not be given the drugs that we are testing. Instead, they will 
be given a placebo. Placebo pills are just pills with no active ingredient in them. 
 
You will be given one of the following three drug combinations: 
• 
Placebo for MVC and placebo for DTG 
OR 
• 
DTG active drug and placebo for MVC  
OR 
• 
MVC and DTG active drugs 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you would like to be in this study, after you have read and signed this informed consent form, 
you will come to the clinic for a screening exam to make sure you meet the requirements for 
joining the study.  
 
At Screening 
This visit will take about 1 to 2 hours.  The tests for this visit may be done in more than one day 
if that will be easier for you. At the screening visit: 
 
• 
Your HIV infection status will be confirmed. If there is no record available, another HIV test 
will be done. You may have to sign a separate consent form before this is done.  
• 
We will ask you questions about your medical history, any medications you are taking or 
have taken within the last 30 days, and about the anti-HIV drugs you are taking (such as 
how long you have been taking the anti-HIV drugs you are currently taking, if you stopped 
taking them for any reason for more than 7 days, etc.).  
• 
You will have a physical exam and will be asked questions about your health.  
• 
You will have about 1-2 tablespoons (25mL) of blood drawn to measure your viral load (the 
amount of HIV in your blood), to see if you are infected with the hepatitis C virus (an 
infection of the liver) if there is no record available, to see if you have syphilis (a type of 
sexually transmitted disease), and to have some other routine tests for safety. You will be 
told the results of these tests when they become available.  If the syphilis test shows that 
you have syphilis, your result, by state law, will be forwarded to the  
 
 Board of 
Health (sites please modify as appropriate per your state/local law).   
• 
We will ask you to give a urine sample for safety testing. We will give you the results of this 
test as soon as it becomes available. 
• 
You will be given a liver enzyme test, formerly called liver function test (LFT) to see if you 
have damage to your  liver and if your liver is working well. 


 
 
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• 
You will be asked some questions about yourself, such age, educational level and primary 
language. 
• 
You will take neuropsychological tests, which will take about 1 hour. During the 
neuropsychological tests you will answer questions, list items (such as naming foods, or 
animals, or some other groups you know), and do simple tasks. You will be asked questions 
to see if you forget things, have difficulty understanding facts, or difficulty with your behavior 
and interacting with others.   
− 
Problems with thinking and decision making are an important effect of HIV-1 infection on 
the brain. These problems are known as neurocognitive impairment, and impact specific 
areas of brain functioning such as your ability to use your fingers and hands, 
concentrate, learn and remember, speak and write, think, solve problems and make 
decisions. Neurocognitive impairment has been classified into diagnoses, HIV 
Associated Neurocognitive Disorders, which is abbreviated as HAND. The diagnosis of 
HAND can go from least to most severe. 
− 
The study team will determine if you have HAND and are eligible for the study 
based on combining the results of the neuropsychological testing, gathering data on 
other conditions that can impact brain functioning and therefore your thinking, and also 
seeing how these changes in thinking ability have affected your home, social and work 
life. 
• 
If you are a woman able to become pregnant, we will ask you to give a urine sample or have 
an additional 1 teaspoon (5mL) of blood drawn to see if you are pregnant. You will not be 
able to enroll in this study if you are pregnant. You will be told the result of the test when it 
becomes available.  
• 
You will be asked to complete some questionnaires that ask about how you are feeling, how 
well you are able to perform your daily activities, and about your alcohol and drug use. 
 
At Pre-Entry 
If you are eligible for the study, you will come in for a pre-entry visit. This visit will last about 30 
minutes. At this visit you will have about 5 tablespoons (75 mL) of blood drawn, which will be 
stored for future testing. 
 
The screening and pre-entry visits may be on different days or on the same day.  
 
At Study Entry Visit 
If you are eligible for the study, you will come in for an entry visit. This visit will last about 1 hour. 
At this visit:  
 
• 
You will have a physical exam and will be asked questions about your health and about any 
medicines you have taken or are taking.    
• 
You will have about 1-2 tablespoons (25mL) of blood drawn to measure your viral load, to 
measure your CD4+ cell count (CD4+ cells are cells in your blood that fight infection), and to 
have some other routine safety tests including liver enzyme test. You will be told the results 
of these tests when they become available. 
• 
If you are a woman able to become pregnant, you will have a pregnancy test within 2 days 
before entry into the study. Pregnant women cannot enter the study.  


 
 
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• 
You will have about 5-6 tablespoons (80 mL) of blood drawn, which will be stored for future 
testing. 
• 
We will ask you to fill out a questionnaire to see how well you are taking your anti-HIV drugs. 
 
We will randomize you to one of three groups:  
• 
Group A: placebo for MVC and placebo for DTG 
• 
Group B: DTG active drug and placebo for MVC 
• 
Group C: MVC and DTG active drugs 
 
Randomized means that we will assign you by chance to one of three groups. You have an 
equal chance of being assigned to any group, like flipping a coin. [Sites please modify the 
randomization analogy as appropriate to your local culture].  
 
This study is a double-blind study. This means that you and your study staff will not know which 
group we assign you to.  We are doing this research because we do not know which treatment 
group is best for you.   
 
You will continue taking the anti-HIV drugs that you are currently taking.  You will also be given 
a combination of MVC, DTG or placebo based on the group that you are randomly assigned to.  
You must start the new medications within three days after you are randomized. 
 
After Entry 
After your entry visit, you will come to the clinic at weeks 2, 4, 12, 24, 48, 72, and 96. These 
study visits will last about 1 to 2 hours, except week 12 which will last about 4 hours. During 
these visits: 
 
• 
You will have a physical exam, and will be asked questions about your health and about any 
medicines you have taken or are taking, at every visit.  
• 
You will take neuropsychological tests at weeks 24, 48, 72, and 96. 
• 
We will draw about 2-7 tablespoons (30-105mL) of blood for routine safety tests, to measure 
your viral load, and to measure your CD4+ cell count. You will be told the results of these 
tests when they become available. You will have routine safety tests, including liver enzyme 
test, at weeks 4, 12, 24, 48, 72, and 96; viral load measured at weeks 12, 24, 48, 72, and 
96; and CD4+ cell count measured at weeks 12, 24, 48, 72, and 96. We will also store some 
of your blood for future testing at every visit.  
• 
We will draw an additional 1 teaspoon-1 tablespoon (5-15mL) of blood for pharmacokinetic 
studies (PK) to measure the amount of study drug in your blood at weeks 12, 24, and 48. At 
these visits we will draw blood before you take the study drugs. At week 12 we will also draw 
blood 2 and 4 hours after you take the study drugs. If one of the study drugs you will be 
taking are taken in the evening, 3 days before the PK studies at weeks 12, 24, and 48, 
you will have to switch taking that study drug from the evening to the morning. The 
study staff will contact you before that time to remind you when to make the switch. 
You must also not take the study drugs in the morning on the day of the weeks 12, 24, 
and 48 visits, and instead bring the study drugs with you to the clinic. The study staff 
will give you the doses in the clinic. 
• 
We will ask you to give a urine sample at week 96 for safety testing. You will be told 
the result when it is available. 


 
 
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• 
We will ask you to fill out some questionnaires at weeks 24, 48, 72, and 96 that ask about 
how you are feeling, how well you are able to perform your daily activities, and your alcohol 
and drug use. We will also ask you to fill out a questionnaire about how well you are taking 
your current anti-HIV drugs at weeks 4, 12, 24, 48, 72, and 96. If you are having problems 
taking your anti-HIV drugs correctly, a site staff member will try to help.  
• 
If you are a woman and you think you might be pregnant, you will have a pregnancy test. 
You will be told the result of this test when it becomes available. 
• 
At weeks 12, 24, 48, and 72, your study drugs will be refilled. 
 
At weeks 36, 60, and 84, you will return for refill of your study drugs. These refills should 
take about 30 minutes or less. No other evaluations will be done. 
 
You should inform the study doctor before changing the other anti-HIV drugs that you 
are taking. 
 
Optional Lumbar Puncture 
In this study, there is an optional lumbar puncture. A lumbar puncture (also called a “spinal tap”) 
removes fluid that surrounds the brain and spinal cord. This is done by numbing a small patch of 
skin on your back and inserting a needle in between the bones in your lower back. You will be 
asked to lie in a flat position (with one or no pillows) at the clinic for up to 30 minutes after the 
test. You should also drink plenty of liquids and not do too much activity for up to 24 hours after 
the test. Your clinic may ask that you sign a separate consent form before you have this 
procedure. 
 
The lumbar puncture will be performed to measure inflammatory markers (a measure of the 
body’s response to infection or damage) to see if your brain is affected by HIV.  
 
• 
If you agree to participate in the optional lumbar puncture study, you will have a neurological 
exam at study entry and week 48. The neurological exam will see if you have any nerve 
damage or nervous system problems and will take about 30 to 45 minutes. 
• 
If you had abnormal bleeding or bruising in the past or the study doctor feels you may be at 
risk of having abnormal bleeding, you will also have about 1 teaspoon (6mL) of blood drawn 
to check the number of platelets (the cells in the blood that stop bleeding) in your blood and 
to see how long it takes your blood to clot at study entry and week 48. You will be told the 
results of the tests when they become available. 
• 
If you are eligible for the lumbar puncture, you will have a lumbar puncture at study entry 
and week 48. About 2 to 3 teaspoons of spinal fluid will be collected for routine and study-
specific tests and HIV viral load. 
 
Please indicate and initial below whether you agree to participate in the optional lumbar 
puncture.  
 
________ YES, I agree                     ________ NO, I disagree 
 
Virologic Failure 
You will be tested for virologic failure at weeks 12, 24, 48, 72, and 96. Virologic failure is when 
your anti-HIV drugs are not fully suppressing HIV in the blood. If the study staff sees that your 


 
 
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viral load has gone up, you will be asked to have another viral load test done within 30 days. 
About 2 teaspoons (10mL) of blood will be drawn for the viral load test. We will also draw an 
additional 1-2 teaspoons (6mL) of blood that will be used for tests that check which anti-HIV 
drugs have stopped working on the HIV in your blood (resistance test) and if a specific type of 
anti-HIV drug will be able to control your HIV (tropism test) if the repeat viral load test shows 
that your viral load is still up. We will also ask you to fill out a questionnaire about how well 
you are taking your current anti-HIV drugs. 
 
If your viral load is still up and you are still taking study drug, you will be asked to stop the study 
drug, and come to the clinic within 2 weeks. You will be followed on study and off study 
treatment until the final study visit, week 96. If you have virologic failure at week 96, you will 
have a confirmation of virologic failure within 30 days, and you will be off study. 
 
After you start your study drugs, you should not stop taking any of them unless you 
have discussed it with the study doctor. If you do not take your study drugs or other HIV 
medications consistently, this may result in viral rebound, a condition in which HIV levels 
in your blood become detectable. This could lead to drug resistance and a chance that 
the study drugs, or your other HIV medications, will no longer be effective. Discontinuing 
HIV medications can also result in immune system decline. If your blood test shows 
evidence of drug resistance, you will be taken off the study drugs but will be asked to 
continue follow-up in the study until you complete all visits and procedures. 
 
Although very unlikely, you could develop viral rebound or drug resistance during this 
study. If drug resistance develops, your choices of HIV medications in the future could 
be limited.  
 
If You Have to Stop Taking the Study Drugs Early or You Have to Stop the Study Early 
If you have to stop taking the study drugs early or you have to stop the study early, you will 
come to the clinic for an additional visit. At this visit: 
 
• 
You will have a physical exam and will be asked questions about your health and about any 
medicines you have taken or are taking. 
• 
You will take neuropsychological tests. 
• 
We will draw about 1 tablespoon (15mL) of blood to measure your viral load and CD4+ cell 
count. We will tell you the test results of when they become available.  
• 
We will draw about 2 tablespoons (30mL) of blood and store the blood for future study-
related virologic testing. 
• 
If you are a woman and you think you might be pregnant, you will have a pregnancy test. 
We will tell you the test result when it becomes available. 
• 
We will ask you to fill out some questionnaires to see how you are feeling, how well you are 
able to perform your daily activities, if you have been hospitalized recently, and how well you 
are taking your current anti-HIV drugs 
• 
We will ask you to give a urine sample for safety testing. We will give you the results of this 
test as soon as it becomes available. 
 


 
 
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If you do not enroll into the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we 
will still use some of your information. As part of this screening visit, some demographic (age, 
gender, race), clinical (disease condition, diagnosis), and laboratory (CD4 cell count, viral load) 
information is being collected from you so that ACTG researchers may help determine whether 
there are patterns or common reasons why people do not join a study. 
 
Other 
Some of your blood or spinal fluid (if you have a lumbar puncture) that is left over after all 
required study testing is done may be stored (with usual protectors of identity) and used for 
ACTG-approved HIV-related research. Storage of leftover blood or spinal fluid is not a 
requirement to participate in the study and you may withdraw your approval for the storage of 
your leftover blood or spinal fluid at any time, and your samples will be destroyed. These 
samples may be held for an indefinite length of time. We cannot ensure that you will be told of 
the results of the research done on these samples. Please indicate and initial below whether 
you approve the use of your leftover blood or spinal fluid.  
 
________ YES                     ________ NO 
 
At sites outside the US, biological specimens may be shipped and stored outside the 
country from which they were collected (e.g., sites that do not have a central testing 
laboratory in-country and storage of left-over specimens). 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 186 people will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 24 months (2 years).   
 
 
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: 
• 
your primary care physician no longer thinks that participating in the study is in your best 
interest 
• 
the study is stopped or cancelled  
• 
you are not able to attend the study visits or perform the assessments as required by the 
study 
 
The study doctor may need to take you off the study drugs without your permission if: 
• 
you become pregnant or start breastfeeding 
• 
continuing the study drug(s) may be harmful to you 
• 
you need a treatment that you may not take while on the study 


 
 
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• 
you are not able to take the study drug(s) as required by the study 
 
If you must stop taking the study drug(s) before the study is over, the study doctor may 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-provided drugs, or once I leave the study, how would 
they be provided? 
 
During the study: 
If you must permanently stop taking study-provided drugs before your study participation is 
over, the study staff will discuss other options that may be of benefit to you. 
 
After the study: 
After you have completed your study participation, the study will not be able to continue to 
provide you with the drugs you received on the study. If continuing to take these or similar drugs 
would be of benefit to you, the study staff will discuss how you may be able to obtain them. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
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. If you have questions concerning the additional study 
drug side effects please ask the medical staff at your site. 
 
There is a risk of serious and/or life-threatening side effects when non-study drugs are taken 
with the study drugs. For your safety, you must tell the study doctor or nurse about all drugs you 
are taking (including non-prescription drugs, vitamins and herbal supplements) before you start 
the study and also before starting any new drugs while on the study. You must also tell the 
study doctor or nurse before enrolling in any other clinical trials while on this 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 
 


 
 
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Risks of Social Harm 
Although the study site will make every effort to protect your privacy and confidentiality, it is 
possible that other people could find out that you are in a study and this could cause problems 
for you. For example, other people might figure out that you are infected with HIV. If this 
happens, people could treat you unfairly or family members, friends, and/or the community 
might not accept you. 
 
Risks of Drawing Blood 
Taking blood may cause some discomfort, lightheadedness, bleeding, swelling, or bruising 
where the needle enters the body, and in rare cases, fainting, or infection. 
 
Risk of Spinal Tap 
• 
Leakage of cerebrospinal fluid (CSF) into the tissues in your back, which can cause 
headache  
• 
Back pain or pain where the needle is inserted in the back  
• 
Decreased blood pressure 
• 
CSF leak 
• 
Infection 
• 
Fever 
• 
Nerve injury (very rare) 
• 
Bleeding  
• 
Allergic reaction to medication used to numb the area where the spinal tap will be done.   
• 
Allergic reaction to the substance (such as iodine) that is used to clean the area of the spinal 
tap to prevent infection could include itching, hives, swelling, shortness of breath, difficulty 
breathing, changes in blood pressure and heart rhythm, loss of consciousness, or in a rare 
case, death.  
 
Headaches can be helped by lying down face up and by taking over-the-counter headache 
medicine. Severe headaches should be reported to the study staff or study doctor. 
 
It may be uncomfortable for you to lie on your side while the lumbar puncture is being done and 
to lie flat on your back for the required time afterwards. 
 
Risks of MVC (Selzentry) 
The following serious side effects have been associated with the use of MVC:  
 
Liver problems (liver toxicity) have occurred in people who took MVC. An allergic reaction may 
happen before liver problems occur. Stop taking MVC and call the study doctor or your 
healthcare provider right away if you get any of the following signs or symptoms:  
• 
Rash on your body (allergic reaction) 
• 
Yellowing of the skin or whites of your eyes (jaundice) 
• 
Dark urine 
• 
Vomiting 
• 
Stomach pain 
• 
Elevated liver-related function test – People who are co-infected with hepatitis B might be at 
higher risk of having liver problems.  


 
 
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Heart problems, including heart attack. 
 
Low blood pressure when standing up, which can cause dizziness or fainting. People who have 
serious kidney problems may be at increased risk for dizziness and fainting.   
 
In addition to the serious side effects listed above, additional side effects include: 
• 
Colds 
• 
Cough 
• 
Fever 
• 
Rash  
• 
Dizziness 
• 
Diarrhea 
• 
Swelling of parts of the body 
• 
Flu and flu-like symptoms 
• 
Muscle aches, spasms and pain  
• 
Stomach  pain and bloating 
• 
Sleeping problems 
• 
Runny, congested nose 
• 
Problems with urination 
• 
Low amounts of white blood cell counts (neutropenia) 
 
NOTE: Because of how the drug works in your body, there is a possible increased risk for 
getting other infections or cancer, although there is no evidence from the clinical trials of an 
increase in serious infections or cancer. 
 
MVC contains soy lecithin. If you have a medical history of allergy to soy (soya or soybeans) or 
peanuts, you may develop an allergic reaction to MVC. Before starting MVC, you should inform 
the study staff or study doctor if you are allergic to soy or peanuts.  
 
Risks of DTG (Tivicay) 
The following serious side effects have been associated with the use of DTG. These include 
allergic reactions and liver problems, which may be life-threatening. 
 
Contact the study doctor or your healthcare provider right away if you develop a rash while 
taking DTG, especially if it is associated with any of the symptoms listed below. Stop 
taking DTG and get medical help right away if you develop a rash with any of the following 
signs or symptoms:  
• 
Fever 
• 
Generally ill feeling 
• 
Extreme tiredness 
• 
Muscle or joint aches 
• 
Blisters or sores in mouth 
• 
Blisters or peeling of the skin 
• 
Redness or swelling of the eyes 
• 
Swelling of the mouth, face, lips, or tongue 


 
 
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• 
Problems breathing 
 
Contact the study doctor or your healthcare provider if you have any of the following 
symptoms that could be signs of liver problems:  
• 
Yellowing of the skin or whites of the eyes 
• 
Dark or tea-colored urine 
• 
Pale-colored stools or bowel movements 
• 
Nausea or vomiting 
• 
Loss of appetite 
• 
Pain, aching, or tenderness on the right side below the ribs 
 
People with a pre-existing history of depression or other mental health illness may be at 
greater risk for suicidal thoughts, or attempts, which may lead to death. If your mental 
health illness worsens, or if you develop suicidal thoughts, call the study doctor or your 
healthcare provider right away. 
 
Other side effects of DTG include: 
• 
Changes in liver test results, more common in people with hepatitis B or C 
• 
Trouble sleeping 
• 
Tiredness 
• 
Headache 
 
Tell the study doctor or your healthcare provider about any side effect that bothers you or that 
does not go away. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
The drugs used in this study may be unsafe for unborn babies. If you are having sex that could 
lead to pregnancy, you must agree not to become pregnant. Because of the risk involved, you 
must use at least one method of birth control. You must continue to use birth control for 6 weeks 
after stopping your medicines. You must choose one of the birth control methods listed below:  
• 
Condoms (male or female) with or without a spermicidal agent 
• 
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. The 
test must show that you are not pregnant. If you think you may be pregnant at any time during 
the study, tell your study staff right away. If you are pregnant you will be taken off the study 
treatment, but asked to continue the study evaluations. The study staff will talk to you about 
your choices.  
 
If you become pregnant while on study, the study staff would like to obtain information from you 
about the outcome of the pregnancy (even if it is after your participation in the study ends). If 
you are taking anti-HIV drugs when you become pregnant, your pregnancy will be reported to 


 
 
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an international database that collects information about pregnancies in women taking anti-HIV 
drugs. This report will not use your name or other information that could be used to identify you. 
 
NOTE: It is not known whether the study drug passes through breast-milk and may cause harm 
to your baby. If you are breastfeeding, you cannot take part 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. It is also possible 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 prescription drugs available to you 
• 
treatment with experimental drugs, if you qualify  
• 
no treatment 
 
Please talk to your health care provider about these and other choices available to you. Your 
health care provider will explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
For Sites in the US 
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 applied for/obtained 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 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 
or other government agencies as part of their duties, Food and Drug Administration (FDA), 
(insert name of site) Institutional Review Board (a group that protects the rights and well-being 
of people in research), National Institutes of Health (NIH), study staff, study monitors, the drug 
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 or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 


 
 
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A description of this clinical trial will be available on ClinicalTrials.gov as required by U.S. Law. 
This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time. 
 
For Sites outside the US 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. 
Any publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the ACTG, OHRP, FDA, (insert name of site) IRB, 
National Institutes of Health (NIH), study staff, study monitors, and drug company 
supporting this study. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required 
by US law. This website 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? 
 
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? 
 
[Sites please indicate whether you will provide payment to participants] 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the National Institutes of 
Health. 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. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 


 
 
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We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness 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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SIGNATURE PAGE 
 
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 Legally Authorized  
Legally Authorized Representative’s Signature  
Representative (print) 
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) 
 

Prot_003.pdf: 
 
 
 
A5324, Version 2.0 LOA #3 (08/22/18) 
IND Number: 126,854 
 
 
Page 1 of 3 
 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
 
 
 
 
Telephone: 301-628-3000 
8757 Georgia Avenue, 12th Floor 
 
 
 
 
Fax: 
301-628-3302 
Silver Spring, MD  20910 
 
 
LETTER OF AMENDMENT 
 
 
DATE:  
August 22, 2018 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM: 
A5324 Protocol Team  
 
SUBJECT: 
Letter of Amendment #3 for Protocol A5324, Version 2.0, 08/25/17, entitled “A 
Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral 
Intensification with Maraviroc and Dolutegravir with No Intensification or 
Intensification with Dolutegravir Alone for the Treatment of Cognitive Impairment 
in HIV” 
 
 
The following information impacts the A5324 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. 
 
The following information also impacts the Sample Informed Consent. Your IRB/EC is 
responsible for determining the process of informing participants of the contents of this 
LOA.   
 
Sites are still required to submit an LOA registration packet to the Division of AIDS 
(DAIDS) Protocol Registration Office (PRO) at the Regulatory Support Center. Sites will 
receive a registration notification for the LOA once the DAIDS PRO verifies that all 
required LOA registration documents have been received and are complete. An LOA 
registration notification from the DAIDS PRO is not required prior to implementing the 
LOA. A copy of the LOA registration notification, along with this letter and any IRB/EC 
correspondence, should be retained in the site’s regulatory files. 
 
The main reason for this LOA is to correct discrepancies in the Sample Informed 
Consent about pregnancy testing after study entry to be consistent with the pregnancy 
testing requirement that was updated through LOA #2. The corrections made to A5324, 
Version 2.0, 08/25/17, Sample Informed Consent, are explained below. 
 


 
 
 
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IND Number: 126,854 
 
 
Page 2 of 3 
 
1. Appendix I, Sample Informed Consent, WHAT DO I HAVE TO DO IF I AM IN THIS 
STUDY?: 
 
In the After Entry sub-section, seventh bullet, the following changes have been made: 
 
• 
If you are a woman and you think you might be who can become pregnant, you will 
have a pregnancy test at every study visit. You will be told the result of this test 
when it becomes available. 
 
In the If You Have to Stop Taking the Study Drugs Early or You Have to Stop the Study 
Early sub-section, fifth bullet, the following changes have been made: 
 
• 
If you are a woman and you think you might be who can become pregnant, you will 
have a pregnancy test. We will tell you the test result when it becomes available. 
 
2. Per a new regulatory requirement by DAIDS, a Protocol Signature Page (PSP) is appended 
for submission to DAIDS Protocol Registration System (DPRS) as part of the LOA 
registration packet. 
 
The information above will be incorporated into the next protocol version as necessary if the 
protocol is amended. 


 
 
 
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Page 3 of 3 
 
 
 
A Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral 
Intensification with Maraviroc and Dolutegravir with No Intensification or Intensification 
with Dolutegravir Alone for the Treatment of Cognitive Impairment in HIV 
Version 2.0, 08/25/17 
 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _____________________________________________________ 
 
Print/Type 
 
 
 
 
 
Signed: _______________________________________________Date: _____________ 
 
Name/Title 
 
 
 
 
 

Prot_002.pdf: 
 
 
 
A5324, Version 2.0 LOA #2 (06/04/18) 
IND Number: 126,854 
 
 
Page 1 of 11 
 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
 
 
 
 
Telephone: 301-628-3000 
8757 Georgia Avenue, 12th Floor 
 
 
 
 
Fax: 
301-628-3302 
Silver Spring, MD  20910 
 
 
LETTER OF AMENDMENT 
 
 
DATE:  
June 4, 2018 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM: 
A5324 Protocol Team  
 
SUBJECT: 
Letter of Amendment #2 for Protocol A5324, Version 2.0, 08/25/17, entitled “A 
Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral 
Intensification with Maraviroc and Dolutegravir with No Intensification or 
Intensification with Dolutegravir Alone for the Treatment of Cognitive Impairment 
in HIV” 
 
 
The following information impacts the A5324 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. To eliminate apparent immediate hazards to study participants, 
this LOA may be implemented before receiving your IRB/EC approval.  
 
The following information also impacts the Sample Informed Consent. Your IRB/EC is 
responsible for determining the process of informing participants of the contents of this 
LOA.   
 
Sites are still required to submit an LOA registration packet to the DAIDS Protocol 
Registration Office (PRO) at the Regulatory Support Center. Sites will receive a 
registration notification for the LOA once the DAIDS PRO verifies that all required LOA 
registration documents have been received and are complete. An LOA registration 
notification from the DAIDS PRO is not required prior to implementing the LOA. A copy 
of the LOA registration notification, along with this letter and any IRB/EC 
correspondence, should be retained in the site’s regulatory files. 
 
The World Health Organization (WHO), U.S. Food and Drug Administration (FDA), and 
European Medicines Agency (EMA) released a safety announcement on May 18, 2018, 
regarding a recent unplanned analysis of an ongoing study in Botswana of pregnant HIV-
positive women on antiretroviral therapy. In that analysis, investigators noted 4 neural tube 
defects in infants born to 426 women who conceived while on dolutegravir (0.9%). This was 
compared with 0.1% of infants (14 of 11,173) treated with other antiretroviral agents. This has 
prompted regulatory agencies and the WHO to issue advice to health care professionals and 


 
 
 
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Page 2 of 11 
 
HIV-positive patients that includes avoiding dolutegravir in HIV-positive women who are 
contemplating pregnancy, testing for pregnancy prior to starting dolutegravir, and ensuring 
adequate birth control use among women taking dolutegravir. Based on discussions within the 
U.S. Division of AIDS (DAIDS) and regulatory groups, changes to the A5324 study are needed 
to revise the pregnancy/contraception language for HIV-infected women of reproductive 
potential who receive study treatment. It should be noted that enrollment of HIV-infected women 
of reproductive potential is permissible as long as the pregnancy/contraception inclusion criteria 
of the protocol are met. Of note, birth control is already required of all females of reproductive 
potential who participate in the trial. 
 
The main reasons for this LOA are to update the pregnancy/contraception requirements and 
dolutegravir risk information in the protocol and the sample informed consent form.  
 
 
 


 
 
 
A5324, Version 2.0 LOA #2 (06/04/18) 
IND Number: 126,854 
 
 
Page 3 of 11 
 
TABLE OF CONTENTS 
 
1. Section 2.1, Background/Rationale ................................................................................. 4 
2. Section 4.1.9 .................................................................................................................. 4 
3. Section 6.1, Schedule of Evaluations ............................................................................. 5 
4. Section 6.2.2, Entry Evaluations ..................................................................................... 5 
5. Section 6.2.4, Discontinuation Evaluations ..................................................................... 5 
6. Section 6.3.11, Study Medication Dispensing ................................................................. 5 
7. Section 6.3.12, Laboratory Evaluations .......................................................................... 6 
8. Section 7.3, Pregnancy .................................................................................................. 6 
9. Section 8.1, Premature Treatment Discontinuation ......................................................... 6 
10. Appendix I, Sample Informed Consent, ‘WHAT DO I HAVE TO DO IF I AM IN THIS 
STUDY?’ ........................................................................................................................ 7 
11. Appendix I, Sample Informed Consent, ‘WHY WOULD THE DOCTOR TAKE ME OFF 
THIS STUDY EARLY?’ ................................................................................................... 7 
12. Appendix I, Sample Informed Consent, ‘WHAT ARE THE RISKS OF THE STUDY?’ ..... 7 
13. Appendix I, Sample Informed Consent, ‘ARE THERE RISKS RELATED TO 
PREGNANCY’ ................................................................................................................ 9 
14. Protocol Signature Page ................................................................................................10 
 
 
 


 
 
 
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Page 4 of 11 
 
The specific updates that are being made via this LOA #2 to A5324, Final Version 2.0, 08/25/17, 
are listed below. An italicized statement provides the location of the update within the identified 
section of the protocol. New text resulting from this LOA appears in bold; deleted text is shown 
in strikethrough. Changes that were made in the excerpted text shown below when the protocol 
was amended to Version 2.0 and in LOA #1 are no longer presented in bold. 
 
1. Section 2.1, Background/Rationale 
 
The following has been added as the last paragraph in the DTG (Tivicay) sub-section: 
 
In May 2018, ViiV Healthcare became aware of a potential safety issue related to 
neural tube defects (NTDs) in infants born to women with exposure to dolutegravir 
at the time of conception that was identified from a preliminary unscheduled 
analysis of a study conducted among pregnant women in Botswana (Tsepamo 
study, 4 NTDs among 426 pregnancies on dolutegravir). This represented an 
incidence of about 0.9% with an expected background rate of about 0.1%. In the 
reproductive toxicology studies, including embryo-fetal development studies 
performed in animals prior to drug licensure, there were no adverse development 
outcomes, including NTDs, but dolutegravir was found to cross the placenta. Up 
to now, data from the Antiretroviral Pregnancy Registry (APR), clinical trials, and 
postmarketing use have not indicated a potential safety issue, but data from these 
sources are limited. The FDA recommends that women of childbearing potential 
have a pregnancy test before starting dolutegravir, and that women of 
childbearing age who decide to take a dolutegravir-containing regimen 
consistently use effective contraception while on HIV treatment (www.fda.gov). 
 
2. Section 4.1.9 
 
The following changes have been made to the list of acceptable forms of contraception:  
 
Females of reproductive potential must agree not to participate in the conception 
process (i.e., active attempt to become pregnant, in vitro fertilization), and if participating 
in sexual activity that could lead to pregnancy, must use at least one reliable form of 
contraception. Female participants must use contraceptives while receiving study 
treatment and for 6 weeks after stopping study treatment. 
 
Acceptable forms of contraception include: 
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) or intrauterine system 
• 
Hormonal contraceptive (contraceptive subdermal implant, combined estrogen 
and progestogen oral contraceptive, injectable progestogen, contraceptive 
vaginal ring, and percutaneous contraceptive patches) 
 


 
 
 
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Page 5 of 11 
 
Females who are not of reproductive potential or whose male partner(s) has 
documented azoospermia are not required to use contraceptives. Any statement of self-
reported sterility or that of her partner’s must be entered in the source documents.  
NOTE: Acceptable documentation of lack of reproductive potential is oral or written 
documentation from the participant. 
 
3. Section 6.1, Schedule of Evaluations 
 
The schedule of pregnancy testing has been changed to: 
 
Evaluation 
Screening Pre-
Entry  Entry 
Post-Entry Evaluations 
(Weeks) 
Confirmation  
of  VF 
Premature 
Study/Treatment 
Discontinuation 
2 
4 12 24 36 48 60 72 84 96 
Pregnancy 
Testing 
X 
 
X 
Whenever pregnancy is suspected 
 
If pregnancy is 
suspected  
X 
X X X X X X X X X 
X 
 
4. Section 6.2.2, Entry Evaluations 
 
The following change has been made to this section: 
 
Entry evaluations must occur at least 24 hours after pre-entry unless otherwise 
specified. Participant must begin treatment within 3 days after randomization. Refer to 
section 6.3.12 Laboratory Evaluations, Pregnancy Test sub-section, for the 
pregnancy test requirement for females of reproductive potential if treatment 
cannot be started on the same day as randomization. 
 
5. Section 6.2.4, Discontinuation Evaluations 
 
The following paragraph has been added as the last paragraph in the Premature Treatment 
Discontinuation Evaluations sub-section: 
 
Refer to section 7.3 Pregnancy, Pregnancy Outcomes and Reporting sub-section, 
for additional guidance for monitoring women who become pregnant while on 
study and prematurely discontinue study treatment. 
 
6. Section 6.3.11, Study Medication Dispensing 
 
The following change has been made to this section: 
 
At study entry, dispense either a 12-week supply of study medication or a sufficient 
quantity to last until the participant’s next visit. Beginning with the week 12 visit, study 
medications will be dispensed every 12 weeks. At weeks 36, 60, and 84, participants will 
return for study medication dispensing only. No other study evaluations will be 
performed. 
 


 
 
 
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Page 6 of 11 
 
7. Section 6.3.12, Laboratory Evaluations 
 
The following changes have been made to the second paragraph in the Pregnancy Test 
sub-section: 
 
Negative pregnancy test must be obtained within 48 hours prior to study entry 
randomization for females of reproductive potential as defined in section 4.1.8. If study 
treatment cannot be started within 72 hours of obtaining the negative pregnancy 
test for randomization, a repeat test must be performed and must be negative 
before starting treatment. After entry, perform a pregnancy test when pregnancy is 
suspected. Refer to section 7.3 for pregnancy and pregnancy outcome reporting 
requirements. 
 
After entry, perform a pregnancy test in females of reproductive potential as 
indicated in section 6.1. Refer to section 7.3 for pregnancy and pregnancy 
outcomes reporting requirements. 
 
8. Section 7.3, Pregnancy 
 
The following changes have been made to the first paragraph in the Pregnancy Outcomes 
and Reporting sub-section: 
 
The core team (actg.corea5324@fstrf.org) should be notified immediately if a participant 
becomes pregnant after study entry. Study medications must be discontinued and the 
underlying ART regimen continued at the discretion of the site investigator. Participants 
will come in for a premature treatment discontinuation evaluation visit within 14 days 
after stopping study medications. Participants who choose should be encouraged to 
stay on study will continue to be followed for on study/off study treatment follow-up 
visits, but will not have blood drawn for PK studies and stored plasma/PBMCs. They 
also will not have to complete the adherence questionnaire. The investigator must 
ensure that participants are referred and enrolled into appropriate obstetrical care. 
 
9. Section 8.1, Premature Treatment Discontinuation 
 
The following has been added to the criteria for premature treatment discontinuation 
(inserted as second and third bullets in this section): 
 
• 
Actively trying to get pregnant 
• 
Female participant of reproductive potential refuses to use one of the required 
contraception methods while on study treatment 
 


 
 
 
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Page 7 of 11 
 
10. Appendix I, Sample Informed Consent, ‘WHAT DO I HAVE TO DO IF I AM IN THIS 
STUDY?’ 
 
The following change has been made to the last paragraph in the At Study Entry Visit sub-
section: 
 
You will continue taking the anti-HIV drugs that you are currently taking. You will also be 
given a combination of MVC, DTG or placebo based on the group that you are randomly 
assigned to. You must start the new medications within three days after you are 
randomized. If you will start taking the new medications after the day you are 
randomized, you may need another pregnancy test before starting. If you are 
pregnant you cannot start the new medications. 
 
The following changes have been made to the second to the last paragraph in the After 
Entry sub-section: 
 
At weeks 36, 60, and 84, you will return for refill of your study drugs. If you are a 
woman and able to become pregnant, you will also have a pregnancy test. These 
refills visits should take about 30 minutes or less. No other evaluations will be done. 
 
11. Appendix I, Sample Informed Consent, ‘WHY WOULD THE DOCTOR TAKE ME OFF THIS 
STUDY EARLY?’ 
 
The following addition has been made to the reasons the study doctor may take a 
participant off the study drugs without permission of the participant: 
 
The study doctor may need to take you off the study drugs without your permission if: 
• 
you become pregnant or start breastfeeding 
• 
you decide that you want to become pregnant or actively try to get pregnant 
• 
you do not want to use one of the required birth control methods while on the 
study treatment 
• 
continuing the study drug(s) may be harmful to you 
• 
you need a treatment that you may not take while on the study 
• 
you are not able to take the study drug(s) as required by the study 
 
12. Appendix I, Sample Informed Consent, ‘WHAT ARE THE RISKS OF THE STUDY?’ 
 
The following changes have been made to this section: 
 
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. If you have questions 
concerning the additional study drug side effects please ask the medical staff at your 
site. 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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Page 8 of 11 
 
 
There is a risk of serious and/or life-threatening side effects when non-study drugs are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about 
all drugs you are taking (including non-prescription drugs, vitamins and herbal 
supplements) before you start the study and you must ask for approval for taking also 
before starting any new drugs while you are on the study. You must also tell the study 
doctor or nurse before enrolling in any other clinical trials while on this study. 
 
The following changes have been made to the Risks of DTG (Tivicay) sub-section: 
 
The following serious side effects have been associated with the use of DTG. These 
include allergic (hypersensitivity) reactions and liver problems, which may be life-
threatening. 
 
Contact the study doctor or your healthcare provider right away if you develop a rash 
while taking DTG, especially if it is associated with any of the symptoms listed below, 
which could be signs of an allergic reaction. Stop taking DTG and get medical help 
right away if you develop a rash with any of the following signs or symptoms:  
• 
Fever 
• 
Generally General ill feeling 
• 
Extreme tiredness 
• 
Muscle or joint aches 
• 
Blisters or sores in mouth 
• 
Blisters or peeling of the skin 
• 
Redness or swelling of the eyes 
• 
Swelling of the mouth, face, lips, or tongue 
• 
Problems breathing 
 
Contact the study doctor or your healthcare provider if you have any of the following 
symptoms that could be signs of liver problems:  
• 
Yellowing of the skin or whites of the eyes (jaundice) 
• 
Dark or tea-colored urine 
• 
Pale-colored stools or bowel movements 
• 
Nausea or vomiting 
• 
Loss of appetite 
• 
Pain, aching, or tenderness on the right side below the ribs 
• 
Changes in liver test results, more common in people with hepatitis B or C 
 
People with a pre-existing history of depression or other mental health illness may be at 
greater risk for suicidal thoughts, or attempts, which may lead to death. If your mental 
health illness worsens, or if you develop suicidal thoughts, call the study doctor or your 
healthcare provider right away. 
 
Other side effects of DTG include: 
• 
Changes in liver test results, more common in people with hepatitis B or C 
• 
Trouble sleeping 


 
 
 
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Page 9 of 11 
 
• 
Abnormal dreams 
• 
Tiredness 
• 
Headache 
• 
Anxiety (fear, worry) 
• 
Dizziness 
• 
Abdominal pain  
• 
Flatulence (gas in the abdomen) 
• 
Nausea/Vomiting 
• 
Muscle and joint aches 
 
Dolutegravir and Pregnancy: 
Early results from a large study in Botswana of pregnant women showed a 
possible increased risk of certain types of serious birth defects involving the brain 
and spinal cord in babies born to women who received DTG for HIV treatment at 
the time of becoming pregnant or early in their pregnancy. No cases of babies 
born with these types of birth defects have been reported among women who 
started DTG later in pregnancy. 
  
Tell the study doctor or your healthcare provider about any side effect that bothers you 
or that does not go away. 
 
13. Appendix I, Sample Informed Consent, ‘ARE THERE RISKS RELATED TO PREGNANCY’  
 
The following changes have been made to this section: 
 
Recently, some new information about DTG from another study being done in 
Botswana was reported. This study found that women taking DTG when they 
became pregnant appeared to be more likely to have babies with an abnormality 
called a neural tube defect than women who were taking other HIV medicines 
when they became pregnant. A neural tube defect is an abnormality of the spine 
or brain that can be severe. This abnormality can cause babies to die. Neural tube 
defects usually happen in about 1 out of every 1000 babies. In the Botswana 
study, neural tube defects were found in about 1 out of every 100 babies born to 
women who were taking DTG when they became pregnant. A baby’s neural tube is 
formed in the first 4 weeks after conception. In the Botswana study, no neural 
tube defects were found in babies born to women who started taking DTG during 
pregnancy, after the neural tube had formed. The drug company and regulatory 
authorities and different researchers are looking into this issue to see if DTG 
really does cause neural tube defects. In the meantime, the U.S. FDA and other 
groups have recommended that women who are going to start taking DTG have a 
pregnancy test first. They also recommend that women use birth control to 
prevent pregnancy while taking DTG. HIV-infected women who are able to become 
pregnant are allowed to participate in this study, but they must use birth control 
(intrauterine device [IUD] or hormone-based contraceptive) in order to not become 
pregnant while in this study. If you do become pregnant while on study and taking 
the study drugs, you must call the study doctor right away. 
 


 
 
 
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Page 10 of 11 
 
The drugs used in this study may be unsafe for unborn babies. If you are having sex that 
could lead to pregnancy, you must agree not to become pregnant. Because of the risk 
involved, you must use at least one method of birth control. You must continue to use 
birth control for 6 weeks after stopping your medicines. You must choose one of the birth 
control methods listed below:  
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) or intrauterine system 
• 
Hormone-based contraceptive (contraceptive subdermal implant, combined 
estrogen and progestogen oral contraceptive, injectable progestogen, 
contraceptive vaginal ring, and percutaneous contraceptive patches) 
 
If you do not want to use one of the birth control methods listed above, you will be 
taken off the study treatment, but asked to continue the study evaluations. 
 
If you can become pregnant, you must have a pregnancy test before you enter this 
study. The test must show that you are not pregnant. Women who can become 
pregnant will have testing for pregnancy at every study visit. If you think you may 
be pregnant at any time during the study, tell your study staff right away. If you decide 
at any time while you are in this study that you want to become pregnant and start 
trying to become pregnant, you must tell your study staff right away. If you are 
pregnant or trying to become pregnant, you will be taken off the study treatment, but 
asked to continue the study evaluations. The study staff will talk to you about your 
choices.  
 
If you become pregnant while on study, the study staff would like to obtain information 
from you about the outcome of the pregnancy (even if it is after your participation in the 
study ends). If you are taking anti-HIV drugs when you become pregnant, your 
pregnancy will be reported to an international database that collects information about 
pregnancies in women taking anti-HIV drugs. This report will not use your name or other 
information that could be used to identify you. 
 
NOTE: It is not known whether the study drug passes through breast-milk and may 
cause harm to your baby. If you are breastfeeding, you cannot take part in this study. 
 
14. Protocol Signature Page 
 
Per a new regulatory requirement by the Division of AIDS (DAIDS), a Protocol Signature 
Page (PSP) is appended for submission to the DAIDS Protocol Registration System (DPRS) 
as part of the LOA registration packet. 
 
 
The information above will be incorporated into the next protocol version as necessary if the 
protocol is amended.


 
 
 
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Page 11 of 11 
 
A Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral 
Intensification with Maraviroc and Dolutegravir with No Intensification or Intensification 
with Dolutegravir Alone for the Treatment of Cognitive Impairment in HIV 
Version 2.0, 08/25/17 
 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _____________________________________________________ 
 
Print/Type 
 
 
 
 
 
Signed: _______________________________________________Date: _____________ 
 
Name/Title 
 
 
 
 
 

Prot_004.pdf: 
A5324, Version 2.0 LOA #4 (10/23/20) 
IND Number: 126,854 
Page 1 of 5 
 
ACTG NETWORK COORDINATING CENTER 
Social & Scientific Systems, Inc., a DLH Company 
 
 
 
 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714  
 
 
 
 
 
 
Phone: 301-628-3000 
Fax: 301-628-3302 
 
 
 
LETTER OF AMENDMENT 
 
DATE:  
October 23, 2020 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM:  
A5324 Protocol Team  
 
SUBJECT: 
Letter of Amendment #4 for Protocol A5324 
 
 
The following information affects the A5324 study and must be forwarded to each site’s 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their information 
and review. This Letter of Amendment (LOA) must be approved by the IRB/EC before 
implementation.  
 
The following information may also affect the Sample Informed Consent. The site IRB/EC is 
responsible for determining the process of informing participants of the contents of this LOA. 
 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this LOA, 
sites should implement the LOA immediately. Sites are still required to submit an LOA registration 
packet to the DAIDS Protocol Registration Office (PRO) at the Regulatory Support Center. Sites 
will receive a registration notification for the LOA once the DAIDS PRO verifies that all required 
LOA registration documents have been received and are complete. An LOA registration 
notification from the DAIDS PRO is not required prior to implementing the LOA. A copy of the LOA 
registration notification, along with this letter and any IRB/EC correspondence, should be retained 
in the site’s regulatory file. 
 
This LOA is being implemented for the following reasons: 
• 
To update the protocol team roster.  
• 
To incorporate the instructions for alternate study product dispensing and completion of post-entry 
evaluations that were provided through A5324 Version 2.0 Clarification Memo (CM) #3 for participant 
and site staff safety and flexibility to complete study visits during the ongoing COVID-19 pandemic. 
• 
To update the sample informed consent (SIC) to include information for participants about 
adjustments that may be made to their study visits during the ongoing COVID-19 pandemic.  
 
The following are changes (noted in bold or strikethrough) to A5324, Version 2.0, 08/25/20, titled “A 
Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral Intensification with 
Maraviroc and Dolutegravir with No Intensification or Intensification with Dolutegravir Alone for the 
Treatment of Cognitive Impairment in HIV.” These changes will be included in the next version of the 
A5324 protocol if it is amended at a future date. Changes that have already been made (either by LOA or 
by CM) have been incorporated in the excerpted text shown below (and are no longer presented in bold 
or strikethrough).  
 
1. A Protocol Signature Page (PSP) is appended for submission to DAIDS Protocol Registration System 
(DPRS) as part of the LOA registration packet. 
 


A5324, Version 2.0 LOA #4 (10/23/20) 
IND Number: 126,854 
Page 2 of 5 
 
2. In the Protocol Team Roster, the following updates have been made: 
 
Data Manager 
Thomas Miller, BS 
Frontier Science & Technology Research Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 
E-mail: tmiller@fstrf.org 
Dave Rusin, MT (ASCP), CCRP 
Frontier Science & Technology Research Foundation, Inc.  
4033 Maple Road  
Amherst, NY  14226-1056 
Phone: 716-834-0900 x7333  
FAX: 716-834-8432 
E-Mail: rusin.david@fstrf.org 
 
DAIDS Pharmacist 
Justine Beck, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9D39 
Rockville, MD 20852 
Phone: 301-761-5288 
Fax: 240-627-3112 
E-mail: justine.beck@nih.gov 
Nayri Khairalla, PharmD, BS 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane, 9D35 
Rockville, MD 20852 
Phone: 301-761-6659 
FAX: 240-627-3112 
E-Mail: nayri.khairalla@nih.gov 
 
Neuropsychologist 
Robert H. Paul, PhD 
University of Missouri, St. Louis 
Missouri Institute of Mental Health 
ITE Building 
4633 World Parkway Circle 
Berkeley, MO 63134 
Phone: 314-516-8403 
Fax: 636-544-8522 
E-mail: robert.paul@mimh.edu 
 
NIMH Representative 
Deborah Ann Colosi, PhD 
Division of AIDS Research 
National Institute of Mental Health/NIH  
6001 Executive Boulevard 
NSC 6115D-9619 
Bethesda, MD 20892  
Phone: 301-443-8542 
E-Mail: Deborah.Colosi@nih.gov 
 


A5324, Version 2.0 LOA #4 (10/23/20) 
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Page 3 of 5 
 
Laboratory Data Manager 
Kacey Matecki, BS 
Frontier Science & Technology Research Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, Ext. 7272 
E-mail: matecki@frontierscience.org 
Andee Fox, MPH 
Frontier Science & Technology Research Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7276 
E-Mail: fox@fstrf.org 
 
3. In section 5.1.2, Administration and Dispensing, the following paragraph has been added as the last 
paragraph in this section, below item number 5.1.2.2: 
 
For rare instances or emergency cases, the Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks permits shipment by mail or courier of study product from the site 
directly to participants. This method should only be used on a short-term basis and if 
permissible by the site’s institution. If this method is to be implemented, each site’s 
Pharmacist of Record (PoR) must develop appropriate procedures for the shipment or courier 
of study product to identified participants in accordance with these guidelines, and document 
chain of custody. Prior to implementation, the site PoR must coordinate with site clinic staff to 
determine the appropriateness of this method for applicable protocols and participants. 
 
4. In section 6.1, Schedule of Evaluations, the visit window for weeks 36 to 96 has been changed as 
shown below: 
 
Evaluation Screening Pre-
Entry  Entry 
Post-Entry Evaluations 
(Weeks) 
Confirmation 
of  VF 
Premature 
Study/Treatment 
Discontinuation 
2 4 12 24 36 48 60 72 84 96 
Visit 
Windows 
 
 
 
± 1 
wk 
± 2 
wks 
- 4 wks, + 8 12 wks 
 
 
 
5. In section 6.2.3, Post-Entry Evaluations, the following instructions have been added to the On-
Treatment Evaluations subsection: 
 
Alternate Completion of Post-Entry Evaluations 
• 
If the participant’s visit is postponed within the extended visit window, the site should 
ensure that the participant has sufficient supply of the study products to last him or 
her to the point when he or she can come to the clinic. 
• 
If the participant does not have enough supply of study products to allow the visit to 
be postponed, the site must attempt to contact the participant by phone or other 
method available. 
− 
During the remote contact for visit week 72 or week 96, the site should conduct a 
safety follow-up (such as inquiring about signs and symptoms) to determine if any 
AEs or serious adverse events (SAEs) have occurred since the last visit and if the 
participant needs medical follow-up. Additionally, the site should complete the 
questionnaires and adherence assessment per section 6.3.9, section 6.3.10, and 
MOPS section 4. All other evaluations and stored samples that will be missing for 
the visits, and the reason why they are missing, must be documented in the 
participant’s study file. 
− 
At all visits except week 96, the site should confirm if the participant is able to 


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Page 4 of 5 
 
receive a new supply of study medications if it is shipped via mail or sent via 
courier (see section 5.1.2). If a participant is unable to pick up or receive study 
medications via shipment or courier, the site should consult the study core team 
(actg.corea5324@fstrf.org) for further guidance. 
− 
If safety laboratory evaluations, and a pregnancy test for female participants of 
reproductive potential, cannot be performed, the continuation of study treatment is 
at the discretion of the Investigator of Record (IoR). The site should inform the 
study core team of the decision of the IoR. 
 
6. In section 6.2.4, Discontinuation Evaluations, the following instructions have been added to the 
Premature Treatment Discontinuation Evaluations subsection: 
 
Alternate Completion of Post-Entry Evaluations 
• 
The visit can be postponed within the extended visit window if needed to safely 
conduct a face-to-face clinic visit. If the participant can safely be seen in the clinic, the 
site should perform all the evaluations for the visit per the SOE in section 6.1, Letter of 
Amendment (LOA) #1, and LOA #2. 
• 
If the visit cannot be completed with a face-to-face visit despite the extended visit 
window, the site must attempt to contact the participant by phone or other method 
available. During the remote contact for visit week 72 or week 96, the site should 
conduct a safety follow-up (such as inquiring about signs and symptoms) to determine 
if any AEs or SAEs have occurred since the last visit and the participant needs 
medical follow-up. Additionally, the site should complete the questionnaires and 
adherence assessment per section 6.3.9, section 6.3.10, and MOPS section 4. All other 
evaluations and stored samples that will be missing for the visits, and the reason why 
they are missing, must be documented in the participant’s study file.  
 
7. In Appendix I, Sample Informed Consent (SIC), the following has been added as a new subsection, 
before the Optional Lumbar Puncture subsection, in the section WHAT DO I HAVE TO DO IF I AM IN 
THIS STUDY?: 
 
COVID-19 Pandemic Considerations 
During the ongoing COVID-19 pandemic, the following adjustments may be made to your 
study visits: 
• 
If there is an outbreak of COVID-19 in your community and you are unable to come to 
the study clinic, your study doctor or staff member will try to contact you by phone or 
other remote method if you have a study visit due. During this contact: 
− 
You will be asked about your health since your last study visit or contact. 
− 
If there are questionnaires to be completed for a particular study visit, you will be 
asked some questions about how you are feeling, how well you are able to perform 
your daily activities, your alcohol and drug use, and how well you are taking your 
current anti-HIV drugs. 
− 
If you did not have to stop taking the study medications early: 
o 
You will be asked if you are able to pick up your new supply of study 
medications from the study clinic. If you are not able to pick up the study 
medications, you will be asked if you can receive the study medications 
through the mail or a courier. You and your study doctor or staff member 
will decide on the best way to make sure you receive your new supply of 
study medications. 
o 
Your study doctor or staff member will inform you if you can continue 
taking the study medications. 
 


A5324, Version 2.0 LOA #4 (10/23/20) 
IND Number: 126,854 
Page 5 of 5 
 
A Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral Intensification with 
Maraviroc and Dolutegravir with No Intensification or Intensification with Dolutegravir Alone for the 
Treatment of Cognitive Impairment in HIV 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division of 
AIDS) and institutional policies. 
 
 
 
 
 
Principal Investigator: _____________________________________________________ 
 
Print/Type 
 
 
 
 
 
Signed: _______________________________________________ Date: _____________ 
 
Name/Title 
 
 
 
 
 

Prot_001.pdf: 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
 
 
 
 
Telephone: 301-628-3000 
8757 Georgia Avenue, 12th Floor 
 
 
 
 
Fax: 
301-628-3302 
Silver Spring, MD  20910 
 
 
LETTER OF AMENDMENT 
 
 
DATE:  
March 29, 2018 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM: 
A5324 Protocol Team  
 
SUBJECT: 
Letter of Amendment #1 for Protocol A5324, Version 2.0, 08/25/17, entitled “A 
Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral 
Intensification with Maraviroc and Dolutegravir with No Intensification or 
Intensification with Dolutegravir Alone for the Treatment of Cognitive Impairment 
in HIV” 
 
 
The following information impacts the A5324 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This Letter of Amendment (LOA) must be approved by your 
IRB/EC before implementation.  
 
The following information may also impact the Sample Informed Consent. Your IRB/EC is 
responsible for determining the process of informing participants of the contents of this 
LOA. 
 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit an 
LOA registration packet to the DAIDS Protocol Registration Office (PRO) at the 
Regulatory Support Center. Sites will receive a registration notification for the LOA once 
the DAIDS PRO verifies that all required LOA registration documents have been received 
and are complete. An LOA registration notification from the DAIDS PRO is not required 
prior to implementing the LOA. A copy of the LOA registration notification, along with 
this letter and any IRB/EC correspondence, should be retained in the site’s regulatory 
files. 
 
 
 
 


 
 
 
A5324 Version 2.0, LOA #1 (03/29/18) 
IND Number: 126,854 
 
 
Page 2 of 7 
 
Page 
TABLE OF CONTENTS 
 
1. 
Section 5.1.2 ....................................................................................................................... 3 
2. 
Section 6.1 .......................................................................................................................... 3 
3. 
Section 6.2.4 ....................................................................................................................... 3 
4. 
Section 6.3 .......................................................................................................................... 3 
5. 
Section 6.3.5 ....................................................................................................................... 4 
6. 
Section 6.3.11 ..................................................................................................................... 4 
7. 
Section 6.3.15 ..................................................................................................................... 4 
8. 
Section 10.2.1 ..................................................................................................................... 4 
9. 
Section 10.2.2 ..................................................................................................................... 4 
10. Section 11.3.2 ..................................................................................................................... 5 
11. Section 12.2 ........................................................................................................................ 5 
12. Sample Informed Consent, WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? .............. 5 
13. Sample Informed Consent, WHAT ARE THE RISKS OF THE STUDY? ............................. 5 
14. Sample Informed Consent, WHAT ABOUT CONFIDENTIALITY? ....................................... 6 
15. Protocol Signature Page ..................................................................................................... 6 
 
 
 


 
 
 
A5324 Version 2.0, LOA #1 (03/29/18) 
IND Number: 126,854 
 
 
Page 3 of 7 
 
The specific updates that are being made via this LOA #1 to A5324, Version 2.0, 08/25/17, 
are listed below. An italicized statement provides the location of the update within the identified 
section of the protocol. New text resulting from this LOA appears in bold; deleted text is shown 
in strikethrough. Changes that were made in the excerpted text shown below when the protocol 
was amended to Version 2.0 are no longer presented in bold. 
 
1. Section 5.1.2 
 
The paragraph below is being added as the second paragraph in this section. 
 
At study entry, dispense either a 12-week supply of study medication or a sufficient 
quantity to last until the participant’s next visit. Refer to section 6.3.11 for the study 
medication dispensing schedule. 
 
2. Section 6.1 
 
In this section, Stored Plasma is being deleted from the Confirmation of VF visit as shown 
below. 
 
Evaluation Screening 
Pre-
Entry  Entry 
Post-Entry Evaluations 
(Weeks) 
Confirmation 
of VF 
Premature 
Study/Treatment 
Discontinuation 
2 
4 12 24 36 48 60 72 84 96 
Stored 
Plasma 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
3. Section 6.2.4 
 
In this section, the Premature Treatment Discontinuation Evaluations sub-section is being 
updated as shown below. 
 
Premature Treatment Discontinuation Evaluations  
Participants who discontinue the study medications before the end of the study should have 
the premature treatment discontinuation evaluations done within 14 days after stopping 
study medications. Participants will be followed off study treatment/on study. They should be 
encouraged to continue to attend all study visits and receive study evaluations as per 
section 6.1, with the exception of the adherence questionnaires PK studies, and optional 
lumbar puncture, through completion of the study. 
 
4. Section 6.3 
 
The first paragraph in this section is being updated as shown below. 
 
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 website for 
information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/sourcedocappndx.pdf 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf. 


 
 
 
A5324 Version 2.0, LOA #1 (03/29/18) 
IND Number: 126,854 
 
 
Page 4 of 7 
 
 
5. Section 6.3.5 
 
In this section, height measurement at week 12 is being removed from the Targeted 
Physical Exam sub-section. 
 
Targeted Physical Exam 
After screening, a targeted physical examination, including height (at entry and week 12 
only), weight, and vital signs (temperature, pulse, and blood pressure) should be per section 
6.1, along with additional assessments based upon previously identified findings, diagnoses, 
or new signs or symptoms since the last visit. 
 
6. Section 6.3.11 
 
This section is being updated as shown below. 
 
At study entry and thereafter, dispense either a 12-week supply of study medication or a 
sufficient quantity to last until the participant’s next visit. Beginning with the week 12 
visit, study medications will be dispensed every 12 weeks. At weeks 36, 60, and 84, 
participants will return for study medication dispensing only. No other study evaluations will 
be performed. 
 
7. Section 6.3.15 
 
In this section, the second paragraph in the Plasma sub-section is being deleted.  
 
Plasma  
Plasma will be collected and stored for single copy assay (SCA).   
 
Plasma collected at the confirmation of VF visit will be stored for resistance and tropism 
testing if VF is confirmed (see sections 6.3.19 and 6.3.20). 
 
8. Section 10.2.1 
 
In this section, the sentence below is being added to the end of the first paragraph. 
 
The last three doses of study medication taken before the PK sample collection will 
be recorded on the CRF. 
 
9. Section 10.2.2 
 
In this section, the sentence below is being added to the end of the first paragraph. 
 
The last three doses of study medication taken before the trough sample collection 
will be recorded on the CRF. 
 


 
 
 
A5324 Version 2.0, LOA #1 (03/29/18) 
IND Number: 126,854 
 
 
Page 5 of 7 
 
10. Section 11.3.2 
 
This section is being updated as shown below. 
 
The site investigator will make study documents (eg, 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(s) or 
designee, and other local, US, and international regulatory entities for confirmation of 
the study data. 
 
11. Section 12.2 
 
This section is being updated as shown below. 
 
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 local, US, or international regulatory authorities as part of their 
duties, or the industry supporter(s) or designee. 
 
12. Sample Informed Consent, WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
In this section, the first paragraph in the Virologic Failure sub-section is being updated as 
shown below. 
 
You will be tested for virologic failure at weeks 12, 24, 48, 72, and 96. Virologic failure is 
when your anti-HIV drugs are not fully suppressing HIV in the blood. If the study staff sees 
that your viral load has gone up, you will be asked to have another viral load test done within 
30 days. About 2 teaspoons (10mL) of blood will be drawn for the viral load test. We will also 
draw an additional 1-2 about 4 teaspoons (20mL) (6mL) of blood that will be used for tests 
that check which anti-HIV drugs have stopped working on the HIV in your blood (resistance 
test) and if a specific type of anti-HIV drug will be able to control your HIV (tropism test) if the 
repeat viral load test shows that your viral load is still up. We will also ask you to fill out a 
questionnaire about how well you are taking your current anti-HIV drugs. 
 
13. Sample Informed Consent, WHAT ARE THE RISKS OF THE STUDY? 
 
In this section, the list of other side effects of dolutegravir (DTG) under the Risks of DTG 
(Tivicay) sub-section is being updated as shown below. 
 
Other side effects of DTG include: 
• 
Changes in liver test results, more common in people with hepatitis B or C 
• 
Trouble sleeping 
• 
Abnormal dreams 
• 
Tiredness 


 
 
 
A5324 Version 2.0, LOA #1 (03/29/18) 
IND Number: 126,854 
 
 
Page 6 of 7 
 
• 
Headache 
• 
Anxiety 
• 
Dizziness 
• 
Abdominal pain 
• 
Flatulence 
• 
Nausea, vomiting 
• 
Muscle and joint aches 
 
14. Sample Informed Consent, WHAT ABOUT CONFIDENTIALITY? 
 
The following updates are being made in this section: 
 
a. The second paragraph in the For Sites in the US sub-section is being updated as 
shown below. 
 
People who may review your records include the ACTG, U.S. Office for Human 
Research Protections (OHRP) or other government agencies as part of their duties, 
U.S. Food and Drug Administration (FDA), or other local, U.S., and international 
regulatory entities as part of their duties, (insert name of site) Institutional Review 
Board (a group that protects the rights and well-being of people in research), 
National Institutes of Health (NIH), study staff, study monitors, the drug 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. 
 
b. The second paragraph in the For Sites outside the US sub-section is being updated 
as shown below. 
 
Your records may be reviewed by the ACTG, U.S. Office for Human Research 
Protections (OHRP), U.S. Food and Drug Administration (FDA), or other local, 
U.S., and international regulatory entities as part of their duties, (insert name of 
site) IRB Institutional Review Board or Ethics Committee (a committee that 
protects the rights and safety of participants in research), National Institutes of 
Health (NIH), study staff, study monitors, and drug company supporting this study, 
and their designees. 
 
15. Protocol Signature Page 
 
Per a new regulatory requirement by the Division of AIDS (DAIDS), a Protocol Signature 
Page (PSP) is appended for submission to the DAIDS Protocol Registration System (DPRS) 
as part of the LOA registration packet. 
 
 
The information above will be incorporated into the next protocol version as necessary if the 
protocol is amended.


 
 
 
A5324 Version 2.0, LOA #1 (03/29/18) 
IND Number: 126,854 
 
 
Page 7 of 7 
 
 
 
 
A Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral 
Intensification with Maraviroc and Dolutegravir with No Intensification or Intensification 
with Dolutegravir Alone for the Treatment of Cognitive Impairment in HIV 
Version 2.0, 08/25/17  
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _____________________________________________________ 
 
Print/Type 
 
 
 
 
 
Signed: _______________________________________________Date: _____________ 
 
Name/Title 
 
 
 
 
 

SAP_005.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approvals


 
 
 
 
A5324 
Primary Statistical Analysis Plan 
Version 3.0 
 
A Randomized, Double-Blinded, Placebo-Controlled Trial 
Comparing Antiretroviral Intensification with Maraviroc and 
Dolutegravir with No Intensification or Intensification with 
Dolutegravir Alone for the Treatment of Cognitive Impairment in 
HIV 
 
Protocol Version 2.0 
 
ClinicalTrials.gov Identifier: NCT02519777 
 
02/12/2021 
 
This is ACTG A5324 SAP Version 3.0 with names of authors, names of publication writing 
team members and analysis timeline redacted. 
 


 
Page 1 of 15 
 
Table of Contents 
 
TABLE OF CONTENTS ................................................................................................................... 1 
1 
INTRODUCTION ........................................................................................................................ 2 
1.1 
Purpose ............................................................................................................................ 2 
1.2 
Version History ............................................................................................................... 2 
2 
STUDY OVERVIEW ................................................................................................................... 3 
2.1 
Study Design ................................................................................................................... 3 
2.2 
Hypotheses ...................................................................................................................... 3 
2.2.1 
Primary ................................................................................................................. 3 
2.2.2 
Secondary ............................................................................................................ 3 
2.3 
Study Objectives ............................................................................................................. 3 
2.3.1 
Primary ................................................................................................................. 4 
2.3.2 
Secondary ............................................................................................................ 4 
2.4 
Overview of Sample Size Considerations .................................................................... 4 
2.5 
Overview of Formal Interim Monitoring ........................................................................ 5 
3 
OUTCOME MEASURES ........................................................................................................... 5 
3.1 
Primary Outcome Measures .......................................................................................... 5 
3.2 
Secondary Outcome Measures ..................................................................................... 7 
3.3 
Other Outcome Measures .............................................................................................. 8 
4 
STATISTICAL PRINCIPLES ..................................................................................................... 9 
4.1 
General Considerations ................................................................................................. 9 
4.2 
Analysis Approaches ..................................................................................................... 9 
4.2.1 
Primary Analysis ................................................................................................... 9 
4.2.2 
Secondary Analyses .......................................................................................... 10 
4.2.3 
Other Analyses ................................................................................................... 10 
5 
REPORT CONTENTS ............................................................................................................. 11 
6 
APPENDIX: NEUROPSYCHOLOGICAL NORMS FOR ACTG A5324 .................................. 12 
7 
APPENDIX: IADL SCORING .................................................................................................. 14 
8 
ASSOCIATED DOCUMENTS ...................................... ERROR! BOOKMARK NOT DEFINED. 
 
 
 


 
Page 2 of 15 
 
1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary outcome 
measures and additional outcome measures of the A5324 study that will be included in the 
primary manuscript, and which address, at a minimum, the major primary and secondary 
objectives of the study. The Primary SAP outlines the general statistical approaches that will be 
used in the analysis of the study. It has been developed to facilitate discussion of the statistical 
analysis components among the study team, and to provide agreement between the study team 
and statisticians regarding the statistical analyses to be performed and presented in the Primary 
Analysis Report. It also describes the results for the primary and secondary outcome measures 
that will be posted on ClinicalTrials.gov. 
Detailed outlines of tables, figures, and coding descriptions that will be included in the Primary 
Analysis Report are included in the Analysis Implementation Plan (AIP). 
Analyses for the Primary Analysis Report will be finalized once the last participant has completed 
the week 96 study visit, all queries have been resolved, and the study database closure/data lock 
has been completed. 
Outlines of analyses for other objectives and outcome measures not included in the Primary SAP 
will be provided in a separate SAP. 
1.2 
Version History 
Major changes to the previous version are noted in bold face throughout the document. 
The SAP has been updated prior to final analysis and based on discussions with the study team. 
 
Version 
Changes Made 
Date Finalized 
1 
Original Version 
05/19/2017 
2 
Update for Protocol v2.0, LOA #3 
03/28/2019 
3 
Updated for final analysis and LOA #4: Updated the viremia 
outcome to exploratory, added a BDI-related exploratory 
outcome, updated the functional status analysis, added missing 
data handling, and added appendices describing neurocognitive 
test scoring procedures and IADL scoring procedures; 
clarifications throughout 
02/12/2021 
 


 
Page 3 of 15 
 
2 
Study Overview 
2.1 
Study Design 
This is a phase IV randomized, double-blinded, placebo-controlled study to assess the efficacy of 
adding Maraviroc (MVC) and Dolutegravir (DTG) to the current antiretroviral therapy (ART) of 
HIV-infected individuals with undetectable (<50 copies/mL) plasma HIV-1 RNA, who have mild to 
moderate neurocognitive impairment, with a primary outcome of improvement in neurocognitive 
performance. 
DURATION 
96 weeks 
SAMPLE SIZE 
186 participants 
POPULATION  
Participants will have HIV-associated neurocognitive disorder (HAND) as 
defined by the Frascati criteria, plasma HIV-1 RNA <50 copies/mL within 90 
days prior to entry, and no more than one plasma HIV-1 RNA ≥50 and <200 
copies/mL in the past 6 months prior to entry with a subsequent plasma 
HIV-1 RNA <50 copies/mL, and on stable ART for at least 6 months prior to 
entry with no plans to change treatment. 
STRATIFICATION  Participants will be randomized in a stratified manner. Stratification variables 
will be CD4+ nadir (≤100 vs. >100 cells/mm3), and HAND severity 
(asymptomatic neurocognitive impairment [ANI] vs. mild neurocognitive 
disorder [MND] / HIV-associated dementia [HAD]). 
REGIMEN 
At entry participants will be randomized to one of the following: 
- Arm A: Add to their existing ART: placebo for MVC and placebo for DTG 
- Arm B: Add to their existing ART: DTG and placebo for MVC  
- Arm C: Add to their existing ART: MVC and DTG 
2.2 
Hypotheses 
2.2.1 
Primary 
In HIV-1-infected participants with suppressed plasma viremia and at least mild neurocognitive 
impairment, improved neurocognition and increased functional capacity over 48 weeks will be 
seen with addition of Maraviroc (MVC) plus Dolutegravir (DTG) (Arm C) compared to DTG only 
(Arm B) and compared to placebos (Arm A). Addition of DTG only (Arm B) compared to placebos 
(Arm A) will result in improved neurocognition over 48 weeks and increased functional capacity. 
2.2.2 
Secondary 
Changes in peripheral blood and cerebrospinal fluid (CSF) biomarkers will parallel improvement 
in neurocognitive performance following addition of DTG alone or MVC and DTG. 
2.3 
Study Objectives 
Analysis of the study objectives below will be analyzed under a superiority framework, to conduct 
pairwise comparisons of the three arms. 


 
Page 4 of 15 
 
2.3.1 
Primary 
1. To determine whether intensification with MVC and DTG (Arm C) will improve 
neurocognitive functioning at week 48 in participants who have at least mild 
neurocognitive impairment, are on a stable antiretroviral therapy (ART) regimen, and 
have plasma HIV-1 RNA <50 copies/mL, over DTG plus placebo for MVC (Arm B) and 
over placebo of both drugs (Arm A). 
2. To determine whether DTG with placebo for MVC (Arm B) will improve neurocognitive 
functioning at week 48 over placebo of both drugs (Arm A). 
2.3.2 
Secondary 
1. To determine the safety and tolerability of MVC and DTG when added to a stable ART 
regimen. The safety and tolerability measures will include time to discontinuation of any 
study medication due to adverse events (AEs), proportion of Grade 3 or Grade 4 clinical 
AEs, proportion of Grade 3 or Grade 4 laboratory abnormalities, and summaries of all 
treatment related AEs. 
2. To determine whether intensification with MVC and DTG will improve neurocognitive 
functioning at weeks 24, 72, and 96. 
3. To determine whether functional status improves at week 48 after intensification with 
MVC and DTG (Arm C) to a greater extent than when intensified with DTG and placebo 
for MVC (Arm B) or placebo of both drugs (Arm A). 
4. To assess the effect of adding MVC and DTG on biomarkers in peripheral blood and 
CSF. 
5. To assess the association between plasma and CSF biomarkers, neuropsychological 
performance, and DTG and MVC pharmacokinetics (PK) throughout the course of the 
study. 
6. To assess whether the addition of DTG alone (Arm B) or DTG and MVC (Arm C) is 
associated with maintenance of plasma HIV-1 RNA <50 copies/mL. 
7. To assess changes in blood CD4+/CD8+ counts after intensification with DTG and MVC 
(Arm C), DTG alone (Arm B) or placebos (Arm A). 
8. To determine associations between peripheral blood immunologic markers (s100β, 
soluble CD14) and changes in neurocognitive function at week 48. 
9. To determine the relationship between changes in CCR5 ligand levels (MIP-1b) and 
inflammatory marker changes in both peripheral blood and CSF. 
10. To determine the effect of DTG intensification on residual viremia, cellular HIV-1 RNA 
expression, total cellular HIV-1 DNA, and 2 long terminal repeat sequences (LTR) DNA, 
and to determine whether these virologic changes are associated with week 48 
neurocognitive function. 
2.4 
Overview of Sample Size Considerations 
Based on previous studies, a standard deviation (SD) of 0.7 in the 48-week change in normalized 
neurocognitive test score is assumed. In the sample size calculation, the null hypothesis is that 
there is no difference in changes of neurocognitive functioning from baseline to week 48 across 
the treatment arms, while the alternative hypothesis is that the change of neurocognitive 
functioning is at least 0.5 higher for the (MVC and DTG) arm. A Bonferroni correction has been 
applied to account for multiple comparisons between treatments. One interim analysis of efficacy 


 
Page 5 of 15 
 
is planned in the middle of the study and the adjusted sample sizes assume a 15% loss to follow-
up. To achieve a power of 90%, we would expect a sample size of 62 participants per group for a 
total 186 participants on study. See Protocol section 9.4 for further details. 
2.5 
Overview of Formal Interim Monitoring 
Routine SMC reviews by the Neuro SMC assess the study progress via reviewing accrual, study 
status, screening failures, and toxicity at least annually. In the middle of the study, when 50% of 
participants are enrolled and followed for 48 weeks, an efficacy interim review will occur. This 
review will consist of a review of the assumed standard deviation (SD=0.7) and pairwise 
comparisons between the three blinded treatment arms. The pairwise comparisons will be made 
using repeated confidence intervals and Bonferroni correction, and will use a threshold p-value of 
0.0007 for each comparison to assess significance. See Protocol section 9.5 for details. 
3 
Outcome Measures 
3.1 
Primary Outcome Measures 
1. The change in normalized composite neurocognitive test score at week 48 from pre-
entry. This test score is further defined below. 
 
Aligns with Primary Objectives 1 & 2 
The normalized neurocognitive test score for domestic participants is defined as the average of z-
scores on the following tests: 
 
Stroop color naming [English: NE7041, Spanish: NE7101] 
 
Stroop word reading [English: NE7041, Spanish: NE7101] 
 
Stroop interference trial [English: NE7041, Spanish: NE7101] 
 
Grooved pegboard dominant [NE7046] 
 
Grooved pegboard non-dominant [NE7046] 
 
HVLT-R Learning trials [NE7097] 
 
HVLT-R Delayed recall [NE7097] 
 
HVLT-R Delayed recognition [NE7097] 
 
Semantic verbal fluency [NE7098] 
 
Letter fluency [NE7098] 
 
Trail Making A [NE7099] 
 
Trail Making B [NE7099] 
 
WAIS-III Symbol search [NE7101] 
 
Digit Symbol [NLW0016] 
 
The WRAT-4 word reading total [English: NLW0018] (WAT Spanish Word List word reading 
total [Spanish: NLW0020]) was also administered at domestic sites but will not be included 
in the average z-score calculation and instead will be analyzed separately. 
 
The normalized neurocognitive test score for international participants is defined as the average 
of z-scores on the following tests: 
 
Grooved pegboard dominant [NE7046] 
 
Grooved pegboard non-dominant [NE7046] 
 
HVLT-R Learning trials [NE7097] 


 
Page 6 of 15 
 
 
HVLT-R Delayed recall [NE7097] 
 
HVLT-R Delayed recognition [NE7097] 
 
Semantic verbal fluency [NE7098] 
 
Digit Symbol [NLW0016] 
 
Timed Gait [NE7090] 
 
Finger Tapping Dominant [NE7095] 
 
Finger Tapping Non-dominant [NE7095] 
 
Color Trail 1 [NE7096] 
 
Color Trail 2 [NE7096] 
The International HIV Dementia Scale (IHDS) [NE7061] was also administered at 
international sites but will not be included in the average z-score calculation and instead 
will be analyzed separately.  
 
For time point assessment of impairment (baseline, weeks 24, 48, 72, 96), z-scores will be 
calculated by subtracting a demographically appropriate (adjusted for age, race, sex, and years of 
education) norm and dividing by a demographically appropriate standard deviation. Z-score 
calculations are described in detail in Section 0. The z-scores will be calculated using the raw 
scores from the neurocognitive tests. 
 
Assessment of change over time in neurocognitive impairment will be calculated by subtracting 
the average z-scores of the two time points of interest. 
The individual scores are separated into six component domains (plus the two separate tests 
WRAT and IHDS mentioned above). The z-score for each domain is the average of 
standardized individual NP z-scores listed under each domain: 
 
Fine motor Skills/Complex Perceptual 
o 
Grooved pegboard dominant – both domestic and international 
o 
Grooved pegboard non-dominant – both domestic and international 
o 
Finger Tapping dominant – international 
o 
Finger Tapping non-dominant – international 
o 
Timed Gait - international 
 
Speed of Information Processing 
o 
Digit Symbol – both domestic and international 
o 
Stroop color naming – domestic 
o 
Stroop word reading – domestic 
 
Executive Function 
o 
Trail Making B – domestic 
o 
Stroop interference trial – domestic 
o 
Letter Fluency – both domestic and international 
o 
Semantic Verbal Fluency – both domestic and international 
o 
Color Trails 2 – international 
 
Verbal Learning 
o 
HVLT-R Learning Trial – both domestic and international 
 
Verbal Memory 
o 
HVLT-R Delayed recall – both domestic and international 


 
Page 7 of 15 
 
o 
HVLT-R Delayed recognition – both domestic and international 
 
Attention/Working Memory 
o 
Trail Making A – domestic 
o 
WAIS-III symbol search – domestic 
o 
Color Trails 1 – international 
 
IHDS – international 
 
Premorbid Skills 
o 
WRAT-4 Reading / WAT Spanish Word List – domestic 
 
Based on the z-scores, domain deficit scores (DDS) will be computed for the domains, and the 
global deficit score (GDS) will be computed using the total battery. The GDS emphasizes 
impairment, reduces minimal learning/practice and has the advantage of reducing ‘sum to zero’ 
effects seen with counterbalancing positive and negative scores in a subject’s assessment. 
However, this approach does minimize the ability to observe subtle changes as scores are 
grouped into larger categories. 
 
DDS and GDS are derived from the standardized scores by the following algorithm: 
 
If z-score is greater than -1.0, then DS is 0; 
 
If z-score is [-1.5, -1.0] then DS is 1; 
 
If z-score is [-2.0, -1.5) then DS is 2; 
 
If z-score is [-2.5, -2.0) then DS is 3; 
 
If z-score is [-3.0, -2.5) then DS is 4; 
 
If z-score is smaller than -3.0 then DS is 5; 
 
If z-score is missing then DS is missing; 
 
The DS categories are defined as: 
  0 – Normal 
1 – Mild 
2 – Mild to Moderate 
3 – Moderate 
4 – Moderate to Severe 
5 – Severe 
3.2 
Secondary Outcome Measures 
1. Treatment related adverse events 
 
Aligns with Secondary Objective 1 
 
Time to discontinuation of any study medication due to adverse events 
 
Proportion of Grade 3 or Grade 4 clinical AEs 
 
Proportion of Grade 3 or Grade 4 laboratory abnormalities 
 
Summaries of all AEs where the site indicated some relationship to study 
treatment. 
2. Change from baseline of normalized composite neurocognitive test score at weeks 24, 
72, and 96. Change from baseline of normalized component neurocognitive test scores at 
weeks 24, 48, 72, and 96 will also be examined. 
 
Aligns with Secondary Objective 2 
 
See primary outcome for details on composite neurocognitive test scores 
 
Component neurocognitive test scores consist of domain scores 


 
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 
Change from baseline in the domain deficit scores and GDS to weeks 24, 48, 72, 
96 
3. Change from baseline in functional status scores based on the IADLs form at weeks 24, 
48, 72, and 96. 
 
Aligns with Secondary Objective 3 
 
Functional change is defined as a change from baseline in IADL score. The 
IADL scoring is defined in Section 7. 
4. Change from baseline of peripheral blood and CSF biomarkers at week 48. 
 
Aligns with Secondary Objective 4 
 
Potential list of biomarkers includes: 
i. Blood: sCD14, MIP-1β, TNFr-II, VCAM-1, NFL 
ii. CSF: MIP-1β, NFL, neopterin, IP-10 
5. Plasma HIV-1 RNA ≥ 50 copies/mL at weeks 24, 48, and 96. 
 
Aligns with Secondary Objective 6 
6. CD4+ T-cell counts and changes from baseline to weeks 24, 48, and 96. 
 
Aligns with Secondary Objective 7 
7. CD8+ T-cell counts and changes from baseline to weeks 24, 48, and 96. 
 
Aligns with Secondary Objective 7 
3.3 
Other Outcome Measures 
1. Changes from baseline to week 48: residual viremia, cell-associated HIV-1 RNA/DNA/2-
LTR circles and SCA, T-cell and monocyte activation. 
 
Aligns with Secondary Objective 10 
 
Looking specifically at the comparison between DTG only arm and placebo arm 
to determine the effect of DTG intensification on these factors 
 
NOTE: This outcome measure was listed as secondary in the protocol but 
the intention was as an exploratory outcome due to lack of funding for 
testing, specifically for T-cell and monocyte activation 
2. Beck Depression Inventory (BDI) evaluations 
 
New outcome measure 
 
Change in BDI score (evaluated as the sum of the 21 items) from baseline 
to weeks 24, 48, 72, and 96 
 
Change from baseline in BDI score by subscales: 
o Cognitive (items 1, 2, 3, 5, 6, 7, 8, 9, and 14) 
o Affective (items 4, 10, 12, and 13) 
o Somatic (items 11, 15, 16, 17, 18, 19, 20, and 21) 
 
Percent of participants with a BDI score ≤13 vs. >13 at weeks 24 , 48, 72, 
and 96 
3. Associations of neuropsychological performance with plasma and CSF biomarkers 
and at weeks 0, 24, 48, 72, and 96 (0 and 48 only for CSF biomarkers); and with 
DTG and MVC PK at weeks 24 and 48. 
 
Aligns with Secondary Objectives 5, 8, 9 


 
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4 
Statistical Principles 
4.1 
General Considerations 
 
The primary analysis and secondary analyses will use the ITT principle (i.e. all 
randomized participants will be included in the primary analyses). 
 
The primary analyses will use “as randomized” for group assignment. 
 
The missing values for neurocognitive test scores will be imputed at the test 
level in the following manner: 
o 
When missing values can be attributed to neurologic impairment, the worst 
1% score will be imputed for the missing values. Note: If the participant was 
unable to perform the test due to a disability related to HIV-associated 
neurological disease (e.g., unable to follow or understand directions, severe 
impairment in motor controls) this was indicated on the appropriate 
neuropsychological examination form. 
o 
If the reason for missingness is unknown and observations exist both before 
and after the missing value, these scores will be averaged and that averaged 
value will be imputed for the missing value. 
o 
If the reason for missingness is unknown and observations do not exist 
after the missing value, scores will be imputed by the last observation 
carried forward method. 
 
Missing data prevalence (of visits and of neurocognitive test scores) will be 
summarized. 
 
For the neurocognitive test scores, Winsorized estimates may be used for 
extreme outliers after observing the data. 
 
All programs that create permanent study-specific derived datasets or that contribute 
to analyses of the primary or secondary objectives will be validated according to 
CBAR SOPs. Primary and key secondary objective results will be verified through 
independent double programming. 
 
Visit and analysis window details: 
o 
Visits occurred at screening, entry, and weeks 2(±1), 4(±1), 12(±2), 24(±2), 
48(-4,+8), 72(-4,+8), and 96(-4,+8). 
o 
Analysis windows will be formed around each study visit using the 
midpoints between adjacent visits as cutoffs and potentially including 
assessments collected outside the recommended visit windows described 
in the protocol. 
4.2 
Analysis Approaches 
4.2.1 
Primary Analysis 
The Kolmogrov-Smirnov test will be employed to check whether the primary outcome is normally 
distributed. If the normality assumption is not rejected, the two-sample t-test will be used for 
pairwise comparisons between any two arms. Otherwise, the nonparametric analogue of the two-
sample t-test (ie, Wilcoxon rank-sum test) will be used as an alternative. The test will be stratified 
by CD4+ nadir (≤100 vs. >100 cells/mm3) and HAND severity (ANI vs. MND/HAD). All pairwise 
comparisons will be conducted among the three study arms. 


 
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Treatment comparisons will be summarized by sex and by race. Treatment interactions with sex 
and race will be tested as required by NIH using multiple variable regression analyses. Subgroup 
analyses will be performed for the primary outcome in each participating country. In presence of 
significantly different results by country, the changes of neurocognitive functioning will be 
compared by adjusting for country effects by Van Elteren tests. 
Sensitivity analyses will be conducted under different assumptions (e.g., impute missing z-scores 
of a test at week 48 by the smallest/largest/median of observed values in the same treatment 
arm) to assess the impact and informativeness of missing data. A per-protocol analysis which will 
restrict the analysis to participants who adhere perfectly to the instructions in the study protocol 
will be performed. In addition, a sensitivity analysis of the effect of the Trails B score 
imputation (see Section 6 Appendix) will be reviewed by setting imputed scores to 
incomplete and then re-evaluating the primary outcome. 
  
4.2.2 
Secondary Analyses 
1. Treatment related AEs: Time to discontinuation of medication due to AEs will be 
compared by treatment arm using the Kaplan-Meier approach and log-rank test; 
Proportion of participants with Grade 3 or Grade 4 clinical AEs or laboratory 
abnormalities will be compared by treatment arm, using Fisher’s exact tests. 
2. Change in neurocognitive scores: See 4.2.1 Primary Analysis above. 
3. Change in functional status: Pairwise comparisons will be performed among three 
treatment arms using the Wilcoxon rank-sum test. 
4. Change in biomarkers: The Wilcoxon signed-rank test will be used to assess the changes 
from baseline to week 48 in specified biomarkers. Comparisons of changes in these 
biomarkers between any two treatment arms will be conducted through Wilcoxon rank-
sum test. 
5. Plasma HIV-1 RNA: For each treatment arm, the proportion of participants with ≥50 
copies/mL and associated 95% CI will be provided in a table and plotted over time; Two-
sided 95% CIs will also be provided for the difference between arms. 
6. Changes in CD4+ cell counts: Average CD4+ counts and their associated 95% CIs will 
be provided and plotted over time for each treatment arm; changes in CD4+ counts from 
baseline to weeks 24, 48, and 96 will be compared pairwise among treatment arms 
through Wilcoxon rank-sum test. 
7. Changes in CD8+ cell counts: Average CD8+ counts and their associated 95% CIs will 
be provided in a table and plotted over time for each treatment arm; changes in CD8+ 
counts from baseline to weeks 24, 48, and 96 will be compared pairwise among 
treatment arms through Wilcoxon rank-sum test. 
4.2.3 
Other Analyses 
1. Changes in virologic measures: Wilcoxon rank-sum test will be used to compare Arm A 
and Arm B to assess the effect of DTG intensification on virologic changes. 
2. BDI Analyses: Change will be compared pairwise among the three treatment arms 
using the Wilcoxon rank-sum test. Percent of participants with BDI score >13 vs 
≤13 will be compared by arm using the Chi-Square test. 


 
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3. Correlation Analyses: Spearman correlations and scatterplots will be used to assess 
associations between: 
a. Peripheral blood and CSF biomarkers and neuropsychological performance at 
weeks 0, 24, 48, 72, 96 (weeks 0 and 48 only for CSF biomarkers). 
b. Changes in blood immunologic markers and changes in neurocognitive 
performance from baseline to week 48. 
c. Changes in blood biomarkers from baseline to week 48. 
d. DTG and MVC PK and neuropsychological performance at weeks 24 and 
48. 
5 
Report Contents 
Detailed descriptions of the content for each of the following sections are given in the AIP. 
 
CONSORT Diagram 
 
Accrual – summarize enrollment 
 
Baseline characteristics 
o 
Age 
o 
Sex 
o 
Race 
o 
IV drug use 
o 
Country 
o 
Education 
o 
Primary Language 
o 
HAND diagnosis 
o 
Nadir CD4 count 
o 
CD4 count 
o 
Log10 HIV-1 RNA 
o 
Neurocognitive test score 
 
Study status 
 
Treatment status 
o 
Premature study treatment discontinuation reasons 
 
Study conduct 
o 
Missed visits 
 
Safety Summary 
 
Analysis of primary outcome measures 
o 
Subgroup analyses 
o 
Sensitivity analyses 
 
Analysis of secondary outcome measures 
 
Analysis of other outcome measures 
 
 


 
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6 
Appendix: Neuropsychological Norms For ACTG A5324 
 
Domestic Sites 
 
Trail Making A & B, Grooved Pegboard, Semantic and Letter Fluency 
Norm source: Heaton RK, Miller SW, Taylor MJ, Grant I. (2004). Revised comprehensive 
norms for an expanded Halstead-Reitan battery: demographically adjusted 
neuropsychological norms for African American and Caucasian adults. Lutz, FL: 
American Psychological Assessment Resource, Inc. 
 
T scores were generated using the manual look-up tables. 
 
T scores were then converted to z-scores. 
 
Norms for African Americans were used for Hispanic and Native American 
participants. 
 
Trails B used a cut-off time of 240 seconds instead of the expected time out 
score of 300 seconds. Scores ≥240 are imputed to 300 for calculating the T 
score (unless a comment from the site provides an exact time). 
 
Grooved Pegboard did not use a cut-off time during testing. For analysis, all 
scores >300 are set to 300 for calculating the T score. 
 
Stroop (Commali version) 
Norm source: Mitrushina M, Boone KB, Razani J, D’Elia L. (2005). Handbook of 
normative data for neuropsychological assessment. 2nd ed. New York: Oxford University 
Press. 
 
Tables A6.7.-A6.10., pages 666-668 in Mitrushina manual. 
 
Note- the tables were originally published by Demick and Harkins, 1997. 
 
Raw scores were converted to z-scores. 
 
WAIS-III Symbol Search and Digit Symbol 
Norm source: Weschler, D. (1997). Wechsler Adult Intelligence Scale, Third Edition. 
 
Scaled scores were defined using the manual look-up table. 
 
Scaled scores were converted into T scores. 
 
T scores were then converted to z-scores. 
 
Hopkins Verbal Learning Test-Revised 
Norm source: Brandt, J., & Benedict, R. H. B. (2001). Hopkins Verbal Learning Test – 
Revised. Administration manual. Lutz, FL: Psychological Assessment Resources. 


 
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 
Raw scores were converted into T scores based on the manual look-up tables. 
 
T scores were then converted to z-scores. 
 
Raw scores below the range of T scores in the look-up tables were converted to 
z-scores using the mean and SD for the reference group as provided at the 
bottom of each look-up table in the manual. 
 
Wide Range Achievement Test-4 (Green form) 
Norm source: Wilkinson, G. S., & Robertson, G. J. (2006). Wide Range Achievement 
Test: Fourth Edition. Lutz, FL: Psychological Assessment Resources. 
 
Raw scores were converted into standard scores using the look-up table. 
 
Standard scores were then converted into z-scores. 
 
Word Accentuation Test 
Norm source: Gomar, J. J., Ortiz-Gil, J., McKenna, P. J., Salvador, R., Sans-Sansa, B., 
Sarró, S., Guerrero, A., & Pomarol-Clotet, E. (2011). Validation of the Word 
Accentuation Test (TAP) as a means of estimating premorbid IQ in Spanish speakers. 
Schizophrenia research, 128(1-3), 175–176. 
 
Raw scores were converted into standard scores. 
 
Standard scores were then converted into z-scores. 
 
International Sites 
 
Raw scores were converted into z-scores using neurocognitive normative 
comparison test data from ACTG A5271. 
 
 
 


 
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7 
Appendix: IADL Scoring 
IADL scoring uses the following questions from NRQ0004, and scores them according to a binary 
scoring system using the ‘NOW’ response. The IADL score is the sum of the scores as defined 
below: 
1. Housekeeping 
a. I maintain my house/apartment by myself or only need occasional 
help for larger jobs……………………………………………………………..1 
b. I only perform light daily tasks (wash dishes, make bed)……………….0 
c. I perform some light tasks, but have difficulty keeping my place clean.0 
d. I need help with all housekeeping tasks……………………………..……0 
e. I am fully able to do housekeeping, but choose not to do so….………..1 
 
2. Managing Monies 
a. I manage all of my monies by myself…………………………………….…1 
b. I manage routine small purchases, but need help with other 
checking and balancing accounts………………………………………………0 
c. I am not able to handle money accurately………………………………….0 
d. I am able to handle my own monies, but someone else does them 
for me……………………………………………………………………………….1 
4. Cooking 
a. I plan, prepare and serve many of my own meals……………..………….1 
b. I prepare meals if someone else provides me with the 
right ingredients…………………………………………………………………..0 
c. I heat and serve meals provided by others………………………………….0 
d. I need to have meals prepared and served to me………………………….0 
e. I am able to plan, prepare, and serve my own meals 
but someone else does it for me………………………………………………..1 
7. Transportation 
a. I drive my own car or take public transportation on my own 
(if you do not own a car)………………………………………………………..1 
b. I arrange my own travel using taxis, but do not drive 
or use public transportation………………………………………….…………0 
c. I can travel on public transportation or use taxis if I am 
assisted by another…………………………………………………..………….0 
d. I am entirely dependent on others to take me where I need to go…..…..0 
8. Using the telephone 
a. I handle using the telephone without difficulty 
(looking up and dialing new numbers, etc.)……………………………………1 
b. I only dial a few well-known numbers………………………………………0 
c. I answer the telephone, but do not dial…………………………………….0 
d. I do not use the telephone at all…………………………………………….0 
e. I do not have access to a telephone……………………………………….N/A 
12. Shopping (e.g., clothes, other non-food goods) 
a. I take care of all of my shopping needs……………………………………1 
b. I only make small purchases…………………………………….…………..0 
c. I need someone to go with me on any shopping trip………….….……….0 
d. I am unable to shop…………………………………………….….……..…..0 


 
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e. I am able to shop, but choose to have someone 
else do my shopping for me…………………………………………..…………1 
 
13. Laundry 
a. I do all of my own laundry…………………………………………………….1 
b. I need occasional help in doing the laundry…………………………………0 
c. I launder only small items (e.g., rinse socks, stockings, etc.)……………..0 
d. All laundry must be done by others……………………………………………0 
e. I am able to do my own laundry, but choose 
to have others do it for me…………………………………………………….1 
14. Taking/keeping track of medication 
a. I can take my medication without help………………………………………1 
b. I take medications that are prepared by someone else……….………….0 
c. I am unable to track my own medications……………………….…………0 
d. I am able to take care of my own medications, but 
choose to have someone else do it for me……………………….……………1