Clinical trial NCT03739996
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2019-12-31; Completion date: 2024-04-29
Enrollment: 75 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to assess the safety, tolerability, antiviral activity, and pharmacokinetics of long-acting cabotegravir (CAB LA) plus the broadly neutralizing monoclonal antibody VRC-HIVMAB075-00-AB (VRC07-523LS), in adults living with HIV-1 with suppressed plasma viremia.

Detailed description:
This study had a single, open-label arm and was conducted in three steps.

At Step 1 entry, all participants discontinued their current antiretroviral therapy (ART) regimen, except for the 2 nucleoside reverse transcriptase inhibitors (NRTIs) and started oral CAB. Viral load monitoring occurred at entry, Week 4, and, conditionally, Week 5.

During Step 1, participants who tolerated oral CAB plus their two NRTIs, maintained viral suppression, and met the other Step 2 eligibility requirements, registered for Step 2. Participants in Step 1 who were not eligible for Step 2 returned to their standard of care (SOC) regimen and were followed for an additional 4 weeks before being taken off the study.

In Step 2, participants received CAB LA every 4 weeks through Step 2 Week 44 (12 injections) plus VRC07-523LS every 8 weeks through Step 2 Week 40 (6 infusions). Viral load monitoring occurred every 2 weeks through Week 8 and then every 4 weeks through Week 48. Any participant with a viral load of HIV-1 RNA ≥ 200 copies/mL had to attend an additional virologic failure confirmation visit within 14 days of the measured value. If virologic failure was confirmed (i.e., two consecutive HIV-1 RNA values ≥ 200 copies/mL), the participant transitioned to Step 3.

After completion of Step 2 (Week 48), confirmed virologic failure, or premature treatment discontinuation, all participants who received any CAB LA or VRC07-523LS entered Step 3 and returned to SOC ART for 48 weeks, with visits at step entry and weeks 4, 12, 24, 36, and 48.

The study's primary virology outcome pertains to Step 2 and only includes participants who started the CAB LA plus VRC07-523LS combination. The study's primary safety outcome pertains to Step 2 and Step 3 follow-up for participants who started the CAB LA plus VRC07-523LS combination.

Study visits included physical examinations, clinical assessments, and blood and urine collection.

The study opened to accrual in late December 2019. However, in March 2020 the study temporarily closed to screening and enrollment (including registration to Step 2) due to the COVID-19 pandemic. No participant had reached Step 2 of the study when the pause occurred. Participants in Step 1 were instructed to immediately stop the oral CAB plus 2 NRTI combination, resume their SOC regimen, and discontinue the study. The study reopened to screening and enrollment in September 2020. Analyses for this study only included participants who enrolled after the study reopened in September 2020. Participants previously enrolled were invited to rescreen and reenroll, if still eligible.

Arms: arm 1: Step 1: CAB administered orally as one 30 mg tablet once daily, plus two NRTIs, for up to 5 weeks.

Step 2: CAB LA loading dose (600 mg) administered as one IM injection at Step 2 entry study visit, and maintenance dose (400 mg), starting at 4 weeks after CAB LA loading dose, and then every 4 weeks through Week R2+44 (for a total of 12 injections).

VRC07-523LS (40 mg/kg) administered as an IV infusion starting at Step 2 entry and then every 8 weeks through Week R2+40 (for a total of 6 infusions).

Step 3: Standard of Care (SOC) ART regimen for approximately 48 weeks.
Interventions: intervention 1: Oral Cabotegravir (CAB) intervention 2: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) intervention 3: Long-Acting Injectable Cabotegravir (CAB LA) intervention 4: VRC07-523LS intervention 5: Standard of Care (SOC) ART
Intervention descriptions: intervention 1: 30 mg tablets administered orally intervention 2: NRTIs were not provided by the study. Participants obtained NRTIs outside of the study through routine care. intervention 3: 600 mg loading dose followed by 400 mg maintenance doses administered by intramuscular (IM) injection intervention 4: 40 mg/kg administered as an intravenous (IV) infusion intervention 5: SOC ART was not provided by the study. Participants obtained SOC ART outside of the study through routine care.

Protocol documents:
Prot_ICF_000.pdf: 
 
A5357 
 
A Study of Long-Acting Cabotegravir Plus VRC-HIVMAB075-00-AB (VRC07-523LS) 
to Maintain Viral Suppression in Adults Living with HIV-1 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
Sponsored by: 
 
National Institute of Allergy 
and Infectious Diseases 
 
In Collaboration with: 
 
Vaccine Research Center, National Institutes of Health 
 
Industry Support Provided by: 
 
Monogram Biosciences, Inc. 
ViiV Healthcare 
 
 
IND #141518 
 
 
The ACTG Antiretroviral Therapy Strategies 
Transformative Science Group: 
Timothy Wilkin, MD, Chair 
 
Protocol Co-Chairs: 
Babafemi Taiwo, MBBS 
 
Pablo Tebas, MD 
 
Protocol Vice Chair: 
Leah Burke, MD 
 
DAIDS Clinical Representative: 
Pablo Francisco Belaunzaran 
Zamudio, MD, DTM&H, MSc 
 
Clinical Trials Specialist: 
Jennifer Tiu, MPH 
 
 
 
 
 
FINAL VERSION 4.0 
March 11, 2022


 
 
A5357 
FINAL VERSION 4.0 
 
 
11Mar2022 
 
 
A Study of Long-Acting Cabotegravir Plus VRC-HIVMAB075-00-AB (VRC07- 523LS) to 
Maintain Viral Suppression in Adults Living with HIV-1 
 
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 
 


 
 
A5357 
FINAL VERSION 4.0 
 
 
11Mar2022 
 
 
TABLE OF CONTENTS 
Page 
SIGNATURE PAGE .................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY .................................................................................... 5 
PROTOCOL TEAM ROSTER ..................................................................................................... 6 
STUDY MANAGEMENT ........................................................................................................... 10 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 12 
SCHEMA .................................................................................................................................. 13 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 16 
1.1 
Hypothesis ......................................................................................................... 16 
1.2 
Primary Objectives ............................................................................................. 16 
1.3 
Secondary Objectives ........................................................................................ 16 
1.4 
Exploratory Objective ......................................................................................... 16 
2.0 
INTRODUCTION ........................................................................................................... 17 
2.1 
Background ........................................................................................................ 17 
2.2 
Rationale ........................................................................................................... 21 
2.3 
Significance ....................................................................................................... 29 
3.0 
STUDY DESIGN ........................................................................................................... 30 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 31 
4.1 
Step 1 Inclusion Criteria ..................................................................................... 31 
4.2 
Step 1 Exclusion Criteria .................................................................................... 34 
4.3 
Step 2 Inclusion Criteria ..................................................................................... 35 
4.4 
Step 2 Exclusion Criteria .................................................................................... 36 
4.5 
Step 3 Inclusion Criterion ................................................................................... 36 
4.6 
Step 3 Exclusion Criterion .................................................................................. 37 
4.7 
Study Enrollment Procedures............................................................................. 37 
4.8 
Co-enrollment Guidelines ................................................................................... 38 
5.0 
STUDY TREATMENT ................................................................................................... 38 
5.1 
Study Product .................................................................................................... 38 
5.2 
Study Product Regimen, Administration, and Duration ....................................... 38 
5.3 
Study Product Preparation ................................................................................. 39 
5.4 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 46 
5.5 
Concomitant Medications ................................................................................... 47 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 49 
6.1 
Schedule of Evaluations..................................................................................... 49 
6.2 
Timing of Evaluations ......................................................................................... 54 
6.3 
Instructions for Evaluations ................................................................................ 57 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ......................................................... 64 
7.1 
Definition of Adverse Events .............................................................................. 64 
7.2 
Adverse Event Collection Requirements for this Protocol ................................... 64 
7.3 
Expedited Reporting of Adverse Event (EAE) to DAIDS..................................... 65 
7.4 
Study Monitoring ................................................................................................ 66 


 
 
A5357 
 
 
FINAL VERSION 4.0 
 
CONTENTS (Cont’d) 
11Mar2022 
 
 
 
Page 
 
8.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 67 
8.1 
Toxicity .............................................................................................................. 67 
8.2 
Clinical Abnormalities ......................................................................................... 69 
8.3 
Allergic Reactions .............................................................................................. 71 
8.4 
Local Reactions ................................................................................................. 73 
8.5 
Pregnancy.......................................................................................................... 73 
8.6 
Breastfeeding ..................................................................................................... 74 
8.7 
Virologic Failure ................................................................................................. 74 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 74 
9.1 
Permanent and Premature Study Treatment Discontinuation ............................. 74 
9.2 
Premature Study Discontinuation ....................................................................... 75 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................... 75 
10.1 
General Design Issues ....................................................................................... 75 
10.2 
Outcome Measures ............................................................................................ 75 
10.3 
Participant Registration ...................................................................................... 77 
10.4 
Sample Size and Accrual ................................................................................... 77 
10.5 
Data and Safety Monitoring ................................................................................ 78 
10.6 
Analyses ............................................................................................................ 79 
10.7 
Unblinding .......................................................................................................... 81 
11.0 
PHARMACOLOGY PLAN .............................................................................................. 81 
11.1 
Pharmacology Objective .................................................................................... 81 
11.2 
Pharmacology Study Design .............................................................................. 81 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis .............................. 81 
11.4 
Anticipated Outcomes ........................................................................................ 82 
12.0 
DATA COLLECTION AND MONITORING ..................................................................... 82 
12.1 
Records to Be Kept ............................................................................................ 82 
12.2 
Role of Data Management ................................................................................. 82 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 82 
13.0 
PARTICIPANTS ............................................................................................................ 83 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 83 
13.2 
Participant Confidentiality ................................................................................... 83 
13.3 
Study Discontinuation ........................................................................................ 83 
14.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 83 
15.0 
BIOHAZARD CONTAINMENT ...................................................................................... 84 
16.0 
REFERENCES .............................................................................................................. 85 
SAMPLE INFORMED CONSENT ............................................................................................. 90 
APPENDIX I: STUDY VISITS .................................................................................................. 112 
 


 
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SITES PARTICIPATING IN THE STUDY 
 
This study is a multicenter study that will be implemented at ACTG US clinical research sites 
(CRSs). 
 


 
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PROTOCOL TEAM ROSTER 
 
Co-Chairs 
Babafemi Taiwo, MBBS 
Northwestern University CRS 
Feinberg School of Medicine 
Division of Infectious Diseases 
645 North Michigan Avenue, Suite 900 
Chicago, IL 60611 
Phone: 312-695-4994 
Cell Phone: 312-404-0745 
Assistant’s Phone: 312-926-9877 
Fax: 312-695-5088 
E-mail: b-taiwo@northwestern.edu 
 
Pablo Tebas, MD 
Hospital of the University of Pennsylvania CRS 
Division of Infectious Diseases 
536 Johnson Pavilion 
36th Street and Hamilton Walk 
Philadelphia, PA 19104-6073 
Phone: 215-615-4321 
Phone: 215-349-8092 
Fax: 215-615-4360 
E-mail: pablo.tebas@uphs.upenn.edu 
 
Vice Chair 
Leah Burke, MD 
Weill Cornell Chelsea CRS 
Weill Cornell Medical College 
1300 York Avenue, Box 125 
New York, NY  10065 
Office Phone: 212-746-4177 
Office Fax: 212-746-8852 
Work Cell: 203-361-7913 
E-mail: leah.burke@ynhh.org 
DAIDS Clinical Representative 
Pablo Francisco Belaunzaran Zamudio, 
MD, DTM&H, MSc 
DAIDS/NIAID/NIH/HIVRB 
Therapeutics Research Program 
5601 Fishers Lane 
Room 9E40B 
Rockville, MD 20852 
Phone: 240-292-4423 
E-mail: belaunzaranzapabf@niaid.nih.gov 
 
Clinical Trials Specialist 
Jennifer Tiu, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3000 
E-mail: jennifer.tiu@dlhcorp.com 
 
Statisticiens 
Katherine Rodriguez, MS 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 
FXB Building, Room 643A 
Boston, MA 02115 
Phone: 617-432-5229 
Fax: 617-432-2843 
E-mail: krodrigu@sdac.harvard.edu 
 
Yu (Evelyn) Zheng, PhD 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 
FXB Building, Room 615 
Boston, MA 02115 
Phone: 617-432-2480 
Fax: 617-432-2843 
E-mail: ezheng@sdac.harvard.edu 


 
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FINAL VERSION 4.0 
 
PROTOCOL TEAM ROSTER (Cont’d) 
11Mar2022 
 
Data Managers 
Scott Anderson, MS 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 
E-mail: sanders@frontierscience.org 
 
Sheldon Tetewsky 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 
E-mail: tetewsky@frontierscience.org 
 
DAIDS Pharmacists 
Katherine Shin, PharmD 
DAIDS/NIAID/NIH 
Pharmaceutical Affairs Branch 
5601 Fishers Lane 
Room 9D30 
Rockville, MD 20852 
Phone: 240-627-3047 
Fax: 301-402-1506 
E-mail: kashin@niaid.nih.gov 
 
Cynthia Parker, PharmD 
DAIDS/NIAID/NIH 
Pharmaceutical Affairs Branch 
5601 Fishers Lane 
Room 9D37 
Rockville, MD 20852 
Phone: 301-761-7199 
Fax: 301-402-1506 
E-mail: cindy.parker@nih.gov 
 
Pharmacologist  
Jennifer Kiser, PharmD, PhD 
University of Colorado Hospital CRS 
Pharmaceutical Sciences 
12850 E Montview Boulevard, C238 
Aurora, CO 80045 
Phone: 303-724-6131 
Fax: 303-724-6135 
E-mail: jennifer.kiser@cuanschutz.edu 
 
Investigator 
Katharine Bar, MD 
University of Pennsylvania 
502D Johnson Pavilion 
3610 Hamilton Walk 
Philadelphia, PA 19104-6073 
Phone: 215-573-8497 
Fax: 215-349-5111 
E-mail: bark@upenn.edu 
 
VRC Scientific Advisors 
Lucio Gama, PhD 
National Institutes of Health 
Vaccine Research Center 
Building 40, Room 5502 
40 Convent Drive 
Bethesda, MD 20814 
Phone: 301-761-7580 
E-mail: lucio.gama@nih.gov 
 
Richard Koup, MD 
National Institutes of Health 
Vaccine Research Center 
Building 40, Room 3502 
40 Convent Drive 
Bethesda, MD 20814 
Phone: 301-594-8585 
Fax: 301-480-2779 
E-mail: richard.koup@nih.gov 
 


 
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FINAL VERSION 4.0 
 
PROTOCOL TEAM ROSTER (Cont’d) 
11Mar2022 
 
Field Representative 
Jenifer Baer, RN 
Infectious Diseases Center 
Cincinnati CRS 
Holmes Division 
231 Albert Sabin Way 
Cincinnati, OH 45267-0405 
Phone: 513-584-8022 
Fax: 513-584-8454 
E-mail: baerjk@uc.edu 
 
Laboratory Technologist 
Sikhulile Moyo, MSc, MPH, PhD 
Gaborone CRS 
Botswana Harvard Partnership 
Bag BO 320 
Gaborone 0000 
Botswana 
South Africa 
Phone: 267-3902671 Ext. 2207 
Fax: 267-3901284 
E-mail: smoyo@bhp.org.bw 
 
Community Scientific Subcommittee (CSS) 
Representative 
Michael Dorosh, MA 
University of Colorado Hospital CRS 
38 W Maple Avenue 
Denver, CO 80223 
Phone: 303-777-5737 
E-mail: michael@ontheten.org 
 
Industry Representatives 
Mark Baker, PhD 
ViiV Healthcare 
5 Moore Drive 
Research Triangle Park, NC 27709 
E-mail: mark.x.baker@viivhealthcare.com 
 
Industry Representatives (Cont’d) 
David Margolis, MD 
ViiV Healthcare 
5 Moore Drive 
Research Triangle Park, NC 27709 
E-mail: david.a.margolis@viivhealthcare.com 
 
Christos Petropoulos, PhD 
Monogram Biosciences, Inc. 
345 Oyster Point Boulevard 
South San Francisco, CA 94080 
Phone: 650-866-7439 
E-mail: petropc@labcorp.com 
 
Kimberly Smith, MD, MPH 
ViiV Healthcare 
5 Moore Drive 
P.O. Box 13398 
Research Triangle Park, NC 27709 
Phone: 919-491-2167 
E-mail: kimberly.y.smith@viivhealthcare.com 
 
Paul Wannamaker 
ViiV Healthcare 
5 Moore Drive 
Mail Stop 5.3C 
Research Triangle Park, NC  27703 
E-mail: paul.g.wannamaker@viivhealthcare.com 
 
Laboratory Data Managers 
Laura Hovind, BS, MS 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7468 
Fax: 716-833-0655 
E-mail: hovind@frontierscience.org 
 


 
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FINAL VERSION 4.0 
 
PROTOCOL TEAM ROSTER (Cont’d) 
11Mar2022 
 
Laboratory Data Managers (Cont’d) 
Sarah Wojcinski, BS 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7267 
E-mail: wojcinski@frontierscience.org 
 
Laboratory Specialists 
Deborah Anisman-Posner, BA, CPT 
ACTG Laboratory Center at UCLA 
11075 Santa Monica Boulevard 
Suite 200 
Los Angeles, CA 90025 
Phone: 310-825-5382 
E-mail: danisman@milabcentral.org 
 
Emma Duffy 
ACTG Laboratory Center at UCLA 
11075 Santa Monica Boulevard 
Suite 200 
Los Angeles, CA 90025 
Phone: 617-407-8713 
E-mail: eduffy@milabcentral.org 


 
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FINAL VERSION 4.0 
 
11Mar2022 
 
 
STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5357@fstrf.org via 
email. The appropriate team member will respond with a "cc" to actg.teamA5357@fstrf.org. A 
response should generally be received within 24 hours (Monday-Friday). 
 
Protocol Email 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.protA5357 email group. 
Include the protocol number in the email participant line. 
• 
Send an email message to actg.user.support@fstrf.org 
 
Clinical Management 
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact the Clinical Management Committee (CMC). 
• 
Send an email message to actg.cmcA5357@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to pharmacologic laboratory tests, contact the protocol team 
pharmacologist. 
• 
Send an email message to actg.teamA5357@fstrf.org (ATTENTION: Jennifer Kiser). 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), registration, and other data management issues, contact the data manager. 
Completion guidelines for eCRFs and participant-completed eCRFs can be downloaded 
from the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Scott 
Anderson and Sheldon Tetewsky directly. 
• 
For other questions, send an email message to actg.teamA5357@fstrf.org (ATTENTION: 
Scott Anderson and Sheldon Tetewsky). 
• 
Include the protocol number, PID, and a detailed question. 
 
Participant Registration 
For participant registration questions or problems and study identification number SID lists. 
• 
Send an email message to rando.support@fstrf.org or call the DMC Randomization Desk at 
716-834-0900, extension 7301. 
 
DMC Portal and Medidata Rave Problems 
Contact DMC User Support: 
• 
Send an email message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 


 
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FINAL VERSION 4.0 
 
STUDY MANAGEMENT (Cont'd) 
11Mar2022 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the clinical trials specialist. Send an 
email message to actg.teamA5357@fstrf.org (ATTENTION: Jennifer Tiu). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send an email message to ACTGNCC@dlhcorp.com. 
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 email message to Protocol@tech-res.com or call 
301-897-1707. 
 
Protocol Activation 
For questions related to protocol activation, contact the clinical trials specialist. 
• 
Send an email message to actg.teamA5357@fstrf.org (ATTENTION: Jennifer Tiu). 
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Katherine Shin and Cynthia Parker, protocol pharmacists, at 240-627-3047. 
 
Orders for Study-Provided Drugs 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions 
The IND number is available on the PSWP. For any questions related to the IND submission, 
contact the DAIDS RSC at Regulatory@tech-res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions 
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710. 
 
Phone Calls 
Sites are responsible for documenting any phone calls made to A5357 team members. 
• 
Send an email to actg.teamA5357@fstrf.org. 
 
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 
 
AE 
adverse event 
ART 
antiretroviral therapy 
ARV 
antiretroviral 
bNAb 
broadly neutralizing antibody 
CAB 
cabotegravir 
CAB LA 
long-acting cabotegravir 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendment 
eCRF 
electronic case report form 
IRC  
infusion report card 
IM 
intramuscular 
ISR 
injection site reaction 
LA 
long-acting 
NNRTI 
nonnucleoside reverse transcriptase inhibitor 
NRTI 
nucleos(t)ide reverse transcriptase inhibitor 
PK 
pharmacokinetics 
PR/RT 
protease/reverse transcriptase 
PT/INR 
prothrombin time/international normalized ratio 
RPV 
rilpivirine 
SAEs 
serious adverse events 
SDMC 
Statistical and Data Management Center 
SMC 
Study Monitoring Committee 
SOC 
standard of care 
SOE 
schedule of evaluations 
Study drugs 
oral CAB for Step 1 
 
CAB LA and VRC-HIVMAB075-00-AB (VRC07- 523LS) for Step 2 
Study treatment 
Step 1: oral CAB (oral cabotegravir) and two NRTIs 
Step 2: CAB LA (injectable CAB) and VRC-HIVMAB075-00-AB (VRC07- 
523LS) via infusions 
Step 3: SOC ART regimen 
Viral rebound 
confirmed HIV-1 RNA ≥200 copies/mL 
Virologic failure 
two consecutive HIV-1 RNAs ≥200 copies/mL or last ≥200 copies/mL 
VRC 
Vaccine Research Center 
VRC07-523LS 
VRC-HIVMAB075-00-AB, a human monoclonal antibody 


 
13 
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FINAL VERSION 4.0 
 
 
11Mar2022 
 
SCHEMA 
 
A5357 
 
A Study of Long-Acting Cabotegravir Plus VRC-HIVMAB075-00-AB (VRC07-523LS) to Maintain 
Viral Suppression in Adults Living with HIV-1 
 
DESIGN 
Phase II, single arm, open-label switch study to assess the safety, 
tolerability, pharmacokinetics, and antiviral activity of long-acting 
cabotegravir (CAB LA) plus the broadly neutralizing monoclonal antibody, 
VRC-HIVMAB075-00-AB (VRC07-523LS) in adults living with HIV-1 with 
suppressed plasma viremia. 
 
At Step 1 entry, all participants will discontinue their current ART regimen 
except for nucleoside reverse transcriptase inhibitors (NRTIs), and initiate 
oral CAB. Viral load monitoring will occur at entry and week 4 (and also at 
week 5 if HIV-1 RNA is 50-199 copies/mL at week 4). 
 
During Step 1, participants tolerating oral CAB plus their current two 
NRTIs with HIV-1 RNA <50 copies/mL at week 4, or HIV-1 RNA of 50-199 
copies/mL at week 4 followed by HIV-1 RNA <50 copies/mL at week 5, 
will register to Step 2 and receive CAB LA every 4 weeks through week 
R2+44 plus VRC07-523LS every 8 weeks through week R2+40. 
Participants in Step 1 who are not eligible for Step 2 entry will be switched 
to a standard of care (SOC) regimen and followed on study every 2 
weeks for a total of 4 weeks and then be taken off study. 
 
Viral load monitoring in Step 2 will occur every 2 weeks until week R2+8 
and then every 4 weeks until week R2+48. All participants who enter Step 
2 will complete the week R2+48 visit; this visit will be used to confirm 
virologic rebound in those with HIV-1 RNA ≥50 copies/mL at week R2+44. 
 
For participants who have a confirmed HIV-1 RNA ≥200 copies/mL during 
Step 2, or confirmed HIV-1 RNA ≥50 copies/mL at week R2+44 and ≥200 
copies/mL at week R2+48, genotypic testing will be performed for 
protease/reverse transcriptase (PR/RT) and integrase resistance. In 
addition, samples from the failure confirmation visit and pre-ART or entry 
(if available) will be tested for viral clonality, integrase resistance, and 
VRC07-523LS neutralization resistance. 
 
All participants who received any dose of CAB LA or VRC07-523LS in 
Step 2 will register to Step 3 (the 48-week follow up on SOC regimen) at 
the final study visit in Step 2 or at premature treatment discontinuation. 
 
DURATION 
Up to 101 weeks (approximately 5 weeks in Step 1, then 48 weeks in 
Step 2, followed by 48 weeks in Step 3) 
 


 
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SCHEMA (Cont'd)  
11Mar2022 
 
SAMPLE SIZE 
74 participants 
 
POPULATION 
Individuals living with HIV-1 ≥18 years of age who have current CD4+ T-
cell count ≥350 cells/mm3 and have maintained viral suppression (<50 
copies/mL) on a conventional ART regimen (i.e., a boosted protease 
inhibitor, an NNRTI, or an integrase inhibitor, plus two NRTIs) for at least 
2 years prior to entry and have been clinically stable on their current 
three-drug regimen for at least 8 weeks prior to study entry with no history 
of a switch due to virologic failure. Eligibility requires documentation of 
susceptibility to VRC07-523LS. 
 
REGIMEN  
In Step 1, all participants will receive oral CAB 30 mg daily plus their 
current two NRTIs. 
 
NOTE: For participants currently on Truvada (emtricitabine/tenofovir 
disoproxil fumarate), or Descovy (emtricitabine/tenofovir alafenamide), or 
Epzicom (abacavir/lamivudine) without continued access, reimbursement 
for these drugs will be provided in Step 1. 
 
At entry into Step 2, participants will stop their oral CAB and NRTIs and 
will receive VRC07-523LS infusion (40 mg/kg) plus CAB LA intramuscular 
(IM) injection (600 mg). Post entry in Step 2, participants will receive CAB 
LA IM injection (400 mg) every 4 weeks through week R2+44 plus 
VRC07-523LS infusion (40 mg/kg) every 8 weeks through week R2+40. 
 
At the last visit in Step 2 (week R2+48) or at premature study 
discontinuation, all participants who received any CAB LA or VRC07-
523LS will enter Step 3 and switch to SOC ART for approximately 48 
weeks. 
 


 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
The combination of long-acting cabotegravir (CAB LA) and VRC-HIVMAB075-00-AB 
(VRC07-523LS) is safe and will prevent viral rebound (confirmed HIV-1 RNA ≥200 
copies/mL) in individuals who have achieved suppression with conventional antiretroviral 
therapy (ART). 
 
1.2 
Primary Objectives 
 
1.2.1 To evaluate the safety and tolerability of the combination of parenteral VRC07-
523LS plus CAB LA in adults living with HIV-1 with well-controlled viral replication 
 
1.2.2 To evaluate the virologic efficacy of the combination of parenteral VRC07-523LS 
plus CAB LA to prevent viral rebound in adults living with HIV-1 with well-
controlled viral replication 
 
1.3 
Secondary Objectives 
 
1.3.1 To determine the pharmacokinetic (PK) parameters of the combination of 
VRC07-523LS and CAB LA and their associations with viral rebound in adults 
living with HIV-1 
 
1.3.2 To evaluate evidence of anti-idiotype antibodies against VRC07-523LS in 
samples collected from representative time points throughout the study 
 
1.3.3 To evaluate the safety and tolerability of oral CAB 
 
1.4 
Exploratory Objective 
 
1.4.1 To compare genotypic and phenotypic characteristics (viral clonality, 
neutralization resistance, and integrase resistance) from baseline samples (entry 
or pre-ART) and failure HIV-1 isolates in individuals who experience viral 
rebound while receiving the combination of VRC07-523LS and CAB LA. 
 
1.4.2 To evaluate the range of Monogram PhenoSense assay results and its 
correlation with available demographic and clinical variables for all 
participants screened. 
 


 
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2.0 
INTRODUCTION 
 
2.1 
Background 
 
Long-Acting Cabotegravir 
Cabotegravir (CAB), formerly GSK1265744, a structural analogue of dolutegravir (DTG), 
is an integrase strand transfer inhibitor in development in both oral and long-acting 
formulations. CAB LA is a nanosuspension with optimized solubility and particle size that 
allows infrequent dosing. Currently in Phase III clinical trials, it was initially selected for 
development based on its potential for a high genetic barrier to resistance and a PK 
profile that allows low-dose, once-daily, oral dosing or monthly to bi-monthly parenteral 
dosing using a nanosuspension formulation. CAB LA PK has been evaluated in Phase 1 
studies following repeat administration in individuals without HIV. Following a loading 
dose of 800 mg intramuscular (IM) and three monthly (every 28 days) maintenance 
doses, the third monthly 200 mg subcutaneous (SC), 200 mg IM and 400 mg IM 
injections achieved geometric mean plasma Ctau of 1.61g/mL, 1.72 g/mL, and 3.22 
g/mL—9.7-, 10-, and 19-fold above the PA-IC90 (0.166 g/mL), respectively [Spreen 
2014a; Spreen 2014b; ViiV Healthcare 2014]. Following two quarterly 800 mg IM doses, 
geometric mean plasma GSK1265744 Ctau was 1.11 g/mL, 6.7-fold above the PA-IC90. 
 
In the LATTE study for HIV treatment, CAB plus two nucleos(t)ide reverse transcriptase 
inhibitors (NRTIs) once-daily had potent antiviral activity, and the combination of CAB 
plus rilpivirine once-daily provided antiviral activity similar to efavirenz plus dual NRTIs 
through week 96 [Margolis 2015]. The 30 mg once daily dose of oral CAB was selected 
for further development. The safety and efficacy of the combination of CAB LA and LA 
rilpivirine every 4 or 8 weeks has been demonstrated in the LATTE-2 study [Margolis 
2016]. CAB plus rilpivirine (RPV) LA dosing every 4 weeks was selected for the ATLAS 
and FLAIR Phase III trials [Orkin 2019; Swindells 2019], while both the 4- and 8-week 
doses are being investigated in ATLAS-2M. 
 
The absorption rate of CAB LA is variable with slower absorption reported in females 
(35.2% relative to males) and with increasing body mass index [Ford 2014], perhaps due 
to differences in body fat, lean muscle, and physical activity. While there is a significant 
difference in absorption rate for males and females, steady state trough concentrations 
in males and females are similar for similar sized individuals [Landovitz 2017]. CAB has 
a low potential for drug-drug interactions; CAB is primarily metabolized by uridine 
diphosphate glucuronosyltransferase (UGT) 1A1 with a minor contribution from UGT1A9 
[Reese 2014], and is mainly excreted in feces as unchanged drug [Culp 2014]. 
 
Residual concentrations of CAB will remain in the systemic circulation of participants for 
prolonged periods, more than 1 year in some participants [ÉCLAIR Study 2014] despite 
stopping treatment (e.g., for tolerability issues or treatment failure). Participants 
discontinuing CAB LA regimen may be at risk for developing HIV-1 resistance to CAB 
many weeks after discontinuing injectable therapy. In order to mitigate this risk, 
alternative ART regimens will be prescribed within 4 weeks after participants stop CAB 
LA. This is anticipated to result in maintenance of suppression or rapid resuppression of 
HIV-1 RNA thus minimizing the risk of emergent resistance. The participants in this 


 
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study who discontinue CAB LA for any reason will be monitored for approximately 48 
weeks from the time of the last CAB LA injection. 
 
Suicidality Monitoring 
While CAB remains an investigational product, there has not been a direct association 
between CAB and suicidality, or a product-associated risk, identified to date. The 
inclusion of suicidality screening in ongoing CAB studies is primarily intended to create a 
comprehensive data set on suicidality at the time of product submission, in order to 
inform regulatory agencies in their review of products being developed for populations at 
elevated risk of suicidality, including people living with HIV (PLWHIV). This approach is 
highlighted by the absence of prospective suicidality evaluations in studies of CAB for 
PrEP, among individuals without HIV. In addition to the value of prospective suicidality 
monitoring to the overall programmatic analysis of CAB, there is a secondary benefit of 
prospective suicidality monitoring to individual participants with HIV in clinical trials to 
ensure that depression and suicidality is detected when present. It is noted, however, 
that there may be several approaches to this individual participant management, which 
can also be assumed to be part of the routine medical management. The team is aware 
that suicidality is being assessed in A5359 (NCT03635788), but in part, this is a larger 
study, in a different population of individuals who have not been effectively suppressed 
or routinely followed in clinical care. For A5357 specifically, this study is not intended to 
be part of the CAB submission package and includes participants who are more 
effectively tied into care, and have remained suppressed, per study inclusion criteria. 
With these facts noted, the team proposes use of standard and routine medical care 
already being offered to individuals in HIV care as the primary means for monitoring 
suicidality and depression in A5357. As with all studies, adverse events (AEs) of 
depression and suicidality that emerge while on study will be captured in the study 
record. 
 
VRC-HIVMAB075-00-AB (VRC07-523LS) 
The Vaccine Research Center at the National Institutes of Health (National Institute of 
Allergy and Infectious Diseases) developed VRC01LS and VRC07-523LS, highly potent 
and broadly neutralizing HIV-1 human monoclonal antibodies (MAbs) targeted against the 
HIV-1 CD4+ binding site [Rudicell 2014]. The predecessor of VRC01LS and VRC07-
523LS, VRC01, is in clinical trials under IND 113611 for prevention indication, and under 
IND 126001, IND 126664, and IND 133017 for therapeutic indication. VRC01 was 
originally discovered in an individual who had lived with HIV-1 for more than 15 years and 
whose immune system controlled the virus without anti-retroviral therapy [Wu 2012]. The 
VRC01 sequence was modified by site-directed mutagenesis to increase its binding 
affinity for the neonatal Fc receptor (FcRn) and the resulting antibody was designated 
VRC01LS. The LS designation specifies methionine to leucine (L) and asparagine to 
serine (S) (M428L/N434S, referred to as LS) changes within the C- terminus of the heavy 
chain constant region far outside of the antigen-binding site [Zalevsky 2010]. Other than 
the two amino acid difference, VRC01LS is identical to VRC01. VRC01LS has an 
extended half-life in both serum and mucosal tissue compared to VRC01, persists at 
higher concentrations in mucosal tissues, and has demonstrated improved protection 
against primate simian-human immunodeficiency virus (SHIV) infection [Ko 2014]. 
VRC01LS is currently in clinical trials for PK and safety evaluations in adults without HIV 


 
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under IND 125494. The VRC07 (wild-type) heavy chain was identified by 454 deep 
sequencing based on its similarity to the VRC01 MAb and paired with the VRC01 (wild-
type) light chain. The mutations that together define the 523 designations are a glycine to 
histidine mutation at residue 54 of the heavy chain, a deletion of the first two amino acids, 
glutamate and isoleucine, from the light chain, and a valine to serine mutation at the third 
amino acid residue of the light chain. Like VRC01LS, the LS mutation of VRC07-523LS 
was introduced by site-directed mutagenesis to increase the binding affinity for the 
neonatal FcRn, resulting in increased recirculation of functional IgG [Ko 2014; Zalevsky 
2010], thus increasing plasma half-life. 
 
VRC07-523LS Safety Data 
As of January 15, 2018, the VRC 605 study is fully enrolled. Twenty-five (25) of 26 
participants received at least one dose of VRC07-523LS (12 SC and 25 IV 
administrations). One participant withdrew from the study prior to receiving the study 
product. There have been no serious adverse events (SAEs) and no study safety pauses 
for AEs. Overall, 15 of 25 participants who received the product (60%) have had at least 
1 AE with the maximum severity being Grade 1 for 7 participants and Grade 2 for 6 
participants, Grade 3 for 1 participant and Grade 4 for 1 participant. The Grade 3 AE was 
for an elevated creatinine 56 days after the last product administration. This was most 
likely related to dehydration following exercise. The creatinine value was determined to 
be Grade 3, based on the DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table) parameter of an increase of 1.5 to 2 times 
the baseline value, which was still well within the institutional normal range. The Grade 4 
AE was for elevated liver enzymes likely related to starting a concomitant medication, 
fluoxetine, known to cause hepatoxicity, and not related to VRC07-523LS. VRC07-523LS 
administrations were discontinued for this participant due to the concomitant illness. 
While the participant was being followed for safety, liver enzymes tests fluctuated again 
after starting citalopram, which reinforced the assumption that the event was most likely 
caused by an underlying sensitivity to selective serotonin reuptake inhibitor (SSRI) 
medications. This Grade 4 laboratory abnormality was not considered life-threatening as 
it was not clinically significant as there was no hospitalization, jaundice, coagulopathy, 
bleeding, or ascites. Six mild or moderate AEs were assessed as related to study product 
including mild dizziness, four occasions of infusion reactions (one mild and three 
moderate, reported for two participants), and mild abdominal pain. All AEs assessed as 
related to the study product have resolved without residual effects. 
 
Two participants developed infusion reactions shortly after IV product administration. 
Symptoms were typical of infusion reactions observed with other MAbs [Patel 2017]. No 
atypical symptoms or delayed symptoms were seen. Specifically, one participant enrolled 
in the 40 mg/kg IV group experienced a moderate infusion reaction with chills, rigors, 
fever, myalgia, and headache beginning 15 minutes after completion of the infusion. The 
participant was treated with acetaminophen and ibuprofen. All symptoms resolved within 
12 hours. Another participant in the 20 mg/kg IV group experienced three separate 
infusion reactions (n=2 moderate, n=1 mild) after each product infusion. The participant 
experienced nausea, chills, rigors, malaise, tachycardia, headache, myalgia, and 
arthralgia. Symptoms began 15 minutes to 1 hour after completion of each product 
administration and completely resolved within 12 hours. The participant was treated with 


 
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acetaminophen and ibuprofen. Overall, product administrations have been generally well 
tolerated with no unexpected reactions. 
 
For solicited local reactions in the week after VRC07-523LS administrations, one of 17 
participants (5.9%) who received the product by IV administration reported mild bruising 
at the administration site, and 5 of 8 participants (62.5%) who received the product SC 
reported mild pain/tenderness at the injection site [Investigator’s Brochure, Version 4.0, 
dated February 26, 2018; VRC07-523LS VRC-HIVMAB075-00-AB CONFIDENTIAL 45]. 
 
For solicited systemic AEs reported 3 days after product administration, 4 of 17 
participants (25%) receiving VRC07-523LS IV reported mild or moderate systemic 
reactogenicity symptoms. The reported symptoms were malaise (n=2 mild, n=1 
moderate), myalgia (n=2 mild, n=1 moderate), mild headache (n=2), and moderate chills 
(n=2). Five (5) of 8 participants (62.5%) receiving VRC07-523LS SC reported mild 
systemic reactogenicity symptoms: malaise (n=3), myalgia (n=2), headache (n=3), chills 
(n=1), nausea (n=1), and joint pain (n=2). Refer to the IB for more details on the VRC07-
523LS safety data. 
 
Antiviral Effect of VRC07-523LS 
Preliminary viral load data obtained from ACTG study A5378 (NCT02840474) in nine 
viremic adults living with HIV-1 demonstrated that VRC07-523LS has an in vivo 
virological effect on viral load when administered as a single 40 mg/kg IV dose [Chen 
2019]. These participants were not on ARVs when enrolled into the study and did not 
start ARVs during the first 14 days of data collection. Eight of the 9 participants had a 
≥1.2 log10 copies/mL maximum decrease in viral load. Per the Department of Health and 
Human Services (DHHS) guidelines, a ≥0.5 log10 copies/mL decrease in viral load is 
considered to be a positive response to ARV [Panel on Antiretroviral Guidelines for 
Adults and Adolescents 2018]. Evaluation of the VRC07-523LS antiviral effect continues; 
data analysis will be conducted to evaluate a timeline, magnitude of decrease in viral 
load data, and utility of drug sensitivity testing using the monogram assay in predicting 
virological responses. 
 
PhenoSense Neutralizing Antibody Assay 
VRC07-523LS neutralizing antibody susceptibility will be determined using the 
PhenoSense neutralizing antibody assay platform pioneered by Monogram BioSciences, 
Inc. This assay generates HIV pseudovirions that express envelope proteins that are 
representative of the quasispecies of either the cell-associated HIV DNA or circulating 
plasma HIV RNA. This will enable the interrogation of VRC07-523LS neutralizing 
antibody susceptibility of PBMC-derived virus from aviremic individuals. Procedures are 
derived from a well-established assay that has been utilized extensively to evaluate 
autologous and vaccine elicited neutralizing antibody sensitivity of virions pseudotyped 
with a population of envelope proteins that are representative of the HIV RNA 
quasispecies in circulating plasma virus from viremic individuals [Richman 2003]. 
 
These methods were used in ACTG NWCS 413 to determine neutralization sensitivity of 
plasma viruses from treatment naïve individuals (N=61) and PBMC of the same 
individuals after 1 and 3 years of suppression against a number of broadly neutralizing 


 
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monoclonal antibodies (bNAbs) in clinical development. Results showed that VRC07-
523LS was potent against many participants’ viruses.  For PBMC samples from 1 year of 
ART, median IC50 was 0.135 µg/mL (Q1, Q3 of 0.078, 0.247) and median IC80 was 
0.514 µg/mL (Q1, Q3 of 0.245, 0.984).  The correlate of clinical activity in this treatment 
scenario is not known. Eighty-five percent (52/61) of the NWC participant virus swarms 
fell under the threshold of IC80 <1 µg/mL, and this value is more than 50- to 100-fold over 
the plasma levels of VRC07-523LS achievable by the proposed dosing strategy. Thus, an 
IC80 screening cut-off of 1 µg/mL for PBMC-derived virus has been selected to balance 
the desire for potency of the bNAb and reasonable accrual and enrollment of this study. 
Of note, Monogram’s reporting process is based on IC50 levels. Accordingly, an IC50 of 
0.25 µg/mL, which correlates with an IC80 of 1 µg/mL, will be used for screening. In 
addition, we have added a second enrollment condition of a maximum percent inhibition 
>98% (meaning that the virus was neutralized >98% at 50 µg/ml concentrations of 
VRC07-523LS). This additional criterion will likely exclude very few additional 
participants, so will pose minimal logistical challenges, but may help exclude a few 
individuals who may not be completely sensitive to the bNAb. 
 
2.2 
Rationale 
 
Two-Drug Maintenance ART 
Conventional antiretroviral (ARV) regimens include the combination of three active oral 
ARV drugs. However, recent and ongoing studies have demonstrated the safety and 
effectiveness of several two ARV drug combinations. 
 
The GARDEL study demonstrated that dual therapy with lopinavir/ritonavir plus 
lamivudine was non-inferior to triple therapy after 48 weeks of treatment, regardless of 
baseline HIV viral load. The dual therapy regimen showed fewer discontinuations due to 
safety and tolerability, and virologic failure did not result in protease inhibitor resistance 
development, preserving a wide range of drugs for second-line ARV therapy [Cahn 
2013]. 
 
Two Phase 3 trials (SWORD) enrolled 1,024 participants with viral suppression for at 
least 1 year and no history of virologic failure. Participants were randomized to stay on 
their combination ART regimen or to switch to a regimen of once-daily DTG plus RPV. 
Virologic suppression was maintained in 95% to 96% of the participants in both arms at 
48 weeks. A fixed-dose combination of these products has recently been approved 
[Llibre 2017]. 
 
In the LATTE study, the combination of oral CAB plus oral rilpivirine once daily provided 
antiviral activity similar to efavirenz plus dual NRTIs through week 96 and led to fewer 
side effects [Margolis 2015]. Findings from the phase 2b LATTE-2 trial demonstrated 
comparable viral suppression rates (plasma HIV-1 RNA <50 copies/mL) at 48 weeks 
between CAB LA plus long-acting rilpivirine (RPV LA) dosed every 8 weeks (92%) or 
every 4 weeks (91%) versus three drug oral regimen of investigational CAB plus NRTIs 
(89%). The combination of these long-acting injectable drugs was safe and well-
tolerated [Margolis 2016b]. Efficacy of this combination has been demonstrated through 
week 96 in LATTE 2 [Margolis 2017]. The combination of CAB LA and RPV LA has also 


 
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been shown to maintain viral suppression through week 48 in treatment-naïve and 
virologically suppressed individuals in the FLAIR and ATLAS studies, respectively [Orkin 
2019; Swindells 2019; ATLAS Study (ViiV Healthcare) 2018; FLAIR Study (ViiV 
Healthcare 2018)]. 
 
In addition, the ongoing GEMINI studies demonstrated the efficacy of  the combination of 
another two ARVs, DTG and lamivudine at week 48, in treatment naïve participants 
[Cahn 2019], and the results of the same regimen in suppressed participants are 
awaited [TANGO]. 
 
Compared with three-drug ART, regimens containing two drugs have the potential to 
decrease medication burden, cost, and toxicity. 
 
CAB LA Plus VRC07-523LS 
Successful engineering of a new generation of bNAbs has created an opportunity for 
novel exploration of bNAb plus ARV drug(s) as well as bNAb(s) plus bNAb(s) 
combinations for HIV control. In addition to direct antiviral effects, it is possible that some 
bNAbs could have an effect on the size of the HIV reservoir through antibody-dependent 
cell-mediated viral inhibition or antibody dependent cell-mediated cytotoxicity 
(ADCVI/ADCC), which will be enhanced by using this combination approach. Here we 
propose to investigate the combination of CAB LA and VRC07-523LS. 
 
The current design also allows for a careful PK characterization of the levels of both 
compounds required to prevent the re-emergence of viremia. Sequencing of rebound 
virus will provide insights into variants resistant to the intervention. In addition, in-vitro 
testing of viruses collected pre-ART (or at study entry) and after virologic failure will yield 
important information about possible viral factors associated with eventual treatment 
failure, particularly viral resistance to neutralization by VRC07-523LS. 
 
VRC07-523LS Dose of 40 mg/kg IV Q8 weeks 
The pharmacokinetics of VRC07-523LS was modelled using data obtained following its 
administration to adults without HIV in a Phase 1 dose-escalating trial (NCT03015181 
[Gaudinski 2018]). The modelling reflected the observed data (Figure 2.2-1). 
 
 


 
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Figure 2.2-1: VRC07-523LS Serum Concentrations following Administration of 5 mg/kg 
SC and 40 mg/kg IV Overlaid with Median Model Predictions (shading represents the 
90% prediction interval). 
 
Predicted median concentrations following a 40 mg/kg IV infusion were 157 [94 –231] 
µg/mL and 98 [44 - 163] µg/mL at 8 and 12 days respectively. A review of prior bNAb 
data indicated that an effective serum trough level would need to be equivalent to or 
exceed a clinical isolate IC90 value (9 x IC50) and would have a log-normal standard 
deviation of 1.7. 
 
The analysis of prior bNAb clinical effectiveness data, pseudovirus neutralization and 
clinical isolate neutralization suggested that the effective trough would range from the 
clinical isolate IC90 to >5x IC90 (equivalent to 20x and 100x the pseudovirus 
neutralization IC50) and that the variance in the in vitro data needed to be factored into 
the trough. 
 
Trial simulations were performed using: 
• 
The PK 
• 
The PK variance 
• 
Potency (either isolate IC90 or pseudovirus IC50), and 
• 
The variance in potency 
 
to determine the probability that a trial would have >90% of participants with VRC07-
523LS concentrations above the nominal target trough concentration (a trial Probability 
of Success (POS)). Using this approach, the target troughs approximated the 90th 
percentile of the clinical isolate IC90 (or pseudovirus IC50) incorporating any 
multiplicative factor. 
 
A 40 mg/kg IV infusion assessed against the clinical isolate IC90 was predicted to have 
a PoS of 96% [84-100] for a 12-week interval. This predicted PoS declined with reduced 
dose (30 mg/kg Q12W = 93% [77-99]) and increased with a shorter interval (40 and 30 
mg/kg ~99% [90-100]). The PoS was also evaluated against a more stringent threshold 
of 5x IC90 (reflective of a fold multiplication observed following modelling of prior clinical 
efficacy data). The 40 mg/kg IV infusion assessed against the 5x clinical isolate IC90 
was predicted to have a PoS of 68% [47-86] for a 12-week interval. This predicted PoS 
for 40 mg/kg IV increased with a shorter Q8W interval to 91% [72-98]). 
 


 
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Figure 2.2-2: The VRC07-523LS Clinical Isolate Potencies (Thresholds) and 40 mg/kg IV 
Trough Concentrations following Q8W and Q12W Administration – Used within the 
Model to Determine the Probability of a Trial Having >90% of Participants with VRC07-
523LS Concentrations above the Nominal Target Trough Concentration. 
 
A dose of 40 mg/kg Q8W was chosen based on the modelling. Whilst a Q12W interval 
may be sufficient, a Q8W regime provides leeway for any increase in threshold whilst we 
rely on modelling and do not have any clinical data. This dose and interval provided the 
most robust treatment over the thresholds evaluated. 
 
Non-inclusion of Control Arms 
In lieu of a triple ART SOC control arm, we determined the virologic failure rate on 
conventional triple ART rate in a population similar to the participants who will enroll in 
A5357. Specifically, among 2059 participants who suppressed to <50 copies/mL for 96 
weeks in two completed ACTG naïve trials (A5257, NCT00811954 and A5202, 
NCT00118898) and subsequently remained on conventional ART, the cumulative 


 
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probability of virologic failure (two consecutive HIV-1 RNAs ≥200 copies/mL or last ≥200 
copies/mL) using Kaplan-Meier methods was 1%. By week 192 (when participants had a 
median of 10 HIV-1 RNA measurements), this cumulative probability of virologic failure 
was 5%.  These estimates were used in the study’s statistical considerations. 
 
A CAB LA monotherapy arm was not included because there is already evidence that 
integrase inhibitor monotherapy is not non-inferior to SOC [Hocqueloux 2019]. The 
A5357 team agreed with the ACTG’s Scientific Agenda Steering Committee’s position 
that a CAB monotherapy control arm should not be included in A5357, recognizing that 
this design limits our ability to determine the relative contribution of CAB LA or VRC07-
523LS to the study results. 
 
Rationale for Virologic Failure Definition 
Typically the ACTG defines virologic failure as a confirmed HIV-1 RNA ≥200 copies/mL. 
This is because previous ACTG studies have shown there is some variability at the 
lower limit of quantification for the standard virologic assays [Lalama 2015], and that 
confirmed values of low level viremia are less likely to be associated with future virologic 
failure [Ribaudo 2009]. Therefore, the primary efficacy outcome of this study will be 
confirmed HIV-1 RNA ≥200 copies/mL, and a secondary outcome measure will be 
confirmed HIV-1 RNA ≥50 copies/mL. Additionally, if the primary outcome was changed 
to a confirmed HIV-1 RNA ≥50 copies/mL, the historical failure probability used in the 
sample size calculation would be almost doubled, and to obtain a confidence interval 
with the same upper bound as calculated for this study, would inflate the sample size to 
a larger degree and render the study infeasible. 
 
Rationale for CAB LA Dosing Interval of Q4 Weeks Versus Q8 Weeks 
The CAB Q4W dosing regimen achieves the highest exposure of dosing regimens 
studied in Phase 2 and 3 trials (Q4W or Q8W), and clinical efficacy of CAB LA Q4W as 
part of a two-drug regimen has been confirmed in Phase 3 studies, whereas Phase 3 
results for CAB LA Q8W as part of a two-drug regimen are not yet available. 
 
1) Efficacy: Study 200056 (LATTE-2) is an ongoing, Phase 2b dose-ranging study 
evaluating the long-term efficacy and safety of a two-drug, two-class combination of 
CAB LA plus RPV LA given Q4W or Q8W, as compared to an oral three-drug regimen, 
for maintenance of virologic suppression in treatment-naive adults living with HIV. Week 
96 results (Table 2.2-1 below) were supportive of further evaluation of both with the 
Q4W regimen in the Phase 3 ATLAS and FLAIR studies as well as the Q8W regimen in 
the Phase 3 ATLAS-2M study. Participants completing the 96-week Injection Phase 
remained on their randomized LA regimen (either Q4W or Q8W) during the Extension 
Phase (post Week 96), and those participants randomized to the oral comparator arm 
were allowed transition to either LA regimen at Week 96. At Week 160, high proportions 
of participants remained virally suppressed for both CAB LA plus RPV LA Q4W and 
Q8W [Margolis 2018]. 
 


 
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Table 2.2-1: Summary of Study Outcomes (<50 copies/mL) at Weeks 48 and 96 — 
Snapshot (MSDF) Analysis (ITT-ME Population) in LATTE-2 
Endpoint 
(Week) 
Outcome 
Q8W IM 
N=115 n 
(%) 
Q4W IM 
N=115 n 
(%) 
CAB 30 mg 
plus 
ABC/3TC 
N=56 n (%) 
Subtotal IM 
N=230 n 
(%) 
W48 
Virologic Success, n 
(%) 
106 (92)  
105 (91) 
50 (89) 
211 (92) 
Virologic Failure, n (%) 
8 (7)  
1 (<1) 
1 (2) 
9 (4) 
W96 
Virologic Success, n 
(%) 
108 (94) 
100 (87) 
47 (84) 
208 (90) 
Virologic Failure, n (%) 
5 (4) 
0 
1 (2) 
5 (2) 
  
Maintenance therapy with Q4W dosing of CAB LA plus RPV LA was recently reported to 
be non-inferior to standard three-drug oral therapy at Week 48, using the FDA snapshot 
algorithm [Orkin 2019; Swindells 2019]. Efficacy results from the Q8W dosing used in 
ATLAS-2M are expected at a later date. 
 
2) PK: The Q4W dosing of CAB that we have selected is also supported by PK data. 
Figure 2.2-3 shows the concentration-time data for Q4W and Q8W in LATTE-2 
demonstrating higher C with Q4W dosing. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2.2-3: Observed Mean (SD) Concentration-Time Data following CAB LA Q8W 
and Q4W and C following 30 mg PO QD through Week 48 (200056, LATTE-2) 
Both pre-dose and 2 hour post-injection concentrations are shown at Time Zero, Week 
32, and Week 48. 
 


 
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Of note, the loading dose used in LATTE-2 is slightly different from that used in the CAB 
Phase 3 studies and what is proposed in A5357. The predicted CAB profile for the 
proposed Q4W regimen based on population PK modelling is shown in Figure 2.2-4, 
demonstrating CAB levels well above 4X PA IC90 throughout the dosing period. 
 
Figure 2.2-4: Simulated* Median (90% Prediction Interval [PI]) CAB Plasma Concentrations 
versus Time for the CAB LA Q4W Regimen (600 mg IM Day 1, then 400 mg IM Q4W 
thereafter) 
 
* NOTE: Current simulations based on interim plasma concentration dataset. 
^Study schedule of activities includes a 4-week oral lead in. Therefore, Day 1 
= day of first injections (Week 4b study visit); Week 4 = second injections 
(Week 8 study visit). 
Medium dashed line at 1.35 µg/mL corresponds to the geometric mean Cpa- 
concentration following oral CAB 10 mg once daily (LATTE) and is equivalent 
to 8x PA-IC90. 
Dotted line at 0.664 µg/mL corresponds to 4x PA-IC90. 
 


 
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Rationale for Step 3 SOC Follow-up 
All participants who receive any dose of CAB LA or VRC07-523LS or prematurely 
discontinue study treatment in Step 2 will proceed to Step 3, which is the SOC follow-up, 
beginning at the final study visit in Step 2 or at premature treatment discontinuation. We 
have included a prolonged follow-up phase because data have shown that CAB LA has 
a long pharmacologic tail after IM administration (drug can be detected up to 52 weeks 
after administration in a small proportion of study participants). Current and planned 
trials of CAB LA include prolonged follow-up phases after last administration of CAB LA 
in order to generate critical long-term safety data. Specifically, LATTE-2, HPTN 077 and 
HPTN 083 all include follow-up of 48 to 52 weeks after the final dose of CAB LA 
[Margolis 2016b; NIAID 2014a; NIAID 2014b]. In alignment with these clinical trials, 
A5357 will continue safety monitoring and evaluate the pharmacokinetics of CAB LA for 
approximately 48 weeks after the last injection. 
 
Risk of CAB Monotherapy During A5357 
There is the risk that some of the participants in this study could receive CAB 
monotherapy given that the VRC07-523LS susceptibility testing has not yet been 
validated in clinical specimens. The team has decided to address this issue in several 
ways: 
1. Study candidates with the lowest quartile of susceptibilities in the new Monogram 
assay to test the susceptibility of the integrated provirus to VRC07-523LS will be 
excluded. 
2. Participants will be monitored monthly for virologic failure, and if there is any 
detection of viremia ≥200 copies/mL, it will be confirmed and participants will be 
switched to SOC triple ART. 
3. Study candidates with a history of virologic failure while taking integrase inhibitors 
will be excluded. 
 
CAB has never been given as monotherapy in individuals living with HIV, and it is not the 
intention of the team to investigate or support this. However, the limited experience with 
DTG monotherapy suggests that it takes time to develop resistance to that compound in 
the presence of virologic failure [Greig 2015]. DTG, and similarly CAB, has a high affinity 
to its target, resulting in strong and sustained binding [Brenner 2017]. As a 
consequence, in vitro selection of mutants resistant to DTG is difficult and rare in clinical 
practice. 
 
We agree with the current DHHS guidelines against DTG monotherapy due to risk of 
resistance, and opine that the likelihood of significant resistance emergence is low in 
A5357 given rigorous on-study monitoring. Indeed some European groups have 
presented cohort data that helps contextualize the risks associated with potential CAB 
monotherapy. A retrospective hospital database described 33 virally suppressed 
participants some of them with significant prior ART experience, in whom the treating 
physician had switched to 50 mg of DTG once daily as a single agent. Only one patient, 
with prior raltegravir experience and suboptimal adherence developed low-level virologic 
failure through weeks 4–24 (79 copies/mL; confirmed as 101 copies/mL). HIV RNA 
genotypic resistance tests in confirmation samples at 4 and 24 weeks detected no 
integrase mutations. HIV DNA genotypic resistance tests detected the integrase 


 
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mutation 118R in 7% of the integrated DNA in PBMCs at 24 weeks [Rojas 2015]. In a 
single-hospital observational cohort of 28 participants who were maintained on DTG 
monotherapy, 3 experienced viral rebound with detection of integrase resistance 
mutations by week 24 [Katlama 2015]. Similar to the study by Rojas et al., all the 
participants with virologic rebound had previous exposure to an integrase inhibitor. A 
retrospective cohort of DTG monotherapy maintenance did show emergence of INSTI 
resistance mutations in 9 of 11 virologic failures [Blanco 2017; Rojas 2016]. 
 
In the only randomized trial of DTG monotherapy, monotherapy was non-inferior to 
combination ART at 24 weeks, suggesting that virologic failure takes time to accrue on 
monotherapy. However, virologic failure continued to occur thereafter and led to DTG 
resistance after the participants were viremic for 12 weeks [Wijting 2017]. 
 
Overall, while available limited data suggest that it is unlikely that participants will 
develop resistance to CAB or other integrase inhibitors as a consequence of their 
participation in the study, the monthly viral load monitoring provides additional 
safeguards against emergence of clinically significant integrase resistance during the 
study. 
 
Pregnancy 
In one study evaluating CAB in pregnant rats and their newborn pups, there was a 
higher rate of pups that died at the time of delivery or shortly after delivery in the rats that 
received 1000 milligrams per kilogram dose of CAB compared to pregnant rats who did 
not receive CAB. This finding did not occur in pregnant rats who received two lower 
doses (0.5 and 5 milligrams per kilogram) of CAB. The significance of this finding on 
human pregnancies is not known. Birth defects have not been observed in animal 
studies with CAB, to date (refer to the IB for CAB). 
 
The A5357 team is also aware of the recent preliminary results from the TSEPAMO 
study in Botswana that reported neural tube defects in 4 of 426 (0.9%) babies born to 
individuals who were taking DTG at the time they became pregnant compared to 0.1% 
occurrence in babies born to individuals who were not taking DTG [FDA 2018]. In an 
updated analysis of the TSEPAMO study, no neural tube defects occurred in an 
additional 170 babies exposed to DTG at the time of conception, which translated to a 
revised neural tube defect incidence rate of 0.7% in DTG-exposed babies [Zash 2017]. 
The TSEPAMO study is ongoing. Information about these recent findings has been 
included in the informed consent for A5357. In addition, pregnant individuals will be 
excluded from the study, pregnancy testing will be performed on Steps 1 and 2, and 
individuals who become pregnant on study will be taken off the study treatment, and 
sites will be required to document referral to obstetrical care. 
 
2.3 
Significance 
 
Despite the major success of combination ART in suppressing viral replication and 
preventing disease progression, it is unable to eradicate HIV-1 infection [Siliciano 2014]. 
The burden of daily medication regimens, drug toxicity, development of drug resistance, 
and drug cost underscore the need for a continued search for additional complementary 


 
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therapeutic modalities. Broadly neutralizing antibodies differ from therapeutic modalities 
for HIV-1 infection in several respects, and these differences might allow better control of 
HIV-1 infection. First, they can neutralize the pathogen directly; second, they have the 
potential to clear the virus and infected cells through engagement of innate effector 
responses [Igarashi 1999; Nimmerjahn 2008]; and third, immune complexes produced 
by the passively transferred antibodies may enhance immunity to HIV-1. Since 
antibodies have longer half-lives than currently prescribed antiretroviral drugs [Klein 
2012; Klein 2013], they may also allow for more convenient therapeutic regimens, 
making them optimal agents for combination therapy with long-acting formulations of 
conventional ARV drugs. Therefore, bNAbs may have a role as adjuncts to ART or as 
stand-alone treatment regimens. 
 
Discovery of safe, effective long-acting ART regimens will address a major unmet need 
in HIV treatment. Specifically, adherence to HIV medications is critical to suppressing 
HIV RNA levels and preventing the emergence of drug-resistant virus in order to achieve 
durable clinical and survival benefits. Some HIV studies report the need for >95% 
adherence to ARV medications to ensure complete virologic suppression [Icovicks 2002; 
Paterson 2000], and one recent study found over three-fold higher risk of death in 
participants with less than 95% adherence to contemporary HIV treatment regimens 
[Lima 2009]. While current HIV regimens are potent, well-tolerated and available as 
convenient one-pill, once-daily regimens, even simple HIV regimens may pose 
challenges for some participants. A recent meta-analysis of 84 observational cross-
sectional and cohort studies across 20 countries reported that >90% adherence was 
reported by only 62% of people living with HIV [Ortego 2011]. Thus, interventions to 
improve adherence in people living with HIV are urgently needed. Parenterally delivered 
long-acting HIV regimens, such as CAB LA plus VRC07-523LS, have the potential to 
increase medication compliance and virologic suppression due to directly-observed 
treatment by providers and elimination of pill burden. 
 
3.0 
STUDY DESIGN 
 
A5357 is a phase II, single arm, open-label switch study to assess the safety, tolerability, 
PK, and antiviral activity of CAB LA plus VRC07-523LS in adults living with HIV-1 with 
suppressed plasma viremia. At Step 1 entry, all participants will discontinue their current 
regimen except for NRTIs and initiate oral CAB. For participants currently on Truvada 
(emtricitabine/tenofovir disoproxil fumarate), or Descovy (emtricitabine/tenofovir 
alafenamide), or Epzicom (abacavir/lamivudine) without continued access, 
reimbursement for these drugs will be provided in Step 1. 
 
In Step 1, viral load monitoring will occur at entry and week 4 (and also at week 5 if HIV-
1 RNA is 50-199 copies/mL at week 4). Participants tolerating oral CAB plus their current 
two NRTIs with HIV-1 RNA <50 copies/mL at week 4, or HIV-1 RNA of 50-199 
copies/mL at week 4 followed by HIV-1 RNA <50 copies/mL at week 5, will register to 
Step 2 and receive CAB LA every 4 weeks through week R2+44 plus VRC07-523LS 
every 8 weeks through week R2+40. Participants who have viral load ≥ 200 copies/mL at 
week 4 or ≥50 copies/mL at week 5, or who permanently discontinue or temporarily hold 
oral CAB or NRTIs for >7 days for any reason in Step 1 will be switched to a SOC 


 
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regimen and followed on study every 2 weeks for a total of 4 weeks and then be taken 
off study. 
 
Viral load monitoring in Step 2 will occur every 2 weeks until week R2+8, then every 4 
weeks until week R2+48. All participants will complete the week R2+48 visit in Step 2, 
and this visit will be used to confirm virologic rebound in those with HIV-1 RNA ≥50 
copies/mL at week R2+44. 
 
For participants who have a confirmed HIV-1 RNA ≥200 copies/mL during Step 2 or 
confirmed HIV-1 RNA ≥50 copies/mL at week R2+44 and ≥200 copies/mL at week 
R2+48, genotypic testing will be performed for protease/reverse transcriptase (PR/RT) 
and integrase resistance. In addition, samples from the failure confirmation visit and pre-
ART or entry (if available) will be tested for viral clonality, integrase resistance, and 
VRC07-523LS neutralization resistance. 
 
All participants who receive any dose of CAB LA or VRC07-523LS or prematurely 
discontinue treatment in Step 2 will register to Step 3, the SOC follow-up, at the final 
study visit in Step 2 or at premature treatment discontinuation. These participants will be 
registered to Step 3 and will be switched back to a SOC ART regimen, guided by 
resistance testing, and will undergo study visits at weeks R3+4 and R3+12 and then 
every 12 weeks for approximately 48 weeks. 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Step 1 Inclusion Criteria 
 
4.1.1 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 
RNA viral load. 
 
NOTE:  The term “licensed” refers to a US Food and Drug Administration (FDA)-
approved kit, which is required for all IND studies. 
 
World Health Organization (WHO) and Centers for Disease Control and 
Prevention (CDC) guidelines mandate that confirmation of the initial test result 
must use a test that is different from the one used for the initial assessment. A 
reactive initial rapid test should be confirmed by either another type of rapid 
assay or an E/CIA that is based on a different antigen preparation and/or 
different test principle (e.g., indirect versus competitive), or a Western blot or a 
plasma HIV-1 RNA viral load. 
 
4.1.2 Clinically stable (i.e., in the opinion of the site investigator, doing well and not sick 
from treatment) for at least 8 weeks prior to study entry on a three-drug ART 
regimen that includes a boosted protease inhibitor, a nonnucleoside reverse 


 
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transcriptase inhibitor (NNRTI), or an integrase inhibitor, plus two NRTIs, with no 
history of a switch due to virologic failure. 
 
NOTE: Previous switches for reasons other than virologic failure prior to 
screening are allowed. 
 
4.1.3 Screening CD4+ T-cell count ≥350 cells/mm3 obtained within 60 days prior to 
study entry at any US laboratory that has a Clinical Laboratory Improvement 
Amendments (CLIA) certification or its equivalent. 
 
4.1.4 All available HIV-1 RNA measurements must be <50 copies/mL within the 2 
years prior to study entry except as allowed by the note below. 
 
NOTE: One plasma HIV-1 RNA ≥50 copies/mL but <200 copies/mL is allowed if 
followed by a subsequent HIV-1 RNA value below 50 copies/mL. 
 
4.1.5 Participants must have at least two documented HIV-1 RNA <50 copies/mL 
within 12 months prior to study entry. 
 
NOTE: The HIV-1 RNA level obtained at the screening visit can be used as the 
second measurement, but must meet the requirements of section 4.1.6. 
 
4.1.6 Screening plasma HIV-1 RNA <50 copies/mL by any FDA-approved assay with 
minimum limit of detection of ≤50 copies/mL obtained within 60 days prior to 
study entry by any US laboratory that has a CLIA certification or its equivalent. 
 
4.1.7 The following laboratory values obtained within 60 days prior to entry at any US 
laboratory that has a CLIA certification or its equivalent. 
• 
Absolute neutrophil count (ANC) ≥750/mm3 
• 
Hemoglobin: 
o ≥11.0 g/dL for cisgender men and transgender women 
o ≥10.0 g/dL for cisgender women and transgender men 
• 
Platelet count ≥100,000/mm3 
• 
Calculated creatinine clearance (Cockcroft-Gault formula) ≥50 mL/min 
 
NOTE: A program for calculating creatinine clearance by the Cockcroft-Gault 
method is available at www.fstrf.org. 
 
• 
Aspartate aminotransferase (AST) (SGOT) ≤2.0 x ULN 
• 
Alanine aminotransferase (ALT) (SGPT) ≤2.0 x ULN 
 
4.1.8 For persons of child-bearing potential, negative serum or urine pregnancy test 
within 48 hours prior to entry by any clinic or laboratory that has a CLIA 
certification or its equivalent, or is using a point of care (POC)/CLIA-waived test. 
 


 
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NOTE A: 
Child-bearing potential is defined as persons who have reached 
menarche and persons who have had menses within the prior 12 
months, and have not undergone surgical sterilization. If no menses for 
a year or longer, the follicle-stimulating hormone (FSH) should be ≤40 
IU/mL to be considered of child-bearing potential. If an FSH is not 
available, and they have not had menses in 24 or more consecutive 
months, they would be considered not to be of child-bearing 
potential. Persons who have undergone surgical sterilization (e.g., 
hysterectomy, bilateral oophorectomy, tubal micro-inserts, tubal ligation 
or salpingectomy) are considered not to be of child-bearing potential. 
 
NOTE B: 
Participant-reported history of hysterectomy and bilateral 
oophorectomy, tubal ligation, bilateral salpingectomy, tubal micro-
inserts, and menopause is acceptable documentation. 
 
4.1.9 Persons of Child-bearing Potential 
 
Persons of child-bearing potential, who are participating in sexual activity that 
could lead to pregnancy, must agree to use an effective form of contraception 
from 30 days prior to the first dose of study medication, while receiving the study 
drugs, and for 30 days after stopping oral medications, or the duration specified 
in the product label if receiving ARV drugs not supplied by the study, or for 
approximately 48 weeks after last dose of CAB LA or VRC07-523LS.  Acceptable 
methods of contraception include: 
• 
Contraceptive subdermal implant 
• 
Intrauterine device or intrauterine system 
• 
Combined estrogen and progestogen oral contraceptive 
• 
Injectable progestogen 
• 
Contraceptive vaginal ring 
• 
Percutaneous contraceptive patches 
 
Persons Who Are Not of Child-bearing Potential 
Persons who are not of child-bearing potential are eligible to start study 
treatment without requiring the use of contraceptives. Refer to section 4.1.8 for 
definition of persons who are of child-bearing potential. 
 
NOTE: All participants in the study should be counseled on safe sexual practices 
including the use and benefit/risk of effective barrier methods (e.g., male 
condom) and on the risk of HIV transmission to a partner without HIV. 
 
4.1.10 Individuals aged 18 years. 
 
4.1.11 Ability and willingness of participant to provide written informed consent. 
 
4.1.12 Negative HBsAg results obtained within 60 days prior to study entry. 
 


 
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4.1.13 Negative hepatitis C virus (HCV) antibody result obtained within 60 days prior to 
study entry or, if the HCV antibody result is positive, a negative HCV RNA result 
obtained within 60 days prior to study entry. 
 
4.1.14 Susceptibility to VRC07-523LS based on IC50 of 0.25 µg/mL and a Maximum 
Percent Inhibition >98% using the Monogram PhenoSense Assay on sample 
obtained at the screening visit. 
 
NOTE: Participants who had their samples drawn for PhenoSense 
susceptibility testing to VRC07-523LS at a prior screening as part of any 
ACTG study and whose screening lab values have expired do not need to 
repeat the PhenoSense susceptibility testing as part of the re-screening, 
provided there is no documented detectable HIV viral load since the 
original screen. 
 
4.1.15 Adequate venous access in at least one arm. 
 
4.1.16 Willingness to continue current two NRTIs and expects to have continued access 
to NRTIs in Step 1. 
 
NOTE: NRTIs will not be provided by the study. Participants without continued 
access to NRTIs will be provided reimbursement for these drugs by the study. 
 
4.1.17 Willingness to not actively engage in the conception process for the duration of 
the study. 
 
4.2 
Step 1 Exclusion Criteria 
 
4.2.1 Any previous receipt of humanized or human monoclonal antibody (licensed or 
investigational). 
 
4.2.2 Weight >115 kg or <53 kg. 
 
4.2.3 AIDS-defining illness within 60 days prior to study entry. 
 
4.2.4 History of a severe allergic reaction with generalized urticarial, angioedema, or 
anaphylaxis within 2 years prior to study entry. 
 
4.2.5 Currently breastfeeding or pregnant. 
 
4.2.6 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.7 Acute or serious illness that, in the opinion of the site investigator, requires 
systemic treatment, quarantine, and/or hospitalization within 30 days prior to 
entry. 
 


 
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4.2.8 Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV 
vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 60 
days prior to study entry. 
 
NOTE: Participants receiving stable physiologic doses of glucocorticoids, defined 
as the equivalent of prednisone ≤10 mg/day, will not be excluded. Stable 
physiologic glucocorticoid doses should not be discontinued for the duration of 
the study. In addition, participants receiving inhaled or topical corticosteroids will 
not be excluded. 
 
4.2.9 Treatment for hepatitis C within 24 weeks prior to study entry. 
 
4.2.10 Vaccinations within 7 days prior to study entry. 
 
NOTE: Participants are encouraged to get routine vaccinations, such as 
seasonal influenza vaccine outside this window. If vaccination occurs within 7 
days prior to study entry, the entry visit should be postponed for at least 7 days 
after the vaccination. 
 
4.2.11 Initiation of ART during acute HIV-1 infection (as determined by the site 
investigator by history and/or available medical records). 
 
4.2.12 Personal or known family history of prolonged QT syndrome or, in the opinion of 
the site investigator, a clinically significant finding on the screening 
electrocardiogram (ECG) based on an assessment of the screening ECG by that 
site investigator. 
 
4.2.13 Unstable liver disease (as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent 
jaundice), known biliary abnormalities (with the exception of Gilbert’s syndrome 
or asymptomatic gallstones). 
 
4.2.14 Moderate or severe hepatic impairment (Class B or C) as determined by Child-
Pugh classification. 
 
4.2.15 History of seizures or treatment for seizures within the past 2 years prior to study 
entry. 
 
NOTE: For candidates with a remote (> 2 year) history of seizure, consult the 
A5357 CMC for eligibility determination. 
 
4.3 
Step 2 Inclusion Criteria 
 
4.3.1 HIV-1 RNA <50 copies/mL at week 4 (Step 1), or HIV-1 RNA of 50-199 
copies/mL at week 4 followed by HIV-1 RNA <50 copies/mL at week 5 (Step 1). 
 


 
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4.3.2 Persons of child-bearing potential must have a negative serum or urine 
pregnancy test obtained within 48 hours prior to Step 2 registration. 
 
NOTE: Refer to section 4.1.8 for definition of child-bearing potential and 
acceptable documentation. 
 
4.3.3 Confirmation that female participant agrees to continue to use an effective form 
of contraception (see section 4.1.9) while on study, and for approximately 48 
weeks after last dose of CAB LA or VRC07-523LS. 
 
4.3.4  Confirmation of willingness to not actively engage in the conception process for 
the duration of the study. 
 
4.4 
Step 2 Exclusion Criteria 
 
4.4.1 Discontinuation or temporary hold of oral CAB for >7 consecutive days for any 
reason during Step 1. 
 
4.4.2 Discontinuation or temporary hold of NRTIs for >7 consecutive days for any 
reason during Step 1. 
 
4.4.3 Grade 3 or 4 adverse event thought to be related to oral CAB during Step 1 
according to the site investigator. 
 
4.4.4 Vaccination (e.g., influenza) within 7 days prior to the Step 2 registration. 
 
4.4.5 Currently breastfeeding or pregnant. 
 
4.4.6 Any Grade ≥2 ALT (>2.5 times ULN) that developed during Step 1. 
 
4.4.7 Current implants and/or direct silicone injections on or around the 
subcutaneous area where the study product will be administered. 
 
4.4.8 An overlying tattoo (that is located on or around the skin area where the 
study product will be administered) that, per the site investigator’s best 
clinical judgement, would impede clinical care or management in any way. 
 
4.4.9 Current acute illness that, in the opinion of the investigator, will prevent the 
participant from complying with study visits. 
 
4.5 
Step 3 Inclusion Criterion 
 
4.5.1 Received any CAB LA or VRC07-523LS during Step 2. 
 
NOTE: Participants who prematurely discontinue study treatment for any reason 
in Step 2 remain eligible for Step 3. 
 


 
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4.6 
Step 3 Exclusion Criterion 
 
There are no exclusion criteria to Step 3. 
 
4.7 
Study Enrollment Procedures 
 
4.7.1 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 approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received. Site-specific ICF(s) 
will not be reviewed and approved by the DAIDS PRO, and sites will receive an 
Amendment Registration Notification when the DAIDS PRO receives a complete 
registration packet. A copy of the Amendment Registration Notification should be 
retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual. 
 
Once a participant for study entry has been identified, details will be carefully 
discussed with the participant. The participant will be asked to read and sign the 
approved protocol consent form. 
 
Participants from whom a signed informed consent has been obtained may be 
screened and enrolled, if they otherwise qualify. An ACTG Screening Checklist 
must be entered through the Data Management Center (DMC) Participant 
Enrollment System. 
 


 
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4.7.2 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. 
 
4.7.3 Participant Registration 
 
For candidates from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be keyed into the database. 
 
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures. 
 
4.8 
Co-enrollment Guidelines 
 
Sites are encouraged to co-enroll participants in A5128, “Plan for Obtaining Informed 
Consent to Use Stored Human Biological Materials (HBM) for Currently Unspecified 
Analyses.” Co-enrollment in A5128 does not require permission from the A5357 protocol 
chairs. 
 
For specific questions and approval for co-enrollment in other studies, sites should first 
check the PSWP or contact the protocol team via email as described in the Study 
Management section. 
 
5.0 
STUDY TREATMENT 
 
Study treatment is defined in Step 1 as oral CAB (oral cabotegravir) and two NRTIs, in 
Step 2 as CAB LA (injectable cabotegravir) and VRC07-523LS (VRC-HIVMAB075-00-
AB), and in Step 3 as SOC ART regimen. 
 
5.1 
Study Product 
 
Site pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks for standard pharmacy operations. Refer to study schema for an 
overview of steps and study design, and to the investigator’s brochures (IBs) for further 
information about the study products. 
 
A prescription signed by an authorized prescriber that includes PID and SID must be 
provided to the site pharmacist before the pharmacist prepares and dispenses study 
product. 
 
5.2 
Study Product Regimen, Administration, and Duration 
 
5.2.1 Regimen and Duration 
 


 
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Step 1 (Oral Phase) 
At entry, HIV-1 positive study participants with suppressed viremia will 
discontinue their current regimen except for NRTIs and initiate oral CAB daily for 
5 weeks (-7 days/+14 days). The two NRTIs on Step 1 and SOC ART at weeks 7 
and 9 are not considered study products. 
 
Step 2 (Parenteral Phase) 
Participants tolerating oral CAB plus two NRTIs who maintain viral suppression 
(HIV-1 RNA <50 copies/mL at week 4, or HIV-1 RNA of 50-199 copies/mL at 
week 4 followed by HIV-RNA <50 copies/mL at week 5) will register to Step 2 
and receive injectable CAB LA every 4 weeks through week R2+44 and VRC07-
523LS every 8 weeks for R2+40 weeks. 
 
NOTE: For participants who register to Step 2, the initial dose of CAB LA will be 
administered on the same visit day as the final dose of oral CAB on Step 1. 
 
Step 3 (SOC Follow Up) 
All participants who received any CAB LA or VRC07-523LS dose during Step 2 
will register to Step 3 at the final study visit in Step 2 or at premature treatment 
discontinuation in Step 2. In Step 3, participants will switch to a SOC regimen 
and undergo study visits per Table 6.1-3. The SOC ART regimen on Step 3 is not 
considered study product. 
 
5.2.2 Study Product Administration Overview 
 
Oral CAB 30 mg will be administered as one 30 mg tablet orally once daily, with 
or without food, for 5 weeks (-7 days/+14 days) during Step 1. 
 
CAB LA 600 mg loading dose will be administered as one 3 mL (600 mg) IM 
injection in the gluteus medius once, when the participant registers to Step 2. At 
Step 2 registration, participants will receive the first IM CAB LA dose on the same 
visit day as the final dose of oral CAB on Step 1. 
 
CAB LA 400 mg maintenance dose will be administered as one 2 mL (400 mg) 
IM injection in the gluteus medius, starting 4 weeks after the CAB LA 600 mg 
loading dose and then every 4 weeks through week R2+44 for a total of 11 doses 
in Step 2. 
 
VRC07-523LS (40 mg/kg) in 100 mL of Sodium Chloride for Injection USP, 0.9% 
administered as an IV infusion over about 15 to 30 minutes or more as needed 
using a volumetric pump, starting once the participant registers to Step 2 and 
then every 8 weeks for a total of six doses through week R2+40 in Step 2. 
 
5.3 
Study Product Preparation 
 
The site pharmacist(s) must be proficient in the preparation of injectable study products 
using aseptic technique under a pharmacy isolator or biological safety cabinet (BSC) 


 
40 
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Class II or better. Local regulations and site institutional policies and procedures for use 
of personal protective equipment, such as gloves, gowns, masks, and safety glasses, 
must be followed. 
 
5.3.1 CAB LA Preparation 
 
CAB LA 600 mg Loading Dose 
The pharmacist must prepare one syringe containing 3 mL (600 mg) of CAB LA 
study product for the loading dose using aseptic technique under a pharmacy 
BSC/isolator. 
 
CAB LA 400 mg Maintenance Dose 
The pharmacist must prepare one syringe containing 2 mL (400 mg) of CAB LA 
study product using aseptic technique under a pharmacy BSC/isolator. 
 
Materials required for preparation and administration of CAB LA 
1. Appropriate number of CAB LA vials: 
a. To prepare CAB LA Loading dose 600 mg (3 mL) in a syringe, one CAB 
LA 600 mg/3 mL vial or two CAB LA 400 mg/2 mL vials are needed. 
b. To prepare CAB LA Maintenance dose 400 mg (2 mL) in a syringe, one 
CAB LA 600 mg/3 mL vial or one CAB LA 400 mg/2 mL vial is needed 
2. Becton Dickenson (BD) 3-mL syringe, Leur-Lok Tip, Product No.: 309657 or 
equivalent 
3. Becton Dickinson (BD) 5-mL Syringe, Luer-Lok Tip, Product No.: 309646 or 
equivalent 
4. Needle for aspiration: BD general use sterile hypodermic needle, 21G x 1½ 
inch (e.g. Precision Glide Needle, Product No.: 305165 or equivalent 
5. Needle for intramuscular injection: BD IM sterile hypodermic needle, 23G x 
1½ inch (e.g. Precision Glide Needle, Product No.: 305194) or equivalent. 
 
NOTE: Variable needle lengths and/or needles with different gauges (1½ 
inch, 2 inch; 21 to 25 gauge) are permitted, if needed, based on 
available materials at the study site or to accommodate individual body 
types for IM administration of CAB LA. 
 
Preparation Steps 
1. Remove applicable number of CAB LA vial(s) (200 mg/mL concentration in 2 
mL or 3 mL fill per vial) from storage. If the vials are stored in the refrigerator 
(2°C to 8°C), remove the vial(s) from the refrigerator and wait at least 15 
minutes to equilibrate to room temperature. 
 
2. Vigorously shake the vial(s) for a full 10 seconds by shaking the vial(s) with 
long arm movements. 
3. Invert the vial(s) and inspect to ensure uniform suspension. If solid remains 
undispersed, repeat Steps 2-3 until all material is uniformly suspended. 
 


 
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NOTE: It is normal to see small air bubbles at the end of shaking the vial for 
re-suspension. 
 
4. Using aseptic technique under a pharmacy BSC/isolator, flip off the plastic 
cap from the vial. Wipe the top of the vial with an alcohol pad (isopropyl 
alcohol 70% or similar) and allow to dry. Do not touch the rubber stopper at 
any time. 
 
5. Remove a 3 mL or 5 mL size syringe and 21G x 1½ inch needle (or 
equivalent) for aspiration. Attach the needle to the Luer connection of the 
syringe. 
 
6. With the needle sheath on, pull the syringe plunger rod to allow 
approximately 1 mL of air into the syringe. Remove the needle sheath. 
 
7. With the vial in the inverted position and the syringe with the needle in the 
upright position, push the needle through vial stopper and inject 
approximately 1 mL of air into the vial. 
 
8. While keeping the syringe with the needle in the upright position, withdraw 
needed volume of CAB LA suspension from the vial(s) into the syringe. 
• 
For LOADING DOSE, withdraw total of 3 mL (600 mg) suspension from 
the vial(s) into a syringe. 
o If using two CAB LA 400 mg/2 mL vials to prepare the loading dose, a 
second new aspiration needle should be used to withdraw suspension 
from the second vial. Remove the first needle that was used to 
withdraw the suspension out of the first vial and discard properly. 
Attached the new 21G x 1½ inch needle to the syringe already 
containing suspension per instructions in Step 5 and repeat Steps 6 
and 7 to withdraw the remaining needed volume from the second vial. 
• 
For MAINTENANCE DOSE, withdraw 2 mL (400 mg) of suspension from 
a vial into a syringe. 
Since the suspension can contain some air after having shaken the vial, 
withdraw enough suspension from the vial in order to be able to de-aerate 
the syringe properly. 
 
9. Remove the needle that was used to withdraw the suspension out of the vial 
and discard the needle properly. 
 
10. Attach a 23G x 1½ inch (or equivalent) needle to the Luer connection of the 
prepared CAB LA syringe for IM injection for the participant. Alternatively, the 
site pharmacist can attach a syringe cap to the prepared syringe. The study 
staff can then attach the appropriate needle for administration to the prepared 
syringe in the clinic before administration. 
 


 
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NOTE: The participant-specific prepared CAB LA syringe is to be de-aerated 
by administrator prior to injection so that the correct volume can be 
administered. 
 
De-aerate the syringe by first tapping with a finger against the syringe and 
then by moving the plunger rod carefully forward with the top of the syringe in 
an upright position until the first drop of suspension appears. 
 
Remove the excess suspension in order to administer the correct volume (3 
mL for the LOADING DOSE or 2 mL for the MAINTENANCE DOSE). If 
needed, collect the excess suspension in a beaker to avoid spilling. 
 
11. Record the time that the suspension was withdrawn from the vial and into the 
syringe in the participant’s pharmacy log. This is the time of preparation. 
 
12. Labeling of Prepared Injectable Study Product 
 
CAB LA 600 mg Loading Dose 
The participant’s loading dose of CAB LA is 600 mg/3 mL in one syringe. 
Label as CAB LA 600 mg including volume (3 mL), route (IM), PID, SID, date 
and time of preparation, and date and time of expiration. 
 
CAB LA 400 mg Maintenance Dose 
The participant’s maintenance dose of CAB LA is 400 mg/2 mL in one 
syringe. Label as CAB LA 400 mg including volume (2 mL), route (IM), PID, 
SID, date and time of preparation, and date and time of expiration. 
 
Follow the DAIDS Pharmacy guidelines and local regulations for preparing 
the participant specific study product label. 
 
After withdrawal of the CAB LA suspension from the vial into a syringe, it is 
recommended to inject the suspension immediately. Do not exceed 2 hours 
between withdrawing the contents of the vial(s) into a syringe (Step 8) and 
administration to the study participant. 
 
The prepared CAB LA study product in a syringe must be stored at controlled 
room temperature between 20°C to 25°C (68° F to 77° F) from the time it is 
withdrawn into a syringe to the time it is administered. 
 
Any entered vials and expired filled syringes should be disposed of in 
accordance with institutional or pharmacy policy. 
 


 
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5.3.2 VRC07-523LS Preparation 
 
A prescription signed by an authorized prescriber must be sent to the pharmacy 
prior to study product infusion preparation. The prescription must include the 
participant identifier, weight (kg) from the most recent visit, and calculated 
VRC07-523LS dose (mg). If the participant’s weight on the day of the infusion 
visit has changed by >10% from the weight written on the prescription sent to the 
pharmacy, a new prescription must be provided to the pharmacy to prepare a 
new study infusion dose based on the current actual weight on the day of the 
visit. 
 
Thawing Instructions 
Thaw vials of VRC07-523LS at controlled room temperature (maximum 27°C) for 
a minimum of 1 hour after removal from freezer. 
 
VRC07-523LS is a highly concentrated protein solution and may develop white, 
opaque to translucent particles after thawing. When particles are observed, they 
may disappear after a few hours at controlled room temperature or storage at 
2°C to 8°C. Vials of VRC07-523LS containing particles should be placed in the 
refrigerator as particles may continue to dissipate at 2°C to 8°C. Vials of VRC07-
523LS that previously contained particles but subsequently become clear of 
particles may be used. 
 
Vials that continue to have visible particles after a maximum of 2 weeks at 2°C to 
8°C (36°F to 46°F) are not to be used and must be quarantined. Contact the 
protocol pharmacist for further instructions regarding handling of vials of VRC07-
523LS with particles. 
 
Thawed vials for preparation should contain fluid that is a clear, colorless to 
yellow liquid and no particles are observed. Following thaw, VRC07-523LS vials 
must either be used to prepare an infusion or placed in a refrigerator at 2°C to 
8°C (36°F to 46°F) before reaching the maximum storage of 24 hours at 
controlled room temperature (maximum 27°C). The thawed VCR01LS vials may 
be stored up to 2 weeks at 2°C to 8°C (36°F to 46°F). 
 
If stored at 2°C to 8°C (36°F to 46°F), vials must be equilibrated to controlled 
room temperature (maximum 27°C) for a minimum of 30 minutes and may be 
held at controlled room temperature (maximum 27°C) for up to 8 hours prior to 
product preparation. 
 
VRC07-523LS may not be stored in direct sunlight at any time. 
 


 
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IV Infusion Preparation Instructions 
Participants’ screening weight, entry weight, or last obtained weight may be used 
for estimating the dose to thaw vials. After removal from 2-8°C, vials of VRC07-
523LS should be equilibrated to controlled room temperature (maximum 27°C) 
for a minimum of 30 minutes prior to preparing IV infusions. 
1. Calculate the total milligrams of VRC07-523LS required based on the 
participant’s weight, 40 mg/kg and the total number of vials required based on 
a 6 mL withdrawal volume containing 600 mg of VRC07-523LS or 2 mL 
withdrawal volume containing 200 mg of VRC07-523LS. 
2. Gently swirl thawed vials for 30 seconds with sufficient force to resuspend 
any visible particles, yet avoiding foaming. DO NOT SHAKE THE VIALS. 
Keep the vials upright at all times until ready to withdraw the contents. Do not 
invert the vial during inspection. 
3. Observe vials for particles. If particles are observed refer to the thawing 
instructions for further information. 
4. Add the required volume for the calculated total milligrams of VRC07-523LS 
needed into 0.9% Sodium Chloride Injection, USP, 100 mL IV bag or glass 
bottle using aseptic technique to maintain sterility under a pharmacy isolator 
or Biological Safety Cabinet (Class 2 or better). The 0.9% Sodium Chloride 
Injection, USP, 100 mL bag will accommodate the additional volume required 
for the dose of VRC07-523LS to be used in this study. Do not withdraw fluid 
from the 0.9% Sodium Chloride Injection, USP, 100 mL bag to make room for 
the volume of study product to be added. 
5. Label the IV bag with participant identifier, participant weight (kg), calculated 
dose of VRC07-523LS (mg) added to the 0.9% Sodium Chloride Injection, 
USP, 100 mL, the final volume of the bag, lot number, storage instructions, 
Investigational Use Statement (“Limited by Federal Law to Investigational 
Use”), and manufacturer information. 
 
After VRC07-523LS study product preparation in IV bags, the prepared VRC07-
523LS may be stored at 2°C to 8°C (36°F to 46°F) up to 48 hours or at controlled 
room temperature (maximum 27°C) for a maximum of 4 hours total including 
completion of infusion time. 
 
The prepared study IV bag may not be stored in direct sunlight. 
 
If the prepared study IV bag is stored at 2°C to 8°C, it must be equilibrated at 
controlled room temperature (maximum 27°C) for at least 30 minutes prior to IV 
administration. 
 
The IV bag will also be labeled with a “DO NOT INFUSE AFTER” date and time 
as follows: 
• 
Up to 48 hours if stored at 2°C to 8°C 
• 
Up to 4 hours, including completion of infusion, if at controlled room 
temperature (maximum 27°C). 
 


 
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Any unused portion of a VRC07-523LS vial will not be used for another 
participant. Any empty vials, unused portion of entered vials, or unused IV 
solution which contains study product should be discarded in a biohazard 
containment bag and incinerated or autoclaved in accordance with institutional or 
pharmacy policy. 
 
VRC07-523LS (IV Administration) 
The IV bag label on the IV bag prepared by the pharmacy will include the 
participant’s weight that was used for preparation of the IV bag, the calculated, 
total amount (mg) of VRC07-523LS added to the 100 mL normal saline bag and 
the final volume of the bag. 
 
The clinician responsible for administration and another study staff will each 
check the IV bag label and confirm that the participant identifier is correct and the 
weight on the bag label is within 10% of the participant’s current actual weight 
before beginning the IV administration. 
 
An in-line filter infusion set must be used for IV administration. In-line filter must 
comply with the following specifications: 1.2 micron PES (polyether-sulfone) filter 
membrane, DEHP-free, latex-free (equivalent to Braun # 473994 filter extension 
set). When the in-line filter is added to the tubing, prime the administration set.  
Flush the administration set with about 30 mL or appropriate volume of normal 
saline at the end of product administration. 
 
The investigational study product solution for infusion will be administered IV 
over about 15 to 30 minutes or more as needed using a volumetric pump. The 
rate of infusion (mL/hr) will vary based on the total volume needed to administer 
the full dose. The total time needed to administer the dose may be longer, based 
on factors such as participant tolerance. 
 
Please see the A5357 MOPS for further detail on administration. 
 
5.3.3 Study Product Formulation and Storage 
 
Oral cabotegravir (CAB) tablets are formulated as white to almost white oval-
shaped coated tablets for oral administration. The tablets are packaged in high 
density polyethylene (HDPE) bottles with child-resistant closure that include an 
induction seal. The bottles contain 30 tablets and a desiccant. The tablets are to 
be stored up to 30°C (86°F) in the original container with the desiccant, and 
protected from moisture. 
 
Cabotegravir Long Acting injectable (CAB LA) is formulated as a sterile white to 
slightly pink suspension containing 200 mg/ mL concentration of cabotegravir 
free acid for administration by IM injection. The product is packaged in 2 mL filled 
(400 mg/2 mL) and 3 mL filled (600 mg/3 mL) per vial. Each vial is for single use 
and does not require dilution prior to administration. CAB LA injectable 
suspension in the vial is to be stored up to 30oC (86°F); do not freeze. 


 
46 
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11Mar2022 
 
 
VRC07-523LS will be supplied in 10 mL size glass vial with a 6.25 mL fill volume 
at a concentration of 100 mg/mL and a 3 mL size glass vial with 2.25 mL fill 
volume at a concentration of 100 mg/mL. The vials contain a clear, colorless to 
yellow liquid essentially free of visible particles; some opaque or translucent 
particles may be present. The formulation buffer is composed of 50 mM histidine, 
50 mM sodium chloride, 5% sucrose, and 2.5% sorbitol at pH 6.8. The vials are 
intended for single use and thus do not contain a preservative. 
 
VRC07-523LS product label designates the long-term storage as -35°C to -15°C 
(-31°F to 5°F). Storage in a continuously monitored, temperature-controlled 
freezer with temperature excursion between -45°C to -10°C (-49°F to 14°F) is 
acceptable. 
 
5.4 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.4.1 Study Product Supply 
 
Oral CAB and CAB LA are provided by ViiV Healthcare. 
 
VRC07-523LS is provided by the VRC/DAIDS/NIAID. 
 
NOTES: ART supply, other than oral CAB and CAB LA, will not be provided 
through the study. 
 
Any ART including NRTIs, other than oral CAB and CAB LA, are not to 
be received, stored, or dispensed by the ACTG pharmacist from the 
ACTG pharmacy. 
 
NOTE: Previously enrolled Step 1 participants who are re-
screened for Step 1 and found to be eligible should be instructed 
to bring back their remaining oral CAB bottle supply at the study 
entry visit. 
 
The study participants are to obtain NRTIs outside of the study through 
routine care, which is the same process they were obtaining their NRTI 
regimen before entering the study. 
 
For participants currently on NRTIs, including emtricitabine 200 
mg/tenofovir disoproxil fumarate 300 mg (Truvada®), abacavir 600 
mg/lamivudine 300 mg (Epzicom®), and emtricitabine 200 mg/tenofovir 
alafenamide 25 mg (Descovy®) in Step 1 without continued access to 
NRTIs outside of the study through routine care, reimbursement for 
these drugs will be provided by the ACTG Leadership and Operations 
Center (LOC) with funding support from ViiV. 
 


 
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5.4.2 Study Product Acquisition/Distribution 
 
Oral CAB, CAB LA, and VRC07-523LS will be available from the NIAID Clinical 
Research Products Management Center (CRPMC). The site pharmacist should 
obtain the study products for this protocol by following the instructions in the 
manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks. 
 
5.4.3 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study 
products. In addition, the site pharmacist must maintain records of the 
manufacturer and lot # of 0.9% Sodium Chloride for Injection, USP, locally 
sourced and used to prepare the study infusion. All unused study products in US 
CRSs 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 in the manual Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks. 
 
5.5 
Concomitant Medications 
 
Participants must be advised to notify their investigator of any current or proposed 
concomitant medication, whether prescribed or over-the-counter, because of the 
potential for interactions between such treatments and the study medications. 
Concomitant medications (prescription and non-prescription) will be permitted during the 
course of the study at the investigator’s discretion except for prohibited medications as 
described in section 5.5.2. 
 
Whenever a concomitant medication or study agent is initiated or a dose is changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, investigator’s brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the ACTG Precautionary and Prohibited 
Medications Database located at: http://tprc.pharm.buffalo.edu/home/di_search/. 
 
5.5.1 Required Medications 
 
Step 1: Study-provided oral CAB plus two current NRTIs that are obtained as 
part of clinical care. 
 
Step 2: Study-provided CAB LA plus VRC07-523LS. 
 
Step 3: SOC ART that is obtained as part of clinical care. 
 


 
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5.5.2 Prohibited Medications 
 
The following medications may not be used at any time during this protocol: 
• 
HIV immunotherapeutic vaccines 
• 
Other experimental agents, antiretroviral drugs not otherwise specified in the 
protocol, cytotoxic chemotherapy, or radiation therapy (see exclusion 
criterion: section 4.2.8). 
• 
Systemically administered immunomodulators (such as interleukin and 
interferon agents). This includes topical agents with substantial systemic 
exposure and systemic effects. Use of topical imiquimod is permitted. 
  
The following medications are prohibited during Step 1 and Step 2 since they 
could significantly decrease the levels of either formulation of CAB due to 
enzyme induction: 
• 
Carbamazepine 
• 
Oxcarbazepine 
• 
Phenobarbital 
• 
Phenytoin 
• 
Rifabutin 
• 
Rifampicin / Rifampin 
• 
Rifapentine 
• 
St. John’s wort (Hypericum perforatum) 
 
NOTE: These agents should be discontinued for a minimum of 4 weeks or a 
minimum of three half-lives (whichever is longer) prior to the first dose of CAB.  
 
The following medications are prohibited during Step 2 since participants will be 
receiving CAB LA intramuscular injections: 
• 
Anticoagulation agents for greater than 14 days, with the exception of the use 
of anticoagulation for deep vein thrombosis (DVT) prophylaxis (e.g., 
postoperative DVT prophylaxis) or the use of low dose acetylsalicylic acid 
(≤325 mg). Systemic anticoagulation (including prophylaxis doses) on the day 
of an IM injection should be avoided. 
 
The following medications are prohibited during Step 3: 
• 
All agents that are prohibited in the most current package insert of each of 
the antiretroviral drugs the participant is receiving. 
 
5.5.3 Precautionary Medications 
 
CAB oral administration only: Antacid products containing divalent cations (e.g., 
aluminum, calcium, and magnesium) must be taken at least 2 hours before or at 
least 4 hours after CAB. Concurrent administration of multivitamins is acceptable. 
 


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations 
 
Table 6.1-1:  Step 1 Oral Phase 
Evaluation 
Screen 
Step 
1 
entry 
Step 1 Visits 
(weeks) 
Premature 
Tx/Study 
D/C 
Step 1 SOC Tx 
Visits (weeks); 
see section 6.2.5 
-60 
days 
4 
5, if 
needed;  
see 
section 
6.2.5 
7 
9 
Window 
-7/+14 days; ≥72 
hours between 
these two visits 
 
-7/+14 days 
Documentation of HIV 
X 
 
 
 
 
 
 
Medical and Medication History 
X 
X 
 
 
 
 
 
Documentation of Pre-ART HIV-1 RNA and Nadir 
CD4+ T-cell Count 
 
X 
 
 
 
 
 
Clinical Assessments 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Exam 
X 
 
 
 
 
 
 
Targeted Physical Exam 
 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
Dispensation of Study-provided Oral CAB Plus Current 
Two NRTIs (not provided by the study) 
 
X 
X 
 
 
 
 
Dispensation of SOC ART 
(not provided by the study) 
 
 
 
 
 
X 
X 
Hematology, Liver Function Tests, and Blood 
Chemistries 
X 
X 
X 
X 
X 
 
 
PT/INR 
X 
 
 
 
 
 
 


 
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11Mar2022 
 
Evaluation 
Screen 
Step 
1 
entry 
Step 1 Visits 
(weeks) 
Premature 
Tx/Study 
D/C 
Step 1 SOC Tx 
Visits (weeks); 
see section 6.2.5 
-60 
days 
4 
5, if 
needed;  
see 
section 
6.2.5 
7 
9 
Window 
-7/+14 days; ≥72 
hours between 
these two visits 
 
-7/+14 days 
Urinalysis 
 
X 
 
 
 
 
 
Pregnancy Testing 
X 
X 
X 
X 
X 
X 
X 
Hepatitis Screen 
X 
 
 
 
 
 
 
CD4+/CD8+ T-cells 
X 
 
 
 
 
 
 
Assess Availability of Pre-ART Plasma/Serum for 
Storage 
 
X 
 
 
 
 
 
Plasma HIV-1 RNA  
X 
X 
 
 
 
X 
 
Expedited Plasma HIV-1 RNA  
 
 
X 
X 
 
 
 
Susceptibility Testing to VRC07-523LS 
X 
 
 
 
 
 
 
HIV-1 Drug Resistance Genotype 
 
 
 
X 
 
 
 
ART Adherence Assessment 
 
X 
X 
X 
 
 
 
Stored Plasma and PBMC for Future Studies 
 
X 
X 
 
 
 
 
 
 
 


 
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Table 6.1-2: Step 2 Parenteral Phase 
Evaluation 
Step 2 
Step 2 Visits (weeks) 
VF 
conf. 
Prematur
e 
Tx/Study 
D/C 
Registration 
(R2) 
R2
+ 
2 
R2
+ 
4 
R2
+ 
6 
R2
+ 
8 
R2
+ 
12 
R2 
+ 
16 
R2 
+ 
20 
R2 
+ 
24 
R2 
+ 
28 
R2 
+ 
32 
R2 
+ 
36 
R2 
+ 
40 
R2 
+ 
44 
R2 
+ 
48 
Window 
± 7 days (except for R2+4 
and R2+8 which have a -
7/+0 day dosing window) 
± 7 days 
±14 
days 
Clinical 
Assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted Physical 
Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administration of 
VRC07-523LS 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Administration of 
CAB LA 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Hematology, Liver 
Function Tests, 
and Blood 
Chemistries 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Pregnancy Testing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
CD4+/CD8+ T-cells 
X 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Plasma HIV-1 RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
(see 
section 
6.2.5) 
X 
X 


 
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Evaluation 
Step 2 
Step 2 Visits (weeks) 
VF 
conf. 
Prematur
e 
Tx/Study 
D/C 
Registration 
(R2) 
R2
+ 
2 
R2
+ 
4 
R2
+ 
6 
R2
+ 
8 
R2
+ 
12 
R2 
+ 
16 
R2 
+ 
20 
R2 
+ 
24 
R2 
+ 
28 
R2 
+ 
32 
R2 
+ 
36 
R2 
+ 
40 
R2 
+ 
44 
R2 
+ 
48 
Window 
± 7 days (except for R2+4 
and R2+8 which have a -
7/+0 day dosing window) 
± 7 days 
±14 
days 
HIV-1 Drug 
Resistance 
Genotype 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
(see 
section 
6.2.5) 
X 
 
Stored Plasma (for 
PK of CAB LA) 
X 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
Stored Plasma (for 
Additional PK 
Studies) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum (for VRC07-
523LS  PK) 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum (for 
Antibody to 
VRC07-523LS) 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Distribute Infusion 
Report Card 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Collect Infusion 
Report Card 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Stored Plasma and 
PBMC (for Future 
Studies) 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 


 
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Table 6.1-3: Step 3 SOC Follow-up 
Evaluation 
Step 3 
Step 3 Visits (weeks) 
Registration 
(R3) 
R3+4 
R3+12 R3+24 R3+36 R3+48 
VF 
conf. 
Premature 
Study D/C 
Window 
-/+ 14 days 
Targeted Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Liver Function Tests, and 
Blood Chemistries 
X 
X 
X 
X 
X 
X 
 
X 
CD4+/CD8+ T-cells 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma HIV-1 RNA 
X 
X 
X 
X 
X 
X 
X 
X 
HIV-1 Drug Resistance Genotype 
 
 
 
 
 
 
X 
 
Stored Plasma and Serum (for Additional 
PK Studies) 
 
X 
X 
X 
X 
X 
X 
 
ART Adherence Assessment 
 
X 
X 
X 
X 
X 
X 
X 
Stored PBMC and Plasma for future studies 
 
 
 
 
 
X 
X 
X 
 


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations 
 
Step 1 screening evaluations must occur prior to the participant’s starting oral CAB. 
 
NOTES: All individuals previously enrolled to Step 1 prior to March 16, 
2020, and those screened after that date whose screening lab values have 
expired, and who choose to re-enroll into A5357, may be re-screened for 
Step 1. Screening evaluations that are repeated must be documented and 
keyed on the eCRFs. Previous PhenoSense susceptibility testing to VRC07-
523LS, completed as part of any ACTG study, does not need to be repeated 
as part of the re-screening process, provided there is no documented 
detectable HIV viral load since the original screen. 
 
Screening evaluations to determine eligibility must be completed within 60 days 
prior to study entry unless otherwise specified. In addition, data on participants 
who do not enroll will be captured in a Screening Failure Results form and 
entered into the ACTG database. 
 
Non-reportable Results of the PhenoSense Assay 
If the susceptibility test to VRC07-523LS is resulted as not reportable, the 
participant should be entered as a screen failure. The site may choose to 
re-screen such a participant once at a later date. The CMC should be 
contacted at actg.cmcA5357@fstrf.org to assist with this decision. 
 
6.2.2 Step 1 Oral Phase 
 
Step 1 entry evaluations must occur at least 24 hours after screening evaluations 
and must be completed prior to the initiation of oral CAB. 
 
Participant must begin study treatment within 72 hours after entry. 
 
The week 5 visit (if needed) must occur no earlier than 72 hours after the week 4 
visit is completed. 
 
Adherence counseling per standard of care should be undertaken at every visit 
and whenever a participant is suspected to be poorly adherent to oral therapy. 
 
The availability of the stored pre-ART plasma or serum specimens should be 
determined. 
 
NOTE: Available pre-ART plasma or serum is NOT required for study entry. If 
available, pre-ART plasma or serum should be stored. 
 


 
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6.2.3 Step 2 Parenteral Phase 
 
Participants who meet the inclusion criteria in section 4.3 will register to Step 2 
within 3 weeks after the last visit on Step 1. Registration to Step 2 must occur on 
the same visit day as the last oral CAB dose on Step 1. 
 
Safety laboratory evaluations at Step 2 registration will be performed only if not 
obtained at the last Step 1 visit. 
 
In exceptional circumstances, the protocol team may authorize the use of oral 
CAB as a short-term “bridging” strategy for participants who have begun CAB LA. 
This strategy would only be employed to address any potential gap in CAB LA 
dosing as a result of scheduling conflicts, which would prevent planned dosing. 
Should a participant need “oral bridging”, sites must contact the CMC at 
actg.cmcA5357@fstrf.org for authorization and guidance for treatment strategies 
prior to a missed CAB LA dose. Should a participant not notify the site in 
advance, the CMC must be contacted for further treatment guidance. Refer to the 
A5357 MOPS for additional information or examples for when the bridging 
strategy may be utilized. 
 
NOTE: If a participant does not complete a Step 2 study visit within the visit 
window, sites must notify the CMC at actg.cmcA5357@fstrf.org as soon as 
possible, ideally no later than 24 hours after the visit window closes. The team 
will provide further guidance to sites on a case-by-case basis. 
 
6.2.4 Step 3 SOC Follow-up 
 
Participants who meet the inclusion criteria in section 4.5 will register to Step 3 
within 2 weeks after the last visit on Step 2. Registration to Step 3 may occur on 
the same day as the last Step 2 visit. 
 
Safety laboratory evaluations at Step 3 registration will be performed only if not 
obtained at the last Step 2 visit. 
 
6.2.5 Post-Entry Evaluations 
 
Study visits for Steps 1, 2, and 3 must be scheduled on the weeks indicated in 
the SOE within the visit windows. 
 
NOTE: Screening and enrollment have re-opened, and progression through 
study steps as outlined in the SOE has resumed. 
 
Week 5 on Step 1 
Evaluations listed under week 5 visit in the SOE will occur only for participants 
who have a detectable viral load on week 4 of Step 1 (HIV-1 RNA ≥50 
copies/mL). 
 


 
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NOTE: Safety laboratory evaluations at Step 2 registration will be performed only 
if not obtained at the last Step 1 visit. 
 
Step 1 SOC Treatment Visits 
Participants who have viral load ≥200 copies/mL at week 4 or ≥50 copies/mL at 
week 5, or who permanently discontinue or temporarily hold oral CAB or NRTIs 
for >7 days for any reason in Step 1 will be switched to a SOC regimen. These 
participants will not be eligible for Step 2 and will be followed on study every 2 
weeks for a total of 4 weeks and then be taken off study. NOTE: Previously 
enrolled Step 1 participants who were instructed to discontinue the Step 1 
study treatment and to resume their original complete ART regimen were 
re-screened for Step 1 when the study re-opened to screening and accrual. 
 
Week R2+48 Visit on Step 2 
All participants will complete the Step 2 week R2+48 visit. Only participants who 
have HIV-1 RNA ≥50 copies/mL at week R2+44 will have a repeat HIV-1 RNA at 
the week R2+48 visit. If the HIV-1 RNA ≥200 copies/mL at week R2+48, then 
genotyping will be performed at this time point. 
 
NOTE: For participants who prematurely discontinue from Step 2, the follow-up 
duration will be based on the date of the participant’s last CAB LA dose 
regardless of the last VRC07-523LS infusion. Safety laboratory evaluations at 
Step 3 registration will be performed only if not obtained at the last Step 2 visit. 
 
Confirmation of Suspected Virologic Failure 
Virologic failure is defined as two consecutive HIV-1 RNA levels ≥200 copies/mL 
or last ≥200 copies/mL. Participants with a plasma HIV-1 RNA ≥200 copies/mL 
will have a confirmation of suspected virologic failure visit as soon as possible 
and no later than 2 weeks after the first sample was drawn. If this visit coincides 
with a regularly scheduled visit, the evaluations should be combined. See section 
8.7 for management of participants with confirmed virologic failure. 
 
HIV-1 Drug Resistance Genotype 
See section 6.3.8 for additional information on genotyping for participants with 
confirmed virologic failure or participants who have week R2+44 RNA ≥50 
copies/mL and week R2+48 RNA ≥ 200 copies/mL. 
 
6.2.6 Discontinuation Evaluations 
 
Evaluations for Registered Participants Who Do Not Start Oral CAB on Step 1 
All eCRFs must be completed and keyed for the period up to and including entry. 
No further follow-up is required. 
 
Premature Study Treatment Discontinuation Evaluations 
Participants who permanently discontinue or temporarily hold oral CAB or NRTIs 
for >7 days for any reason in Step 1 will be switched to a SOC regimen and be 
followed every 2 weeks for a total of 4 weeks as outlined in the Step 1 SOE. 


 
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Participants who prematurely discontinue study treatment for any reason in Step 
2 must complete the premature study treatment discontinuation evaluations 
within 2 weeks after stopping CAB LA and VRC07-523LS. These participants will 
register to Step 3 and be switched to a SOC regimen and followed per the SOE 
until study completion. 
 
Participants who become pregnant while on oral CAB, CAB LA, or VRC07-523LS 
must immediately discontinue oral CAB, CAB LA, and VRC07-523LS and will be 
switched to an appropriate SOC regimen. They must complete the premature 
study treatment discontinuation evaluations within 2 weeks after stopping oral 
CAB, CAB LA, and VRC07-523LS. The site must document participant referral to 
appropriate obstetrics care. Participants will be encouraged to remain in the 
study to be followed on study/off study treatment until study completion. 
 
NOTE: Sites must contact the CMC via email at actg.cmca5357@fstrf.org for any 
instances of premature study treatment discontinuation. 
 
Premature Study Discontinuation Evaluations 
Participants who prematurely discontinue study participation after receiving any 
study treatment or who do not initiate any study treatment in Step 1 or Step 2 will 
have the premature study discontinuation evaluations performed per the SOE. 
 
Study Completion Evaluations 
For Step 3, week R3+48 will be the final study visit for participants. 
 
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/score-source-documentation-
requirements.pdf. 
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the DAIDS AE Grading Table and AE reporting of 
adverse events requirements. 
 
The protocol team and/or study monitoring entity (e.g., SMC) may determine that 
additional source data associated with procedures or evaluations performed per 
protocol should be entered into eCRFs so that the data can be used for analysis 
or to otherwise assist with interpretation of study findings. In such cases, sites 
will be officially instructed to enter the additional data into eCRFs from available 
source documentation. 
 


 
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6.3.1 Documentation of HIV-1 
 
Section 4.1.1 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation of the date of diagnosis must be recorded. 
 
6.3.2 Medical and Medication History 
 
The medical history must include all signs and symptoms regardless of grade 
and all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade within the past 30 days. In addition, the following 
diagnoses should be recorded regardless of when the diagnosis was made: 
• 
AIDS-defining conditions (refer to the CDC HIV Classification and the WHO 
Staging System for HIV Infection and Disease) 
• 
Bone fractures (verbal history accepted) 
• 
Coronary artery disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B 
 
The medical history evaluation will be assessed at the screening and entry visit 
and recorded on the eCRFs at the study entry visit. 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history. 
 
Table 6.3.2-1: Medication History 
Medication Category 
Complete History or Timeframe 
Antiretroviral Therapy 
Available ARV history 
Immune-based Therapy 
Within 30 days prior to study 
entry 
Blinded study Treatment 
Within 30 days prior to study 
entry 
HIV-1-related Vaccines 
Within 30 days prior to study 
entry 
Prescription Drugs 
Current use at entry 
Alternative Therapies 
Current use at entry 
Dietary Supplements 
Current use at entry 
Non-prescription drugs (over-the-counter) 
Current use at entry 
Sex-hormone medications or sex-hormone 
analogues or antagonists* 
Current use at entry 
(*Includes: hormone-releasing IUDs (e.g., Mirena inserted in the last 5 years); oral, 
injectable, implanted, or patch contraceptives; vaginal ring, creams, or inserts; estrogen, 
progesterone, or testosterone therapy; leuprolide or other synthetic gonadotropin-


 
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releasing hormone; tamoxifen, raloxifene, aromatase inhibitors or any other androgen, 
estrogen, or progesterone analogue or antagonist therapy.) 
 
Any allergies to any medications and their formulations must also be documented. 
 
6.3.3 Documentation of Pre-ART HIV-1 RNA and Nadir CD4+ T-cell Count 
 
Document the pre-ART HIV-1 RNA level and nadir CD4+ T-cell count. Participant 
recall is acceptable. 
 
6.3.4 Clinical Assessments 
 
Complete Physical Exam 
A complete physical examination will be performed at the screening visit and 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 signs 
and symptoms, diagnoses, and vital signs (height, weight, temperature, pulse, 
respiration rate, and blood pressure). 
 
Targeted Physical Exam 
A targeted physical examination will be performed and is to include vital signs 
(weight, temperature, pulse, respiration rate, and blood pressure) and injection 
site reactions. The targeted physical exam will be driven by any previously 
identified or new signs or symptoms and diagnoses that the participant has 
experienced since the last visit. 
 
Post entry, see section 8.5 for collection requirements for pregnancy. Refer to 
section 7.2 for AE collection requirements. 
 
Height 
Height (cm) will be recorded at screening. 
 
Weight 
Weight (kg) will be recorded at every visit. 
 
Signs and Symptoms 
At Step 1 entry, signs and symptoms of all grades that occurred within 30 days 
prior to entry must be recorded as medical history. For post-entry signs and 
symptoms, refer to section 7.2 for AE reporting requirements. 
 
Diagnoses 
After Step 1 entry, refer to section 7.2 for AE reporting requirements. 
 
Active solicitation of adverse events will be done at every study visit. 
 


 
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Concomitant Medications 
After Step 1 entry, record all new and discontinued concomitant medications, 
including sex-hormone medications or sex-hormone analogues or antagonists 
(see section 6.3.2 for examples), prescription medication, dietary supplements 
and over-the-counter medications taken since the last visit. Ongoing medications 
do not need to be recorded at each visit. 
 
ECG 
At screening, an ECG will be performed on all participants. The screening ECG 
results must be recorded at Step 1 entry. 
 
VRC07-523LS Infusion Monitoring 
Prior to each VRC07-523LS administration, record temperature, blood pressure, 
heart rate (pulse), and weight. A targeted physical examination may be conducted 
(based on signs, reported symptoms, or interim medical history). Sites must observe 
participants for at least 60 minutes following VRC07-523LS administration. During 
the monitoring period, participants will be observed for clinical AEs, and vital signs 
checked every 15 minutes for up to 60 minutes after the completion of infusion. 
 
CAB LA Injection Monitoring 
Record injection site reactions or any other signs and symptoms from CAB LA 
administration at the next scheduled study visit. 
 
6.3.5 Documentation of Study Treatment and SOC ART Administration 
 
Record oral CAB plus two NRTIs in Step 1, including initial dose, any interruption 
regardless of duration, dose modifications, formulation modifications, and 
permanent discontinuations. 
 
Record all VRC07-523LS infusions and CAB LA injections in Step 2, including 
dose administered, time administration initiated, whether administration was 
temporarily halted for any reason, duration and rate of infusion, and whether the 
full dose was administered. If the full dose was not administered, the amount 
(volume and concentration) that was administered should be recorded, along 
with the reason the full dose was not administered. 
 
Record SOC ART regimen administered on Step 3, including initial dose, any 
interruption lasting 3 days or longer, dose modifications, formulation 
modifications, and permanent discontinuations. 
  
6.3.6 Laboratory Evaluations 
 
At screening and entry, record on the eCRF all protocol-required laboratory 
values regardless of grade. For post-entry assessments, record all creatinine, 
creatinine clearance, creatine phosphokinase (CPK), and lipase values 
regardless of grade; record abnormal laboratory findings per section 7.2. 
 


 
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PT/INR 
PT/INR will be performed at the local laboratory. 
 
Hematology 
Hemoglobin, hematocrit, white blood cell count (WBC), differential WBC, 
absolute neutrophil count (ANC), absolute eosinophil count, and platelet count 
will be performed at the local laboratory. 
 
Liver Function Tests 
Total bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase will be 
performed at the local laboratory. 
 
NOTE: For participants on ritonavir boosted atazanavir, total and direct bilirubin 
should be measured. 
 
Blood Chemistries 
Blood urea nitrogen (BUN), creatinine, glucose, creatine phosphokinase (CPK), 
lipase, and electrolytes (sodium, potassium, chloride, and CO2/bicarbonate) will 
be performed at the local laboratory. 
 
Creatinine clearance must be recorded each time that a creatinine level is 
recorded. Creatinine clearance should be estimated by the Cockcroft-Gault 
equation. A program for calculating creatinine clearance by the Cockcroft-Gault 
method is available at www.fstrf.org. 
 
Child-Pugh Score 
Since albumin is needed for the Child-Pugh calculation, albumin will be 
performed as part of liver function tests or chemistries. 
 
Urinalysis 
Dipstick or microscopic exam may be done; if dipstick results are abnormal, 
microscopic exam is required. 
 
Pregnancy Test 
A pregnancy test will be performed for persons of child-bearing potential: 
serum or urine -HCG (urine test must have a sensitivity of at least 25 mIU/mL). 
A serum or urine pregnancy test must be obtained per the SOE. 
 
Record pregnancy and pregnancy outcome per section 8.0. See section 8.5 for 
management of participants who become pregnant while on study. 
 
Hepatitis Screen 
HCV antibody, HCV RNA (if HCV antibody positive; see section 4.1.13), and 
HBsAg testing per the SOE. 
 


 
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6.3.7 Immunologic Studies 
 
CD4+/CD8+ T-cells 
Screening absolute CD4+/CD8+ T-cell count and percentages must be 
performed within 60 days prior to study entry at a laboratory that possesses a 
CLIA certification or equivalent (US sites). 
 
Entry and post-entry absolute CD4+/CD8+ T-cell counts and percentages should 
be performed at the same laboratory, if possible, and that laboratory must 
possess a CLIA certification or equivalent (US sites). 
 
Assess Availability of Pre-ART Plasma or Serum for Storage 
The availability of the stored pre-ART plasma or serum samples will be 
determined but is NOT required for entry into the study. If available, these 
specimens should be stored for later testing. 
 
6.3.8 Virologic Studies 
 
Plasma HIV-1 RNA 
Screening HIV-1 RNA must be performed within 60 days prior to study entry at a 
laboratory that possesses a CLIA certification or equivalent (US sites). Eligibility 
will be determined based on the screening value. 
 
Entry and post-entry plasma HIV-1 RNA must be performed per the SOE. 
Samples must be processed and shipped to the designated central ACTG testing 
laboratory (refer to laboratory processing chart [LPC] for shipping information) in 
an expeditious manner. At weeks 4 and 5 in Step 1, ship the plasma HIV-1 RNA 
samples on the same day the sample is obtained. 
 
Susceptibility Testing to VRC07-523LS 
A sample for susceptibility testing to VRC07-523LS must be obtained at 
screening and shipped to the designated laboratory for testing (refer to LPC for 
details). The results of the PhenoSense assay will be available within 4 weeks 
after testing and will be communicated to sites to determine eligibility for the 
study. Refer to the A5357 MOPS for additional information on the reporting of the 
assay results. 
 
NOTE: Previous PhenoSense susceptibility testing to VRC07-523LS, 
completed as part of any ACTG study, does not need to be repeated as part 
of the re-screening process, provided there is no documented detectable 
HIV viral load since the original screen. 
 
HIV-1 Drug Resistance Genotype 
An HIV-1 drug resistance genotype (virus population sequencing of reverse 
transcriptase, protease, and integrase coding regions of the pol gene) will be 
performed for participants with confirmed virologic failure or participants who 


 
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have week R2+44 RNA ≥50 copies/mL and week R2+48 RNA ≥ 200 copies/mL. 
Refer to the LPC for additional information. 
 
6.3.9 PK Studies 
 
Blood samples will be collected and stored for determination of CAB and VRC07-
523LS levels and serum for PK and antibody to VRC07-523LS according to 
Tables 6.1-2 and 6.1-3. 
 
See section 11.0 for additional details on the planned pharmacokinetic studies. 
 
6.3.10 IRC 
 
Participants will be given an IRC in Step 2 to use as a memory aid for solicited 
AEs. For this study, solicited AEs occurring during the 3 days after receipt of 
VRC07-523LS will include: unusually tired, feeling unwell, muscles aches, 
headache, chills, nausea, and joint pain. Participants will also record highest 
measured temperature daily. 
 
Participants should be instructed to take their temperature at least once daily, 
starting with the day of infusion (day 0), after leaving the clinic, through day 3 
post-infusion. Temperature should be taken orally in the evening whenever 
possible. If more than one measurement is made in a day (for example due to 
feeling unwell), then the highest temperature taken that day should be recorded. 
Sites will provide thermometers and/or instructions on the use of thermometers to 
participants as needed. 
 
The IRCs will be reviewed for accuracy and completeness at follow-up visits. 
Clinicians will collect resolution information for any systemic symptoms that are 
not resolved after 3 days. Additionally, active solicitation of AEs will be done at 
every visit. All reportable signs and symptoms from the IRC will be recorded per 
section 7.2. 
 
6.3.11  ART Adherence Assessment 
 
Adherence to ART medications, including oral CAB and two NRTIs on Step 1 
and to SOC ART on Step 3, will be assessed by self-report per the SOE. 
 
The adherence eCRF is posted on the DMC Portal in the Forms Management 
Utility. 
 
6.3.12  Stored Plasma and PBMC for Future Studies 
 
Cryopreserved plasma and PBMC will be stored per the SOE for future analysis. 
 
For PBMC cryopreservation during the study, all laboratories must be certified for 
protocol testing by the DAIDS Immunology Quality Assurance Program. 


 
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7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Events 
 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or diagnosis that occurs in a study participant at or after 
study entry REGARDLESS of the attribution (i.e., relationship of event to protocol-
imposed intervention). This includes any occurrence that is new in onset or aggravated 
in severity or frequency from the baseline condition. 
 
7.2 
Adverse Event Collection Requirements for this Protocol 
 
All AEs must be recorded on the eCRFs if any of the following criteria have been met. 
• 
All Grade ≥3 AEs 
• 
All AEs that led to a change in study treatment/intervention regardless of grade 
• 
All AEs meeting SAE definition or EAE reporting requirement 
 
NOTE: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system. 
 
Diagnoses 
Post-entry, all targeted diagnoses listed below and diagnoses that led to a change in 
Steps 1 and 2 study treatment (i.e., oral CAB and two NRTIs for Step 1 or CAB LA and 
VRC07-523LS for Step 2) must be recorded regardless of grade. 
• 
Immunologic including AIDS-defining conditions and HIV-associated opportunistic 
infection (OI) 
• 
Bone fractures (verbal history accepted) 
• 
Cardiovascular including coronary heart disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Chronic obstructive pulmonary disease (COPD) 
• 
Diabetes 
• 
Tuberculosis (TB) 
• 
Acute hepatitis C 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B 
• 
Acute hepatitis B 
• 
Autoimmune disorders 
• 
Renal disease 
• 
Pregnancy 
 
Signs and Symptoms 
Post-entry, Grade ≥3 signs and symptoms and all signs and symptoms that led to a 
change in study treatment must be recorded regardless of grade. 
 


 
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Laboratory Evaluations 
For post-entry assessments, Grade ≥2 laboratory findings and all laboratory findings that 
led to a change in study treatment must be recorded regardless of grade. 
 
All AEs must be reported in the eCRFs if the reporting criteria have been met for any 
diagnoses, signs and symptoms, and abnormal laboratory findings as described below. 
 
All AEs that are reported must have their severity graded. To grade AEs, sites must refer 
to the DAIDS AE Grading Table, corrected Version 2.1, July 2017, which can be found 
on the DAIDS RSC website: https://rsc.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables. 
 
Serious Adverse Events (SAEs) 
A SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that 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 other outcomes listed in the definition above). 
 
7.3 
Expedited Reporting of Adverse Event (EAE) to DAIDS 
 
7.3.1 Expedited Reporting of Adverse Events 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 https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-
reporting-adverse-events-daids. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for EAE reporting to DAIDS. In the event of 
system outages or technical difficulties, EAEs may be submitted using the DAIDS 
EAE Form. This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. 
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Please note that site queries may also be sent 
from within the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety 
Office at (DAIDSRSCSafetyOffice@tech-res.com). 
 


 
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7.3.2 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. 
 
The study agents for which expedited reporting are required are: 
• 
Oral CAB (oral cabotegravir) 
• 
VRC07-523LS (via infusions) 
• 
CAB LA (injectable cabotegravir) 
• 
Two NRTIs taken on Step 1 
In addition to SAEs, sites will report in an expedited manner the following events: 
• 
ALT ≥3x ULN AND total bilirubin ≥2x ULN 
• 
Any seizure event 
• 
ALT ≥8x ULN 
• 
ALT ≥3x baseline ALT with signs/symptoms of acute hepatitis 
• 
ALT ≥5x ULN that persists >2 weeks 
• 
Confirmed abacavir hypersensitivity reaction 
 
7.3.3 Grading Severity of Events 
 
The DAIDS AE Grading Table, corrected Version 2.1, July 2017, must be used 
and is available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-tables. 
 
7.3.4  Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is as 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). 
 
7.4 
Study Monitoring 
 
Accrual, baseline characteristics, study conduct (including premature treatment and 
study discontinuations), virologic failures, and all AEs will be monitored during the trial 
on a regular basis by the protocol core team. The protocol core team will review the 
individual safety data frequently to assess the relation of all reported AEs to oral CAB, 
CAB LA, and VRC07-523LS. 
 
The DAIDS clinical representative will review and assess select EAE reports for potential 
impact on the study participant safety and protocol conduct as per DAIDS policies, 
guidance documents, and SOPs as applicable. 
 


 
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To ensure the safety of the participants, the study will be reviewed routinely by an 
independent ACTG appointed study monitoring committee (SMC) at the earlier of (i) the 
25th enrolled participant has reached week R2+24 in Step 2 of the CAB LA plus VRC07-
523LS combination or discontinued the study or study treatment prior to this, or (ii) 1 
year after the study is open for enrollment. After the first interim review, the study will be 
routinely monitored annually by the SMC. 
 
An interim review may be triggered prior to this if (i) three or more participants have 
virologic failures while on Step 2 treatment (see section 10.5 for definition of virologic 
failures considered in the stopping guideline), (ii) one or more participant(s) experience a 
death that is assessed by the protocol core team as possibly, probably, or definitely 
related to CAB LA and/or VRC07-523LS at any time, (iii) two or more participants 
experience a Grade 4 AE that is assessed by the protocol core team as possibly, 
probably, or definitely related to CAB LA and/or VRC07-523LS before 25 participants are 
enrolled and have reached week R2+24 of Step 2, or (iv) four or more participants 
experience a Grade 4 AE that is assessed by the protocol core team as possibly, 
probably, or definitely related to CAB LA and/or VRC07-523LS at any time. 
 
If an interim review is triggered, enrollment into Step 1 and Step 2 will be paused 
pending SMC consultation and participants in Step 1 or Step 2 will continue to follow the 
intended study design including continuing the step-specific study treatment until the 
SMC has been consulted. An interim review may also be convened if a concern is 
identified by the DAIDS clinical representative, the study chairs, or study statisticians in 
consultation with the team. See section 10.0 for statistical and other considerations 
related to interim monitoring. 
 
Detailed plans for study monitoring will be outlined in a Study Monitoring Plan developed 
by the Statistical and Data Management Center (SDMC) prior to enrollment of the first 
participant. 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity 
 
Criteria for participant management, dose interruptions, modifications, and 
discontinuation of study drugs are delineated only for toxicities attributable to study 
treatment on Step 1 and Step 2 (i.e., oral CAB and two NRTIs during Step 1 or CAB LA 
and VRC07-523LS during Step 2). The goal is to maintain participant safety while 
continuing therapy, if possible. If any individual study drug must be interrupted or 
discontinued due to toxicity, then the entire regimen must be interrupted or discontinued. 
Participants who have study treatment discontinued for toxicity should be followed for a 
total of 4 weeks if the discontinuation occurred in Step 1 or for approximately 48 weeks 
as part of Step 3 of the protocol if the discontinuation occurred in Step 2. NOTE: If 
participants discontinue oral CAB in Step 1, they will be considered being on-study/off-
study treatment regardless of continuation of their NRTIs. 
 


 
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NOTE: The CMC must be notified at actg.cmca5357@fstrf.org regarding toxicities that 
result in regimen interruption or discontinuation. The protocol does not allow drug 
substitution for toxicity management. 
 
The general guidelines presented in sections 8.1.1 to 8.1.3 apply to toxicities that are not 
specifically discussed elsewhere. 
 
8.1.1 Grade 1 or 2 
 
Participants who develop a Grade 1 or 2 AE or toxicity may continue the Step 1 
or Step 2 study treatment. If the participant chooses to discontinue the study 
treatment, the site should complete the premature treatment discontinuation 
evaluations, notify the A5357 CMC at actg.cmca5357@fstrf.org, and have the 
participant attend all remaining study visits. 
 
8.1.2 Grade 3 
 
Grade 3 AE or toxicity must be evaluated and managed by the site investigator 
according to the SOC. It may be necessary to discontinue the Step 1 or Step 2 
study treatment. The A5357 CMC must be notified at actg.cmca5357@fstrf.org 
regarding AEs or toxicities that result in a change of study treatment. If the site 
investigator has compelling evidence that the AE or toxicity was NOT caused by 
the Step 1 or Step 2 study treatment, dosing may continue. If the study treatment 
is temporarily held, the participant should be re-evaluated closely until the AE or 
toxicity returns to Grade ≤2, at which time the study treatment may be 
reintroduced at the discretion of the site investigator or according to standard 
practice. 
 
If the site investigator determines that a Grade 3 AE or toxicity is an isolated 
event, the site has the option of confirming the AE or toxicity before holding the 
study treatment. 
 
If the same Grade 3 AE or toxicity recurs within 4 weeks of reintroducing the 
study treatment and is thought to be related to the study treatment (per the site 
investigator), the study treatment must be permanently discontinued. However, if 
the same Grade 3 AE or toxicity recurs after 4 weeks, but is not thought to be 
related to the study treatment (per the site investigator), the management 
scheme outlined above may be repeated. 
 
Participants experiencing Grade 3 AEs or toxicities requiring permanent 
discontinuation of the study treatment should be followed closely until resolution 
of the AE or toxicity. The A5357 CMC must be notified at 
actg.cmca5357@fstrf.org. See section 6.2.6 for management of participants who 
prematurely discontinue study treatment. 
 


 
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8.1.3 Grade 4 
 
Participants who develop a Grade 4 AE or toxicity thought to be related to study 
treatment (per the site investigator) must have the Step 1 or Step 2 study 
treatment temporarily held. If the site investigator has compelling evidence that 
the AE or toxicity has NOT been caused by the study treatment, dosing may 
resume when the AE or toxicity has resolved to Grade ≤2. Notify the A5357 CMC 
at actg.cmca5357@fstrf.org. 
 
Participants experiencing Grade 4 AEs or toxicities requiring permanent 
discontinuation of the study treatment should be followed closely until resolution 
of the AE or toxicity to Grade ≤2, and the protocol team must be consulted. See 
section 6.2.6 for management of participants who prematurely discontinue study 
treatment. 
 
8.2 
Clinical Abnormalities 
 
8.2.1 Liver Function Tests 
 
The Step 1 or Step 2 study treatment may be continued for asymptomatic Grade 
≤3 AST/ALT elevations at the discretion of the site investigator, and in 
consultation with the CMC. All Grade ≥2 ALT elevations must be communicated 
to the CMC for review and discussion regarding re-testing and/or continuation of 
study treatment. 
 
For symptomatic Grade 3 (e.g., fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia) or any Grade 4 elevations in AST 
or ALT with or without symptoms, no further doses of the study treatment should 
be given, and the CMC should be consulted. Refer to the eosinophilia grading 
table below. In addition, for Grade 3 ALT with bilirubin ≥2 x ULN (attempts 
should be made to fractionate the bilirubin), the study treatment should be held 
and the CMC consulted for further guidance. 
 
Table 8.2.1-1: Grading Table for Eosinophilia, by Absolute Eosinophil Count 
Grade Value 
1 
1000/μL to 1499/μL 
2 
1500/μL to 1999/μL 
3 
2000/μL to 10,000/μL 
4 
>10,000/μL  
 
In participants receiving CAB LA plus VRC07-523LS, the study treatment will be 
stopped if any of the following liver chemistry criteria are met: 
• 
ALT ≥3x ULN and total bilirubin ≥2x ULN 
• 
ALT ≥8x ULN 
• 
ALT ≥3x baseline ALT with signs/symptoms of acute hepatitis 
• 
ALT ≥5x ULN that persists >2 weeks 


 
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All participants who permanently discontinue study treatment as a result of liver 
toxicity should be followed weekly until resolution to Grade ≤2. Participants will 
be followed on study/off study treatment after study treatment discontinuation. 
 
Careful assessments should be done to rule out other possible causes (e.g., 
alcohol, non-study-treatment-related toxicity, syphilis, or viral hepatitis) as the 
cause of Grade 3 or Grade 4 AST/ALT elevations. 
 
Evaluations to be considered (but are not required) include: 
• 
Viral hepatitis serology including: hepatitis A IgM antibody, hepatitis B surface 
antigen (HBsAg) and hepatitis B core antibody (IgM), hepatitis C RNA, 
hepatitis E IgM antibody 
• 
Cytomegalovirus IgM antibody 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing) 
• 
Syphilis screening 
• 
Drugs of abuse screen including alcohol 
• 
Serum acetaminophen test (APAP adduct test) 
• 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver 
kidney microsomal antibodies 
• 
Liver imaging to evaluate liver disease. 
 
8.2.2 CPK Elevation 
 
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 
2 to 4 weeks to ensure the result is transient or due to exercise and will not 
require a change in study treatment. A history regarding use of drugs known to 
cause increase of CPK (such as statins) physical activity or exercise preceding 
the CPK evaluation should be obtained. 
 
Grade 4 elevations in CPK should have a repeat assessment after the participant 
has abstained from exercise for >24 hours. For persistent Grade 4 CPK 
elevations that are considered related to study treatment (per the site 
investigator), the Step 1 or Step 2 study treatment should be discontinued. See 
section 6.2.6 for management of participants who prematurely discontinue study 
treatment. 
 
8.2.3 Lipase Elevations and Pancreatitis 
 
Participants with asymptomatic Grade 1 or Grade 2 elevations in lipase may be 
followed closely for the development of symptoms. 
 
Participants with asymptomatic Grade ≥3 elevations in lipase that are considered 
related to study treatment by site investigator should have the Step 1 or Step 2 


 
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study treatment held until serum lipase returns to Grade 2. The lipase assay 
should be repeated within 2 weeks of any Grade ≥3 result. Participants with 
persistence of Grade ≥3 lipase in the absence of other diagnoses or 
reoccurrence of lipase elevation (at Grade ≥2) following reintroduction of study 
treatment should permanently discontinue the study treatment. 
 
Participants with a confirmed diagnosis of clinical pancreatitis that is considered 
related to study treatment by a site investigator should have all study treatments 
held. After complete resolution of the episode, participants may be re-challenged 
with study treatment after discussion with the A5357 CMC, only if the Investigator 
has compelling evidence that the event was not caused by study treatment. Upon 
re-challenge, lipase determinations should be performed every 2 weeks for at 
least 6 weeks after re-initiation of treatment. With any elevation of lipase of 
Grade ≥2 or any recurrence of symptoms, the participant should discontinue all 
study treatments. See section 6.2.6 for management of participants who 
prematurely discontinue study treatment. 
 
8.2.4 Seizure 
 
Any seizure event will result in permanent discontinuation of the Step 1 or Step 2 
study treatment. Local standards should be followed if the event occurred in Step 
3. 
 
8.2.5 Suicidal Ideation 
 
Participants with HIV may occasionally present with symptoms of depression 
and/or suicidality (suicidal ideation or behavior). In addition, there have been 
reports of depression and suicidal ideation and behavior (particularly in 
participants with a pre-existing history of depression or psychiatric illness) in 
some participants being treated with integrase inhibitors, including CAB. 
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. 
 
8.3 
Allergic Reactions 
 
8.3.1 Allergic Reactions During CAB Administration 
 
Participants may continue CAB during Grade 1 or Grade 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. 


 
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Participants with Grade ≥3 allergic reactions that are considered to be related to 
the CAB by site investigator should permanently discontinue the Step 1 or Step 2 
study treatment. Participants should be treated as clinically appropriate and 
followed until resolution of the AE. 
 
See section 6.2.6 for management of participants who prematurely discontinue 
study treatment. 
 
8.3.2 Allergic Reactions During VRC07-523LS Infusion 
 
Participants who develop a Grade 1 or Grade 2 AE or toxicity during infusion may 
complete the VRC07-523LS infusion at the discretion of the site investigator, and 
will be followed carefully. The site investigator may consider reducing the speed 
of the infusion or prescribing antihistamines, topical corticosteroids, or antipruritic 
agents as needed. If a participant chooses to discontinue VRC07-523LS, the site 
should notify the A5357 CMC at actg.cmca5357@fstrf.org and have the 
participant complete follow-up study visits as part of Step 3. Grade 1 or Grade 2 
AEs or toxicities that may be related to VRC07-523LS (per the site investigator) 
should be handled according to standard clinical practice and documented. 
 
Participants who develop a Grade 3 AE or toxicity during infusion should have 
VRC07-523LS discontinued and the A5357 CMC should be notified. Grade 3 
AEs or toxicities that occur following infusion should be handled according to 
standard clinical practice and the A5357 CMC should be notified. 
 
Participants who develop a Grade 4 AE or toxicity during infusion will have all 
study treatments (i.e., CAB LA and VRC07-523LS during Step 2) discontinued. 
Participants experiencing Grade 4 AEs or toxicities should be followed closely 
until the resolution of the AE or toxicity to Grade ≤2 and the A5357 CMC must be 
consulted within 24 hours. 
 
Any participant who has received any dose of study treatment in Step 2 will be 
followed for approximately 48 weeks as part of Step 3 of the protocol. 
 
Pre-Medication 
Pre-medication for infusions is not planned. However, if an infusion 
reaction occurs during administration or if the participant has a medical 
history suggesting a potential benefit from pre-medication, the study 
investigator(s) should determine the appropriate pre-medication. Any pre-
medication given will be documented as a concomitant medication. 
 
If minor infusion reactions are observed, administration of acetaminophen 
500 mg to 1000 mg, antihistamines, and/or other appropriately indicated 
medications may be given prior to the start of infusions for subsequent 
visits. 
 


 
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8.4 
Local Reactions 
 
8.4.1 Injection Site Reactions 
 
Injection site reactions (ISRs) will be managed through site investigator 
assessment and participant infusion report card collection throughout the study. 
All Grade 3 or Grade 4 ISRs must be discussed with the A5357 CMC 
(actg.cmca5357@fstrf.org) to determine etiology and assess appropriate 
continued study participation. 
 
Digital photographs will be obtained where possible for all participants who have 
an ISR that is either serious or Grade 2 or above and that persists beyond 2 
weeks. 
 
ISR discomfort can be managed symptomatically (e.g., cold/warm compress, 
acetaminophen, ibuprofen) if the reaction is interfering with the participant’s 
ability to perform activities of daily living. If a participant chooses to discontinue 
CAB LA, the site should notify the A5357 CMC at actg.cmca5357@fstrf.org and 
encourage the participant to complete follow-up study visits as part of Step 3. 
 
8.5 
Pregnancy 
 
Female participants must not participate in the conception process (e.g., active attempt 
to become pregnant or in vitro fertilization), and if participating in sexual activity that 
could lead to pregnancy, female participants must use an effective form of contraception 
while receiving oral CAB, CAB LA, or VRC07-523LS and for 30 days after stopping oral 
medications, or the duration specified in the product label if receiving ARV drugs not 
supplied by the study, and for approximately 48 weeks after last dose of CAB LA or 
VRC07-523LS. 
 
Acceptable contraceptive methods include: 
• 
Contraceptive subdermal implant 
• 
Intrauterine device or intrauterine system 
• 
Combined estrogen and progestogen oral contraceptive 
• 
Injectable progestogen  
• 
Contraceptive vaginal ring  
• 
Percutaneous contraceptive patches 
 
Individuals who become pregnant while on Step 1 or Step 2 must immediately 
discontinue study treatment and consult with their primary care physicians. Participants 
should have the premature treatment discontinuation evaluations completed within 2 
weeks after stopping study treatment. Participants will be encouraged to remain in the 
study to be followed on study/off study treatment until study completion. 
 
Sites should have an obstetrical care referral plan in place for individuals of child-
bearing potential who become pregnant while receiving CAB or within 48 weeks after the 


 
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final dose of CAB LA. The obstetrical referral is to provide greater assurance for the 
appropriate evaluation of the pregnancy, per SOC, following exposure to CAB or within 
48 weeks of the final dose of CAB LA. If a study participant becomes pregnant, the site 
investigator must document i) referral to obstetrical care, and ii) discussion of the study 
drug(s) received by the participant and any implications for follow-up (e.g., any known 
risk of neural tube defects) with the obstetrical care team and primary care provider. 
 
If an individual has completed the study or chooses to discontinue from the study 
before the end of the pregnancy, then site staff must request permission to contact the 
participant regarding their pregnancy outcomes and infant outcomes at the end of the 
pregnancy. Pregnancy and pregnancy outcome will be recorded on the eCRFs. 
Pregnancy outcomes will be summarized in the final study report. Only pregnancies that 
occur while a female participant is receiving FDA-approved ARV agents on study should 
be reported prospectively to The Antiretroviral Pregnancy Registry. More information is 
available at www.apregistry.com. Telephone: 800-258-4263; Fax: 800-800-1052. 
 
8.6 
Breastfeeding 
 
Female participants who become pregnant and have a live birth while on study should 
refrain from breastfeeding until 48 weeks from the last dose of study treatment in Step 2 
to avoid potential exposure of the infant because non-clinical data suggest that CAB may 
be present in breast milk. 
 
8.7 
Virologic Failure 
 
Refer to section 6.2.5 for confirmation of suspected virologic failure in Step 1. 
 
Participants with confirmed virologic failure on Step 2, per section 6.2.5, will discontinue 
CAB LA and VRC07-523LS infusions and will continue on study in Step 3 where they will 
switch to a non-integrase inhibitor SOC regimen pending the results of genotypic testing. 
The participant should continue on study follow-up with visits and evaluations as outlined 
in the SOE. The A5357 CMC must be notified. 
 
Participants who experience virologic failure in Step 3 will be managed by the site 
investigator according to standard practice and guided by results of genotypic testing. 
Consultation with the A5357 CMC is encouraged. 
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Study Treatment Discontinuation 
 
• 
Request by the participant to discontinue study treatment. 
• 
Drug-related toxicity (see section 8.1). 
• 
Clinical abnormalities (see section 8.2). 
• 
Allergic reactions (see section 8.3). 
• 
Local reactions (see section 8.4). 


 
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• 
Requirement for prohibited concomitant medications (see section 5.5). 
• 
Pregnancy 
• 
Virologic rebound in Step 1 (see section 6.2.5) or virologic failure in Step 2. 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
the toxicity section of the protocol. 
• 
Completion of treatment as defined in the protocol. 
 
9.2 
Premature Study Discontinuation 
 
• 
Non-initiation of study treatment in Step 1 or Step 2. 
• 
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. NOTE: Whenever possible, it is preferable to keep all 
participants on study even if they have to discontinue study treatment. 
• 
Maintained suppression in Step 1 but ineligible for Step 2. 
• 
At the discretion of the IRB, Food and Drug Administration (FDA), NIAID, Office for 
Human Research Protections (OHRP), other government agencies as part of their 
duties, investigator, or industry supporters. 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
General Design Issues 
 
This is an open-label, single arm study to evaluate the safety, tolerability, and virologic 
efficacy of the combination of CAB LA plus VRC07-523LS in participants with HIV-1 with 
well-controlled viral replication. Seventy-four participants will be enrolled over 
approximately 9 to 12 months. It is hypothesized that the parenteral administration of 
CAB LA plus VRC07-523LS after a lead-in period of oral CAB plus two NRTIs will be 
safe and efficacious in preventing HIV-1 RNA rebound (virologic failure is defined as 
confirmed HIV-1 RNA ≥200 copies/mL) up to 44 weeks after initiation of the long-acting 
combination. 
 
To ensure participants’ safety, virologic failures and AEs will be monitored regularly by 
the core team. An independent ACTG appointed Study Monitoring Committee (SMC) will 
review the interim study data (see section 7.4, Study Monitoring). 
 
10.2 
Outcome Measures 
 
Primary and secondary outcome measures listed below will be addressed in the study’s 
primary Statistical Analysis Plan, which will define the content of the Primary Analysis 
Report. This report will form the basis for the primary study manuscript and results 
reporting to ClinicalTrials.gov. Outcomes of interest for secondary and exploratory 
objectives intended for subsequent publications are to be listed under “Other Outcome 
Measures”. 
 


 
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10.2.1 Primary Outcome Measures 
 
10.2.1.1 Either the occurrence of a Grade 3 or higher AE that is possibly, 
probably, or definitely related (as judged by the core team) to the CAB 
LA plus VRC07-523LS combination or premature study treatment 
discontinuation due to an AE (regardless of grade) that is possibly, 
probably, or definitely related (as judged by the core team) to the CAB 
LA plus VRC07-523LS combination. 
 
10.2.1.2 Virologic failure defined as confirmed HIV-1 RNA ≥200 copies/mL at or 
prior to week R2+44 of the CAB LA plus VRC07-523LS combination. 
 
10.2.2 Secondary Outcome Measures 
 
10.2.2.1 PK parameters of the combination of VRC07-523LS and CAB LA. 
 
10.2.2.2 Viral resistance of breakthrough isolates. 
 
10.2.2.3 Virologic failure (confirmed HIV-1 RNA ≥200 copies/mL) at or prior to 
week R2+24 of the CAB LA plus VRC07-523LS combination. 
 
10.2.2.4 Virologic failure (confirmed HIV-1 RNA ≥200 copies/mL) or premature 
discontinuation of the CAB LA plus VRC07-523LS combination at or 
prior to week R2+44. 
 
10.2.2.5 Confirmed HIV-1 RNA ≥50 copies/mL at or prior to weeks R2+24 and 
R2+44 of the CAB LA plus VRC07-523LS combination. 
 
10.2.2.6 Confirmed HIV-1 RNA ≥50 copies/mL or premature discontinuation of 
the CAB LA plus VRC07-523LS combination at or prior to week 
R2+44. 
 
10.2.2.7 Virologic failure (defined by FDA snapshot algorithm) at week R2+44 
of the CAB LA plus VRC07-523LS combination. 
 
10.2.2.8 Measurable levels of anti-idiotype antibodies against VRC07-523LS in 
samples collected from representative time points throughout the 
study. 
 
10.2.2.9 Either the occurrence of a Grade 3 or higher AE that is possibly, 
probably, or definitely related (as judged by the core team) to oral CAB 
or premature oral CAB discontinuation due to an AE (regardless of 
grade) that is possibly, probably, or definitely related (as judged by the 
core team) to oral CAB. 
 
10.2.2.10 Premature discontinuation of oral CAB or the CAB LA plus VRC07-
523LS combination. 


 
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10.2.2.11 Occurrence of a Grade 3 or higher AE that is possibly, probably, or 
definitely related (as judged by the core team) to oral CAB or the CAB 
LA plus VRC07-523LS combination. 
 
10.3 
Participant Registration 
 
This is an open-label, single arm study. All participants will be assigned up to a 5 week 
oral CAB plus two NRTIs lead-in period (Step 1), followed by 44 weeks of CAB LA plus 
VRC07-523LS (Step 2), and 48 weeks of SOC ART (Step 3). There is no randomization 
or stratification. 
 
10.4 
Sample Size and Accrual 
 
The cumulative probability of participants with virologic failure (confirmed HIV-1 RNA 
≥200 copies/mL) at or prior to week R2+44 of the CAB LA plus VRC07-523LS 
combination will be estimated with a two-sided 95% confidence interval (CI) using 
Kaplan-Meier methods. Assuming 74 participants are enrolled, 70 initiate CAB LA plus 
VRC07-523LS, 10% are lost to follow-up and 5% subsequently discontinue CAB LA plus 
VRC07-523LS, there will be 60 analyzable participants. With 60 analyzable participants, 
if the observed virologic failure probability is 5.0%, the 95% CI will be [1.7%, 13.7%]. 
This 95% CI is estimated using the Wilson score method. A 95% CI of [1.7%, 13.7%] 
would provide proof of concept in support of the investigational strategy. Table 10.4-1 
below provides the 95% CI if the virologic failure probability differs from 5.0%. Assuming 
the true rate of failure is 5%, the sample size will provide >90% power to reject a null 
failure rate of 20%. 
 
Table 10.4-1 95% CI at Different Virologic Failure Probabilities with a Sample Size of 
60 Analyzable Participants 
Virologic Failure Probability 
 
95% Wilson Score CI  
1% 
 
[0.1%, 7.8%] 
2% 
 
[0.4%, 9.4%] 
5% 
 
[1.7%, 13.7%] 
8% 
 
[3.4%, 17.6%] 
10% 
 
[4.7%, 20.1%] 
12% 
 
[6.0%, 22.6%] 
 
Using data from participants who remained <50 copies/mL for 96 weeks (approximately 
2 years) from two recently completed ACTG naïve trials (A5257 and A5202), we 
identified 2059 participants who subsequently remained on ART for the rest of follow-up. 
Forty-eight weeks later, the cumulative probability of virologic failure (two consecutive 
HIV-1 RNAs ≥200 copies/mL or last ≥200 copies/mL) using Kaplan-Meier methods was 
1%, and 192 weeks later (when participants had a median of 10 HIV-1 RNA 
measurements), this cumulative probability of virologic failure was 5%. As A5357 will 
measure HIV-1 RNA frequently (>13 measurements on CAB LA plus VRC07-523LS), for 
the sample size we assumed a virologic failure probability of 5.0%. This is additionally 


 
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supported by data from LATTE (Margolis 2015) in which the proportion with protocol-
defined virologic failure in the maintenance phase of the study was 2% and those with 
virologic non-response by the FDA snapshot analysis (≥50 copies/mL) at week 72 of the 
maintenance phase was 9%. 
 
Regarding the assessment of safety and tolerability (see section 10.2.1.1), a sample size 
of 70 CAB LA plus VRC07-523LS treated participants will provide a 94% probability of 
observing a CAB LA plus VRC07-523LS related AE or CAB LA plus VRC07-523LS 
related treatment discontinuation that would occur in 4% of treated participants. 
 
Accrual is anticipated to take 9 to 12 months. Accrual will be frequently monitored by the 
core team. It is expected that at least 18 participants will be enrolled within 3 months of 
the first participant enrollment, and 37 will be enrolled within 6 months. Overall, the study 
aims to enroll at least 15 (20% of 74) female participants. The core team will also 
monitor accrual to ensure that ≥70 participants enroll in Step 2. Additional participants 
will be enrolled into the study if >4 Step 1 participants are ineligible for Step 2. 
 
10.5 
Data and Safety Monitoring 
 
The interim reviews will include data on accrual, baseline characteristics, conduct of the 
study (including premature treatment and study discontinuations), virologic failure, and 
all reported AEs. The efficacy and the safety triggers for the SMC interim reviews are 
outlined in section 7.0, with virologic failure stopping guidelines described below. 
 
To protect participants if virologic failure on the experimental regimen turns out to be 
higher than what may be clinically acceptable, a stringent stopping rule has been put into 
place. However, to guard against premature study stoppage or modification due to 
virologic failures that may be attributed to non-adherence or deviations from the 
specified dosing of the study treatments, virologic failures contributing to the stopping 
criteria must meet additional criteria to ensure that the pure treatment efficacy is 
evaluated. Specifically, virologic failure for the study’s stopping guideline will be defined 
as two consecutive HIV-1 RNA levels ≥200 copies/mL on Step 2, while adhering to study 
treatment (i.e., no missed dose of CAB LA or VRC07-523LS). A missed dose is defined 
as an unadministered dose, inadequate dose, or any dose outside the window specified 
in the protocol. Initial HIV-1 RNA measurements ≥200 copies/mL taken prior to Step 2 
treatment initiation will be excluded from the evaluation of virologic failure for the 
stopping guideline.  Under this definition of virologic failure, a true failure rate ≤2% is 
considered to be acceptable. The reference for the threshold is the recent result from the 
LATTE-2 trial, where the virologic failure rate was 1% through week 96 for the 
combination of CAB LA plus RPV LA as a maintenance therapy for participants 
suppressed on ART [Margolis 2017]. 
 
Note that the virologic failure definition considered for the stopping guideline has more 
stringent adherence criteria than the virologic failure definition for the primary outcome, 
with the intention that the stopping guideline serves the purpose of protecting 
participants if available data indicate that efficacy of the experimental regimen may be 
lower than what is clinically acceptable. Table 10.5-1 estimates the choices of the 


 
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stopping guideline associated with different sample sizes and the probability that the 
guideline will be met under various true probabilities of failure. At any time during Step 2, 
if three or more participants are observed to experience virologic failures defined for the 
stopping guideline, enrollment into Step 1 and Step 2 will be paused, and SMC will be 
promptly convened. The SMC, in such an event, is expected to require all participants in 
Step 1 and Step 2 to enter Step 3 immediately. The stopping criteria will ensure that the 
trial has a high probability (≥85%) to continue when the true failure rate is ≤2%, and is 
likely to stop when the true failure rate is unacceptably high (e.g., when the true failure 
rate is 10%, the trial will stop with a probability of 58%-95% when the sample size is 
≥30). 
 
Table 10.5-1:  Probability that the SMC Will Consider Stopping the Trial under Various 
True Failure Probabilities 
Number of 
Participants 
Examined 
Number of 
failures 
(observed 
failure rate) 
True Failure Rate 
1.0% 
2.0% 
5.0% 
8.0% 
10% 
20% 
20 
3 (15%) 
0.10% 
0.71% 
7.55% 
21.21% 
32.31% 
79.39% 
30 
3 (10%) 
0.33% 
2.17% 
18.78% 
43.46% 
58.86% 
95.58% 
40 
3 (7.5%) 
0.75% 
4.57% 
32.33% 
63.06% 
77.72% 
99.21% 
50 
3 (6%) 
1.38% 
7.84% 
45.95% 
77.40% 
88.83% 
>99% 
60 
3 (5%) 
2.24% 
11.87% 
58.26% 
86.83% 
94.70% 
>99% 
 
The SMC safety triggers assume 95% of participants will initiate CAB LA plus VRC07-
523LS, and have a low chance (9%) to be triggered if there is a low probability of a 
treatment related death (0.1%) and Grade 4 AE (1%), but a higher chance (97%) to be 
triggered if there is a high probability of a treatment related death (1%) and Grade 4 AE 
(10%). 
 
10.6 
Analyses 
 
10.6.1 Primary Analyses 
 
For the primary safety and tolerability analysis (see section 10.2.1.1), all 
participants who have been exposed to CAB LA and VRC07-523LS will be 
included and summaries will include the number and percentage of participants 
experiencing an AE or premature treatment discontinuation defined in section 
10.2.1.1 with a Wilson score 95% CI. 
 
For the primary virologic efficacy analysis (see section 10.2.1.2), the cumulative 
probability of participants experiencing virologic failure at or prior to week R2+44 
of the CAB LA plus VRC07-523LS combination will be estimated using Kaplan-
Meier methods.  If the probability is high, a standard two-sided 95% CI around 
the true virologic failure probability will be calculated using the adaption of 
Greenwood’s variance estimate with a log(-log) transformation [Kalbfeisch and 
Prentice, 1980].  However, if the probability is low, Rothman-Wilson two-sided 


 
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95% CIs will be estimated [Rothman 1978]. Primary virologic efficacy analysis 
will be as-treated (i.e., per protocol) only including participant follow-up on the 
CAB LA plus VRC07-523LS combination. Participants who prematurely 
discontinue the CAB LA plus VRC07-523LS combination will be censored at the 
time of discontinuation. 
 
10.6.2 Secondary Analyses 
 
The secondary safety and tolerability outcome (see section 10.2.2.9) will be 
analyzed in a similar manner to the primary safety and tolerability outcome (see 
section 10.2.1.1) described in section 10.6.1. A similar approach will also be 
taken for the secondary safety outcome (see section 10.2.2.11) describing Grade 
3 or higher AEs related to oral CAB or the CAB LA plus VRC07-523LS 
combination, overall and separately. In addition, all reported Grade 3 or 4 AEs 
(regardless of study treatment relatedness) on oral CAB or the CAB LA plus 
VRC07-523LS combination will be summarized. 
 
Secondary intent-to-treat (ITT) sensitivity analyses will be conducted for the 
primary virologic efficacy outcome measure (see section 10.2.1.2). Participants 
who initiate but then prematurely discontinue LA CAB plus VRC07-523LS will 
only be censored if lost to follow-up prior to virologic failure and HIV-1 RNA 
measures on Step 3 (ART) will be used to determine if the participant had 
virologic failure. 
 
The secondary virologic efficacy outcomes (see sections 10.2.2.3 and 10.2.2.5) 
will be analyzed in a similar manner to the primary efficacy outcome (see section 
10.2.1.2) described in section 10.6.1, but with respect to week R2+24 and/or ≥50 
copies/mL. The secondary virologic failure/premature treatment discontinuation 
outcome (see section 10.2.2.4) will include all participants initiating CAB LA plus 
VRC07-523LS and consider both virologic failure and premature discontinuation 
of LA CAB plus VRC07-523LS as failure. The secondary premature treatment 
discontinuation outcome (see section 10.2.2.10) will include all participants 
initiating oral CAB and consider premature discontinuation of oral CAB, LA CAB, 
or VRC07-523LS as failure, and will summarize them overall and separately with 
reasons for the discontinuation. The secondary virologic rebound/premature 
treatment discontinuation outcome (see section 10.2.2.6) will include all 
participants initiating CAB LA plus VRC07-523LS and consider both virologic 
rebound (HIV-1 RNA ≥50 copies/mL) and premature discontinuation of LA CAB 
plus VRC07-523LS as failure. 
 
The proportion of participants experiencing virologic failure defined by FDA 
snapshot algorithm (see section 10.2.2.7) will be presented along with a Wilson 
score 95% CI. 
 
The percentage of participants with measurable levels of anti-idiotype antibodies 
will be presented along with a Wilson score 95% CI. Neutralization resistance 


 
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and diversity of viral rebound quasispecies will be summarized pre-ART and at 
virologic failure. 
 
See section 11.0, Pharmacology Plan, for more details on the determination of 
the PK parameters of the combination of VRC07-523LS and CAB LA. After PK 
modelling, selected parameters will be associated with viral rebound. 
 
10.7 
Unblinding 
 
Not applicable. 
 
11.0 
PHARMACOLOGY PLAN 
 
11.1 
Pharmacology Objective 
 
The primary pharmacology objective is to determine CAB and VRC07-523LS 
pharmacokinetics when administered in combination. The rationale for this design is to 
provide further data on VRC07-523LS pharmacokinetics and determine if CAB 
pharmacokinetics parameters are influenced by concomitant VRC07-523LS 
administration. 
 
11.2 
Pharmacology Study Design 
 
A population PK study design will be used to describe CAB LA and VRC07-523LS PK. 
The pharmacology design for A5357 is focused on CAB LA but VRC07-523LS will also 
be examined. Oral CAB will be administered as the 30 mg tablet orally once daily, with 
or without food for approximately 5 weeks. CAB LA 600 mg loading dose will be 
administered as one (600 mg) IM injection in the gluteal muscle once the participant 
registers to Step 2 on the same visit day as the final dose (30 mg tablet) of oral CAB. 
CAB LA 400 mg maintenance dose administered as one (400 mg) IM injection in the 
gluteal muscle starting 4 weeks after the CAB LA 600 mg loading dose and then every 4 
weeks through week R2+44 in Step 2. 
 
For CAB LA, plasma will be collected at Step 2 registration. A trough sample will be 
collected at week R2+4, a peak sample at week R2+6 (2 weeks after the week 4 dose), 
and at week R2+8 during Step 2. Additional troughs are scheduled to be collected at 
weeks R2+24 and R2+48. Plasma will also be stored from each study visit, so in case 
any participant experiences viral breakthrough during the 48 weeks of treatment, these 
samples also could be analyzed. 
 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
PK data for both compounds will be modeled using a population approach. CAB LA 
concentration-time data will be incorporated into an existing model developed by 
GlaxoSmithKline/ViiV. The analysis will focus on determining whether CAB LA is similar 
to previously collected data when CAB LA was administered alone or with rilpivirine. 
 


 
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VRC07-523LS concentrations will be analyzed by the NIH Vaccine Research Center to 
further enhance their PK dataset and dosing refinement. An LC/MS/MS assay for CAB 
has been developed at the UAB PSL to support this study. 
 
11.4 
Anticipated Outcomes 
 
It is anticipated that CAB LA PK parameters will fall within the expected range of CAB LA 
administered alone or with rilpivirine. If not, further PK studies will be needed to 
determine whether a clinically significant PK interaction exists between CAB LA and 
VRC07-523LS. It is expected that VRC07-523LS will exhibit a very long half-life, and 
these data will be used to refine the dose and/or dosing interval if needed. 
 
12.0 
DATA COLLECTION AND MONITORING 
 
12.1 
Records to Be Kept 
 
Electronic Case report form (eCRF) screens 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 registration. 
 
12.2 
Role of Data Management 
 
12.2.1 Instructions concerning the entering of study data on eCRFs will be provided by 
the ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.2.2 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. 
 
12.3 
Clinical Site Monitoring and Record Availability 
 
12.3.1 
Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, 
eCRFs, supporting data, laboratory specimen records, and medical records 
(physicians’ progress notes, nurses’ notes, and participants’ 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. 
 
Monitoring visits may be conducted on site or remotely. Remote visits may 
include remote source document verification using methods specified for this 
purpose by NIAID. Remote monitoring visits may be performed in place of, or 
in addition to, on-site visits to ensure the safety of study participants and data 
integrity [FDA 2021]. The site will make available study documents for site 
monitors to review utilizing a secure platform that is HIPAA and 21 CFR Part 11 


 
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compliant. Potential platform options include: Veeva SiteVault, site-controlled 
SharePoint or cloud-based portal, direct access to Electronic Medical Record 
(EMR), and Medidata Rave Imaging Solutions. Other secure platforms that are 
21 CFR Part 11 compliant may be utilized, as allowed by the DAIDS Office of 
Clinical Site Oversight (OCSO). 
 
12.3.2 
The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, eCRFs) and pertinent hospital or clinic records readily available 
for inspection by the local IRB, the site monitors, the FDA, the NIAID, the OHRP, 
the industry supporter or designee, other local, US, and international regulatory 
entities for confirmation of the study data. 
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document 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. 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, and 
this fact will be documented in the participant’s record. 
 
13.2 
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 local, US, and international regulatory entities as part of their duties, or the 
industry supporter or designee. 
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
other government agencies as part of their duties to ensure that research participants 
are protected, or the industry supporter or designee. 
 
14.0 
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. 
 


 
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15.0 
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 NIH. 
 
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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16.0 
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SAMPLE INFORMED CONSENT 
 
 
Sponsor / Study Title: 
  
NIAID / “A Study of Long-Acting Cabotegravir Plus VRC-
HIVMAB075-00-AB (VRC07-523LS) to Maintain Viral 
Suppression in Adults Living with HIV-1” 
 
Protocol Number: 
 
A5357 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
SUMMARY 
 
PURPOSE 
The purpose of this study is to test the safety of cabotegravir (CAB) and 
VRC-HIVMAB075-00-AB (VRC07-523LS, a monoclonal antibody) when 
these two drugs are given together. It will also look at whether this drug 
combination can keep the level of HIV (the virus that causes AIDS) 
controlled and how your body responds to this drug combination. 
 
 
 
NUMBER OF  
PARTICIPANTS 
There will be about 74 participants. 
 
LENGTH OF  
STUDY 
The study will last about 2 years for most people. For a small group of 
participants who are not eligible for the second part of the study, the study 
will only last about 2 months. 
 
You will have 2 study visits for the first month, and up to 15 more visits 
over the next 48 weeks. After that, you will have up to 6 study visits over 
the last 48 weeks of the study. 
 
STUDY 
TREATMENT 
Step 1: oral CAB and two NRTIs 
Step 2: long-acting CAB (CAB LA) injections and VRC-HIVMAB075-00-
AB (VRC07- 523LS) infusions 
Step 3: SOC ART regimen 
 


 
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REQUIRED  
ACTIVITIES 
 
Sample collections 
• 
At all visits, some blood will be collected from a vein in your arm. 
• 
At most visits, your blood will be stored. 
• 
A small amount of urine will be collected from you. 
 
Special procedures 
• 
Long-acting CAB will be given to you as an injection in the muscles of 
your buttock. 
• 
VRC07-523LS will be given to you through a vein in your arm. You will 
be monitored by the study staff for up to 60 minutes after you are 
given the VRC07-523LS. 
• 
An electrocardiogram (ECG), a procedure that tests how your heart is 
doing. This is one of the tests that will be used to check your eligibility 
for this study. 
 
Other evaluations 
• 
On the day that you first receive VRC07-523LS and for 3 days after, 
you will record your temperature and symptoms on the infusion report 
card (IRC). 
 
RISKS 
The following are possible side effects associated with the study drugs: 
• 
Pain, soreness, redness, swelling, and hardening where you had your 
CAB injection. 
• 
Allergic reactions (difficulty breathing or shortness of breath, chest 
discomfort, low blood pressure, hives or rash, blisters or peeling skin, 
swelling in the mouth and face, redness of the eyes, big lymph nodes) 
• 
Fatigue, dizziness, headache, generally not feeling well, fever, and 
joint or muscle pains. 
• 
Risks related to blood draws. 
• 
Liver problems or damage (dark urine, yellowing of your skin or of the 
white of your eyes, pale colored stools, pain or tenderness on your 
right side) 
• 
Nausea or vomiting 
• 
Loss of appetite 
• 
Mental health problems (depression, suicide attempts, suicide) 
• 
Seizures or convulsions 
• 
Drug resistance 
 
BENEFITS 
No direct benefits should be expected from participating in this study. The 
information learned from this study may help others who are living with 
HIV-1. 
 
OTHER CHOICES 
Your participation in this research study is completely voluntary. Instead 
of being in this study, you have the option of continuing with your current 


 
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treatment or starting a new treatment under the care of your regular 
doctor or other health care provider. 
 
 
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) and because you are taking 
anti-HIV drugs that are controlling your HIV infection. 
 
This study is sponsored by the National Institutes of Health (NIH). The doctor in charge of this 
study at this site is listed on the first page of this form. Before you decide if you want to be 
part of this study, we want you to know more about it. 
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign and date this consent form. You will get a copy 
to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
The study is being done to: 
• 
See how safe CAB is when given as an oral pill and to see if it causes side effects in 
persons living with HIV. 
• 
See whether the combination of an experimental HIV drug, cabotegravir (CAB), and a 
monoclonal antibody (VRC-HIVMAB075-00-AB [VRC07- 523LS]) is safe. 
• 
See if the CAB-VRC07-523LS drug combination causes side effects in people living with 
HIV. 
• 
See if the CAB-VRC07-523LS drug combination causes side effects, and, if so, to 
understand what the side effects are. 
• 
Find out if a combination of CAB and VRC07-523LS would work well when taken together in 
keeping HIV virus levels low in the body when CAB is given as long-acting injectable drug 
(given as a shot like a vaccine) and VRC07-523LS is given as infusions (given through a 
needle in a vein). A long-acting drug stays in the body much longer compared to the usual 
form of the medications. This kind of drug combination has never been used before for HIV 
treatment and is not approved for HIV treatment. It is not known whether it will be effective 
or not. 
 
This study is opening under protocol Version 3.0 because changes, including a change in one of 
the study drugs, were made to the original version. The new study drug, VRC07-523LS, is 
expected to be better than the antibody that had been planned for the original version of the 
study. VRC07-523LS is a fully human antibody that is targeted to attack HIV; it is not targeted to 
attack any human protein or the antibody’s structure. 
 
 


 
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HOW MANY PEOPLE WILL BE IN THIS STUDY? 
 
About 74 people (individuals aged 18 years and older) will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 101 weeks (about 2 years or so). 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Information Collected at Screening 
There is some information that we collect on everyone who is screened for an ACTG study. As 
part of your screening visit, some demographic (for example, age, gender, race), clinical (for 
example, disease condition, diagnosis), and laboratory (for example, CD4 cell count, viral load) 
information will be collected from you. We also collect information on whether you use (or have 
used) IV drugs. 
 
We will collect this information even if you do not enroll in this study. This information is 
collected so that ACTG researchers may determine whether there are patterns or common 
reasons why people do not join a study. 
 
If you decide to take part in this research study, you will be asked to sign and date this consent 
form and a screening visit will be scheduled to determine if you can join the study. The 
screening visit will occur prior to your being given any experimental study treatments (i.e., oral 
CAB in Part 1 of the study and long-acting CAB and VRC07-523LS in Part 2 of the study). 
Experimental means the study-provided drugs have not been approved by the Food and Drug 
Administration (FDA). 
 
Part 1 
For Part 1 of this study, you will continue taking your nucleoside reverse transcriptase inhibitors 
(NRTIs) such as lamivudine, tenofovir, and abacavir, but you will stop taking all other HIV 
medications and replace them with CAB, taken orally as a pill for about 5 weeks. 
 
If your HIV viral load (how much HIV is in your body) is undetectable at the week 4 visit of Part 1 
of the study, then you will enter Part 2 of the study. See below study treatment for each part of 
the study. 
 
If your HIV viral load is detectable at week 4, you will return 1 week later to see if it has been 
controlled. If your HIV viral load is still detectable at the week 5 visit or if you stopped oral CAB 
for any reason, then you will not be eligible to enter Part 2 of the study. You will remain in Step 1 
for another 4 weeks (with study visits every 2 weeks) before being taken off study. During this 
time, you will take only your local standard of care (SOC) HIV regimen. 
 


 
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Part 2 
In Part 2 of the study, you will stop all oral HIV treatment, including your NRTIs. You will be 
given VRC07-523LS intravenously (or “IV,” which means, “through a vein”) every 8 weeks for 40 
weeks. You will also be given CAB LA, as intramuscular injections in the gluteus medius (a 
broad muscle on the outer part of the pelvis, which is located on the upper region of the 
buttock), every 4 weeks for 44 weeks. You will receive the first CAB LA injection on the same 
visit day as the final dose of oral CAB on Part 1. To be eligible for Part 2 of the study, you 
should not have any implants or silicone injections or tattoo that is located on or around 
the skin area where VRC07-523LS and CAB LA will be given. 
 
You will need to come to the clinic to receive treatment for Step 2. You will not be given any 
study drugs to take at home. While you are on Step 2, you must not take other ARVs at home. 
Part 2 of the study will last for about 48 weeks. 
 
Part 3 
After Part 2 of the study, you will enter Part 3 of the study, which will last for another 48 weeks. 
In Part 3, you will stop CAB LA and VRC07-523LS and resume taking a local SOC HIV regimen. 
 
The drugs in each of part of the study are: 
 
Part 1: Oral CAB as a pill once daily plus two current NRTIs for up to 5 weeks. 
 
Part 2: One 3mL shot of the CAB LA will be given, and then one 2 mL shot of the CAB LA every 
4 weeks (intramuscular injections) for 44 weeks plus VRC07-523LS infusion given every 8 
weeks (through a needle in a vein) for 40 weeks. 
 
NOTE: The VRC07-523LS dose of 40 mg/kg body weight is based on estimates of how frequently 
VRC07-523LS should be given so that the amount of VRC07-523LS in your blood would stay at 
an effective level.  In a small study, a single VRC07-523LS dose of 40 mg/kg IV was shown to 
work against HIV, but the estimated dosing frequency being used in this study (i.e. every 8 weeks 
over a long time) has not been used in people with HIV before. 
 
Part 3: SOC HIV regimen for 48 weeks. 
 
Oral CAB, CAB LA, and VRC07-523LS will be provided by the study. NRTIs will be required for 
Part 1 and reimbursement for these drugs will be provided by the study for those participants 
who are unable to obtain them in Part 1 of the study. There is no study-provided medication in 
Step 3, and participants will go back to taking their SOC HIV regimen. 
 
For Part 1 of the study, the study staff will let you know how often to take the study regimen and 
whether to take them with or without food. 
 
For Part 2 of the study, you will be given a thermometer and an infusion report card (like a 
notebook log) to record your daily temperature and any symptoms you may have for a few days 
after each VRC07-523LS infusions. The study staff will give you instructions on the use of the 
infusion report card. At each study visit, you must bring back the infusion report card so that the 
study staff can review the information you have recorded. 


 
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Before you are given the VRC07-523LS infusion, the study staff will check your temperature, 
blood pressure, heart rate, and weight. You also might have a brief physical exam. During the 
infusion, you will be asked to sit or recline for about 15 to 30 minutes or more as needed while 
the drug is given. After you receive the VRC07-523LS infusion, you will remain in the clinic for 1 
hour so that the study staff can check your vital signs (weight, temperature, pulse, respiration 
rate, and blood pressure) and look out for any unusual signs or symptoms. 
 
At each visit of Part 2 of the study, you will need to inform the study staff of any symptoms you 
may have while taking CAB LA. 
 
CAB (both the oral and LA injection forms) and VRC07-523LS are experimental. The VRC07-
523LS dose (40 mg/kg) chosen for this study has not yet been studied in a clinical trial. 
 
All other study-required drugs and routine tests are part of standard clinical care. 
 
If you enter this study, you will need to come for clinic visits up to 2 times for the first month or 
so, then up to 15 times for a year, and lastly up to 6 times during the final year (A5357 Appendix 
I: Study Visits provides more detail.) 
 
Visits where you receive an infusion will last between 1 and 2 hours. Other visits will last about 1 
hour. The study staff will tell you how long each visit will last. 
 
You may need to come to the clinic for extra visits if you develop side effects or if you need to 
switch anti-HIV drugs. During the study, you will receive the results of routine laboratory tests 
that are done during the study. The site staff can tell you approximately how much blood 
will be collected at any visit. 
 
 
WHY WOULD THE STUDY DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study without your permission if: 
• 
The study is stopped or cancelled. 
• 
Your primary care doctor believes that remaining on the study is no longer what is best for 
you. NOTE: It is preferred by the study team that you remain on study even if you have to 
stop study treatment. Since the study is being done to look at safety, the more data are 
collected from participants who may have to stop study treatment, the better the study 
becomes with the additional information. 
• 
You are not eligible for Part 2. 
• 
A Safety Monitoring Committee (SMC) recommends that the study be stopped early (A SMC 
is an outside group of experts that monitors the study.) 
 
Also at any time in the study, you can request to stop participating. 
Your study doctor may also need to take you off the study drugs without your permission if: 
• 
Continuing the study drugs may be harmful to you; for example, if the study drugs are 
making you sick or if the study drugs are not controlling the level of HIV in your blood. 


 
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• 
You need a treatment that you may not take while on the study. 
• 
You become pregnant or start breastfeeding. 
If you must stop taking the study drugs before the study is over, the study staff will ask you to 
continue to be part of the study and return for some study visits and procedures. If you want to 
stop the study visits, then the study staff will ask you to return to the clinic for a final visit. 
 
If You Have to Stop Taking the Study Drugs Early or You Have to Stop the Study Early 
If you stop taking the study drugs or leave the study early, you will be asked to come to the 
clinic for at least one additional study visit. At this visit, you will have a targeted physical exam, 
which will assess vital signs, have blood drawn for routine safety blood tests, pregnancy tests, 
and may have urine, CD4+ T-cell count, viral load, and immune tests. In addition, some of your 
blood may be stored for future testing required by the study. 
 
If you stop taking the study drugs early, but are willing to remain in the study, you will continue 
to come in for regularly scheduled study visits. If the discontinuation of study drugs occurred 
during Part 1 of the study (i.e., while on oral CAB and the current two NRTIs), you will be asked 
to remain on the study for about 4 weeks. If the discontinuation of study drugs occurred during 
Part 2 of the study (i.e., while on CAB LA and VRC07-523LS), you will be asked to remain on 
the study for an additional 48 weeks while on Part 3 of the study. This is because the study staff 
will need to monitor you since CAB LA can remain in the body for about 48 weeks after the last 
dose. 
 
During the study: 
If you must permanently stop having CAB LA and VRC07-523LS during Step 2 before your 
study participation is over, the study staff will discuss other options that may be of benefit to 
you. You will be asked to restart your anti-HIV drugs that you were on before you entered the 
study or another ART regimen depending on the results of the resistance testing or other 
considerations by your doctor. 
 
After the study: 
After you have completed your study participation at the end of Part 3, the study will not 
continue to monitor and follow you. Also, the study will not provide you with CAB LA and 
VRC07-523LS that you received on the study because its use in the general population is still 
being studied. You will be asked to return to your regular doctor and resume treatment as 
recommended. 
 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE 
USED FOR? 
 
Use of Your Samples Required for this Study 
The study staff will determine if samples of your blood from before you started HIV medication is 
already stored at your site or at a central storage facility, or stored from an earlier research 
study. If a sample is available, the study team will request storage of some of this sample for 
future testing as part of this study. 
 


 
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During this study, some of your blood samples will be stored and used for testing that is 
required for this study. The tests that will be done include measurement of the amount of HIV in 
the blood cells and plasma, measurement of the levels of CAB LA and VRC07-523LS, and tests 
to determine if there are changes in the immune (infection-fighting) cells before and after 
administration of CAB LA and VRC07-523LS. 
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you. 
 
The tests described above are required by this study. If you do not agree to the storage or 
testing that has been described above, you should not join this study. 
 
 
WHAT IF I BECOME PREGNANT DURING THIS STUDY? 
 
If you can become pregnant, you must have a pregnancy test before entering the study, and the 
test result must be available at the study clinical research site. The test must show that you are 
not pregnant in order for you to take part in the study. You will also be given a pregnancy test at 
the scheduled visits during Parts 1 and 2 of the study. 
 
If you are pregnant, you will need to stop taking CAB and VRC07-523LS right away and will 
complete the premature study treatment discontinuation evaluations. You should also not 
breastfeed for 48 weeks after the last dose of CAB LA. If you are pregnant or become pregnant 
within 48 weeks after the last dose of CAB LA, you may remain on study during your pregnancy 
or you may leave the study. If you agree to remain on the study, you will continue to have 
regularly scheduled study visits and samples collection. Blood tests will be limited to those 
performed to assess safety, measure the levels of CAB LA and VRC07-523LS (i.e., 
pharmacokinetic (PK) studies), and measure antibodies to VRC07-523LS in your body. The 
study staff will talk to you about your choices. 
 
This study will not provide care or cover any cost related to your pregnancy, the delivery of your 
baby, or the care of your baby. The study will not provide any drugs during pregnancy. You 
must arrange for your care and your baby’s care outside of this study. If you need help finding a 
health care provider for your pregnancy, the site staff will try to help you with this. You and your 
primary care doctor will decide which anti-HIV drugs are best for you while pregnant. The study 
doctor will provide your primary care doctor with information about the study drugs that you 
have been exposed to in the course of the study. 
 
Long-term follow-up is recommended for babies whose mothers take anti-HIV drugs during 
pregnancy. The study staff will talk with you about long-term follow-up and the possibility of 
enrolling your baby in a long-term follow-up study. 
Site staff will request to contact you regarding your pregnancy. We will collect information about you 
and about the delivery and health of your baby (even if your participation in the study has ended). 
 
If you become pregnant, your pregnancy will be reported to an international database (The 
Antiretroviral Pregnancy Registry) that collects information about pregnancies in individuals 


 
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taking anti-HIV drugs. This report will not use your name or other information that could be used 
to identify you. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
You should not take part in this study if you are pregnant or intend to become pregnant in the 
next 2 years. Mothers should not breastfeed a baby while on this study. Since CAB (oral and LA 
injections) and VRC07-523LS are experimental, the risks to a pregnant individual or fetus are 
not fully known. 
 
If you are having sex that could lead to pregnancy, you must agree not to become pregnant. If 
you can get pregnant, you must talk to your study doctor about birth control and use it all of the 
time. You must use an effective form of birth control from 30 days before you start the study 
until 48 weeks after your last dose of study drugs in Part 2 of the study. If you do not enter Part 
2 of the study, then you must continue to use effective birth control for only 30 days after your 
last oral dose of study drug in Part 1. You must choose one of the birth control methods listed 
below: 
• 
Intrauterine device or intrauterine system 
• 
Birth control medications that prevent pregnancy given as pills, shots, or placed on or under 
the skin (i.e., contraceptive subdermal implant, combined estrogen and progestogen oral 
contraceptive, injectable progestogen, percutaneous contraceptive patches) 
• 
Contraceptive vaginal ring 
 
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 individuals taking anti-
HIV drugs. This report will not use your name or other information that could be used to identify 
you. 
 
Breastfeeding 
It is unknown whether the study drug passes through the breast-milk and may cause harm to 
your infant. You must not breastfeed if you are in this study. You should also not breastfeed for 
48 weeks after the last dose of CAB LA on Part 2 of the study. 
 
In one study evaluating CAB in pregnant rats and their newborn pups, there was a higher rate of pups 
that died at the time of delivery or shortly after delivery in the rats that received a 1000 milligrams per 
kilogram dose of CAB compared to pregnant rats who did not receive CAB. This finding did not occur 
in pregnant rats who received two lower doses (0.5 and 5 milligrams per kilogram) of CAB. The blood 
levels of CAB given in this study are expected to be lower than the blood levels in pregnant rats 
where this finding was observed. The significance of this finding on human pregnancies is not known. 
Birth defects have not been observed in animal studies with CAB, to date. 
 
Risk of neural tube defects with the HIV-1 Integrase inhibitor dolutegravir (DTG) 
In one ongoing birth outcome study, early results show that 4 of 426 (0.9% or nearly 1 in every 
100) pregnancies of individuals who were taking DTG at the time they became pregnant had 


 
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babies with serious brain and spine defects, compared to 0.1% (one in every 1000) pregnancies 
of individuals who were not taking DTG. These defects happen early in pregnancy, within the 
first month, before many individuals even know they are pregnant. In an updated analysis of 
this same birth outcome study, no neural tube defects occurred in an additional 170 babies 
exposed to DTG at the time of conception, which translated to a revised neural tube defect 
incidence rate of 0.7% in DTG-exposed babies. 
 
CAB is not the same drug as DTG. We do know that CAB and DTG belong to the same class of 
medications and work in a similar way to treat HIV infection. We do not know if CAB can cause 
nervous system defects in babies. There may be unknown risks to a pregnancy, embryo, or 
fetus if you become pregnant. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
You should not expect any direct benefit from being in this study. CAB and VRC07-523LS have 
been given to only a small number of people living with HIV-1. The impact of CAB and VRC07-
523LS on HIV infection is unknown, and no guarantee of any benefit can be made. The 
information learned from this study may help others who are living with HIV-1. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
You can choose not to be in this study, continue with your normal medication regimen, and just 
be followed routinely by your regular doctor or health care provider. 
 
Please talk to your study doctor about these and other choices available to you. Your study 
doctor will explain the risks and benefits of these choices. 
 
 
WILL I RECEIVE THE RESULTS OF ANY TESTS? 
 
You will receive the results of routine laboratory tests (e.g., blood counts, viral load, liver and 
kidney tests) that are performed at the study visits. You will be told of any new information 
learned during the course of the study that might cause you to change your mind about staying 
in the study. At the end of the study, you will be told when study results may be available and 
how to learn about them. As with all studies, if we find out important information that may affect 
your care, you will be provided with those results. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
If you participate in this study, you will stop taking anti-HIV drugs that have been working well to 
control HIV. You will be given an experimental combination that has unknown efficacy. There is 
a risk that HIV could rebound (meaning virologic failure could occur). If HIV rebounds, there is a 
risk that it could become resistant to CAB and/or other anti-HIV drugs in the same class. 
 


 
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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. 
 
If you have questions concerning 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 medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
Use of Combination Antiretroviral (ARV) Drugs 
Immune Reconstitution Syndrome: 
In some people living with advanced HIV, 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 ARV therapy, tell your healthcare 
provider right away. 
 
The use of potent ARV 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 
 
Risks of only Receiving Two NRTIs with Oral CAB 
Two NRTIs plus oral CAB is a three-drug combination that is expected to keep HIV controlled. 
However, there is a risk that there may be side effects from oral CAB or that the combination 
may not work either because of HIV resistance to one or more of the drugs or if the combination 
is not taken correctly. 
 
Risks of Study-Provided Drugs 
 
Cabotegravir (CAB) Tablets and CAB Long Acting Injections 
The following serious effects may occur with the use of CAB: 
• 
Hypersensitivity reactions. This is a type of allergic reaction that may start as a rash. If you 
develop a rash while taking CAB, contact your healthcare provider right away, especially if 
you also have: 
o Blisters or peeling skin 
o Fever 
o General ill feeling 
o Extreme tiredness 
o Muscle or joint pain 


 
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o Blisters or sores in your mouth 
o Redness of the eyes 
o Swelling around your eyes, face, mouth, lips, or tongue 
o Trouble breathing 
• 
Liver problems. Contact your healthcare provider right away if you have any of the following 
possible symptoms of a liver problem: 
o Yellowing of your skin or of the whites of your eyes (jaundice) 
o Dark or tea-colored urine 
o Pale colored stools 
o Nausea (feeling sick to your stomach) or vomiting 
o Loss of appetite 
o Pain, aching, or tenderness on your right side, below your ribs 
• 
Depression, suicide attempts, or suicide, especially in people with pre-existing history of 
depression or other mental health problems. If your mental health problems worsen or if you 
develop suicidal thoughts, call your healthcare provider right away. If you feel in crisis, you 
can call 911 and/or a Nationwide Suicide Hotline that is answered 24 hours a day with 
a skilled, trained counselor. One example is the National Suicide Prevention Lifeline 
at 1-800-273-TALK (8255). 
• 
Seizures/convulsions: If you have a history of seizures at any point in your life, please let 
your study doctor know. 
 
Additional side effects include: 
• 
Headache 
• 
Upper respiratory tract infection. Symptoms may include: 
o Sore throat 
o Cough 
o Runny nose 
o Fever 
o Trouble breathing 
• 
Fever 
• 
Fatigue 
• 
Nausea 
• 
Diarrhea 
• 
Lack of energy or weakness 
• 
Abdominal pain and discomfort 
• 
Back pain 
• 
Trouble sleeping 
• 
Abnormal dreams 
• 
Dizziness 
• 
Joint aches and pains 
• 
Muscle pain and/or breakdown of muscles 
• 
Abnormal liver blood tests 
• 
Increase in the level of enzymes produced in the muscles (creatine phosphokinase) 
 


 
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VRC-HIVMAB075-00-AB (VRC07-523LS) 
VRC07-523LS is a type of monoclonal antibody that was developed after the first monoclonal 
antibody, VRC01. VRC07-523LS has not been tested in studies. Some safety information has 
been collected from other studies using VCR01LS in people, but these studies have not been 
completed. A small group of people without HIV and nine people with HIV have received 
VRC07-523LS and have tolerated it well so far. 
 
With antibody products, most side effects occur within the first 24 hours. This product may have 
serious allergic reactions, but this is unlikely. These reactions can be life-threatening. 
• 
Anaphylaxis is one type of allergic reaction that may occur soon after an antibody product is 
given. It includes difficulty breathing, low blood pressure, hives or rash, and swelling in the 
mouth and face. 
• 
Serum sickness is a delayed type of allergic reaction that may occur several days to 3 
weeks after an antibody product is given. It is characterized by hives or rash, fever, big 
lymph nodes, muscle pains, joint pains, chest discomfort, and shortness of breath. 
• 
You may also experience an increase in liver enzymes, which can be a sign of liver damage. 
 
We expect that there will be a low risk of serious allergic reactions with VRC07-523LS because 
VRC07-523LS is a fully human antibody that attacks a virus. Some antibodies of the type that 
attack human proteins are known to increase the risk of serious infections. VRC07-523LS is not 
expected to increase the risk of serious infections because, as noted above, it attacks a virus. 
 
It is possible that VRC07-523LS will have unexpected effects on the course of your HIV 
infection, such as changes in CD4+ T-cell count and viral load levels, changes in antiretroviral 
(ARV) drug sensitivity, or other unknown effects. In addition to the possible risks that are listed 
above, VRC07-523LS may have other side effects that we do not know about. Participation in 
this study may limit your eligibility for other future monoclonal antibody studies. 
 
In addition to the side effects listed above, other side effects may include: pain, headache, 
fever, nausea and vomiting, dizziness, trouble breathing, shortness of breath, tiredness, 
tightening of the muscles around the bronchial tubes, change in blood pressure (low/high), 
chills, diarrhea, itchiness, rash, hives, swelling (lip or face), increased heart rate, and chest pain; 
fainting may occur after receiving the injection, which may result in falling with injury, shaking, 
stiffening, and other seizure-like activity have also been reported. 
 
Among 25 participants who received VRC07-523LS in a clinical trial, 6 had mild or moderate 
side events. These included mild dizziness, infusion reactions, and abdominal pain. All the side 
effects were judged to be related to VRC07-523LS and all of them resolved without any lasting 
effects. Other symptoms that participants reported included mild bruising at the administration 
site, mild pain/tenderness at the injection site, general discomfort (not feeling well), muscle 
aches, headache, chills, nausea, and joint pain. 
 
We will give you any information (including about risks) that becomes available and that may 
affect your willingness to continue in the study. 
 
This is the first time CAB LA and VRC07-523LS have been given together, so there may be 
risks associated with this combination that are unknown. 


 
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General Side Effects of Injections - Long Acting Medications 
The drugs that you will be given by injections in this study are long acting, meaning they stay in 
your body for a long time. The study medication will be given on a regular set schedule so that 
the amount of medication in your blood would stay at an effective level. Following an injection of 
CAB LA, the medication stays in your body for months. In some people, low levels of CAB may 
be present for more than a year. If you develop a side effect to CAB LA after the injection, there 
will be no way to remove the drug from your body. You will be taking these drugs as tablets first, 
which stay in the body for a shorter amount of time. This will help the study staff understand if 
you might have problems with the drugs when received as an injection. If it appears that you 
would, based on lab tests before Part 1 ends, then you will not be eligible for Part 2. 
 
If you develop a symptom from these drugs, every effort to treat the symptoms will be made. 
The amount of drug will decrease over time and will eventually disappear. 
 
During the time that drug is leaving your body, your HIV virus could develop resistance (stop 
working) to these medicines, even if it is many weeks or months since you last took the drug. 
When discontinuing long acting HIV treatment, it will be very important to start taking other HIV 
medications, as recommended by your doctor, to help prevent your HIV from developing 
resistance to HIV medications. This is why you will re-start your anti-HIV drugs in Part 3 of the 
study. 
 
Injection Site Reactions 
Side effects at the location where you received injections (Injection Site Reactions, ISRs) have 
been seen with CAB LA. Common side effects could include: 
• 
Pain or redness, swelling, itching, bruising, lumps, and irritation where you receive the 
injection(s). Most reactions resolve in a week or less. 
• 
The injections that you receive will be given to you in the muscles of your buttock (gluteal 
muscle). 
 
Study staff may take pictures of ISRs that are thought to be serious and last longer than 2 
weeks. 
 
Vasovagal Reactions 
Receiving injections can cause some people to feel lightheaded or feel like they might pass out. 
This reaction, called a “vasovagal reaction,” can occur with many medical procedures. It 
resolves quickly and is not a direct threat to your health. [Sites: This text can be modified to fit 
local cultural language sensitivities; however, the meaning of the precautionary statement must 
remain.] 
 
Other Drugs Available Through Routine Care 
FTC, TAF, epzicom, abacavir, and lamivudine are available through routine care (i.e., not study-
provided drugs) and have the associated risks, as described below. Please refer to the current 
package insert for additional risks information on these drugs. 
 


 
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Nucleoside Analogues 
Lactic acidosis (elevated lactic acid levels in the blood) and severe hepatomegaly (enlarged 
liver) with steatosis (fatty liver) that may result in liver failure, other complications, or death have 
been reported with the use of ARV nucleoside analogues alone or in combination. The liver 
complications and death have been seen more often in individuals on these drug regimens. 
Some nonspecific symptoms that might indicate lactic acidosis include: 
• 
Unexplained weight loss 
• 
Stomach discomfort 
• 
Nausea, vomiting 
• 
Fatigue 
• 
Cramps 
• 
Muscle pain 
• 
Weakness 
• 
Dizziness 
• 
Shortness of breath 
 
Emtricitabine (FTC, Emtriva®) 
The following side effects have been associated with the use of FTC: 
• 
Headache 
• 
Dizziness 
• 
Tiredness 
• 
Inability to sleep, unusual dreams 
• 
Loose or watery stools 
• 
Nausea or vomiting 
• 
Abdominal pain 
• 
Rash, itching, which sometimes can be a sign of an allergic reaction 
• 
Darkening of the skin on the palms of the hands and/or soles of the feet 
• 
Increased cough 
• 
Runny nose 
• 
Abnormal liver function tests, which could mean liver damage 
• 
Increases in pancreatic enzyme (a substance in the blood), which could mean a problem 
with the pancreas 
• 
Increased triglycerides (a type of fat found in the blood) 
• 
Increased creatine phosphokinase (a substance found in the blood), which could mean 
muscle damage 
NOTE: If you are living with both hepatitis B and HIV-1, your liver function may be affected and 
symptoms caused by hepatitis may get worse if you stop FTC. 
 
Some side effects of FTC may not need any medical attention. As your body gets used to the 
medicine, these side effects may disappear. 
 
Tenofovir Alafenamide (TAF) 
The following side effects have been associated with the use of TAF: 
• 
Nausea, vomiting, gas, loose or watery stools 
• 
Generalized weakness 


 
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• 
Dizziness 
• 
Depression 
• 
Headache 
• 
Abdominal pain 
• 
Worsening or new kidney damage or failure 
• 
Inflammation or swelling and possible damage to the pancreas and liver 
• 
Shortness of breath 
• 
Rash 
• 
Allergic reaction: symptoms may include fever, rash, nausea, vomiting, loose or watery 
stools, abdominal pain, achiness, shortness of breath, a general feeling of illness, or a 
potentially serious swelling of the face, lips, and/or tongue 
• 
Bone pain and bone changes such as thinning and softening, which may increase the risk of 
breakage 
• 
Muscle pain and muscle weakness 
• 
Sleeping problems 
 
NOTES: 
• 
If you are living with both hepatitis B and HIV-1, your liver function may be affected and 
symptoms caused by hepatitis may get worse if you stop TAF. 
• 
Because there is only a small amount of information on TAF in pregnant and breastfeeding 
individuals, you should not use TAF during pregnancy or if breastfeeding. 
 
Emtricitabine (FTC)/Tenofovir Alafenamide (TAF), Descovy® 
No new or unexpected side effects are observed with the FTC 200 mg/TAF 25 mg combination 
tablet than those observed when each drug is given separately. 
 
Abacavir (ABC, ZIAGEN®) 
The following side effects have been associated with the use of abacavir: 
 
People taking abacavir may have a serious allergic reaction that involves several organs of the 
body. This reaction can be severe or may rarely cause death. Your risk of this allergic reaction 
is much higher if you have a certain type of gene called HLA-B*5701.  Your doctor can 
determine if you have this by doing a blood test. If you have tested positive for this blood test 
before, do not take abacavir and let your doctor know right away. If you have two or more of the 
following while taking abacavir, stop taking the abacavir and call your doctor right away: 
• Fever 
• Rash 
• Upset stomach, vomiting, loose or watery stools, abdominal pain 
• General feeling of illness, extreme tiredness, achiness 
• Shortness of breath, cough, sore throat. 
 
This serious reaction usually appears within the first six weeks after starting this drug but can 
occur at any time during treatment. This reaction can be severe and can lead to death 
especially if abacavir is not stopped. IF YOU STOP ABACAVIR BECAUSE OF AN ALLERGIC 
REACTION, YOU SHOULD NEVER TAKE ABACAVIR OR ANY OTHER ABACAVIR-
CONTAINING MEDICINE AGAIN. 


 
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A more severe or fatal allergic-type reactions can occur within hours after abacavir is restarted 
in people who have stopped abacavir therapy for any reason. If you were taking abacavir, be 
sure to contact the medical staff at the site before restarting abacavir. Your doctor may want to 
test your blood for HLA-B*5701. If your doctor decides that it is safe for you to restart abacavir, 
you may need to be monitored more closely in the clinic or in the hospital. 
 
IF YOU THINK YOU MIGHT BE DEVELOPING A REACTION TO ABACAVIR, STOP 
ABACAVIR AND CONTACT THE STUDY DOCTOR AT THE SITE IMMEDIATELY. 
 
Other than a serious allergic reaction, additional side effects may include: 
• Upset stomach 
• Vomiting 
• Vague overall feeling of discomfort 
• Feeling tired 
• Decrease in appetite 
• Loose or watery stools 
• Pancreatitis (inflammation of the pancreas), with one or more of the following: stomach pain, 
 
nausea or vomiting 
• Headache 
 
Note: It is unclear if abacavir may be associated with heart disease. If you have risk factors for 
heart disease tell your doctor. 
 
Lamivudine (3TC, EPIVIR®) 
The following side effects have also been associated with use of lamivudine: 
• Headache 
• Feeling tired 
• Dizziness 
• Numbness, tingling, and pain in the hands or feet 
• Depression 
• Trouble sleeping 
• Rash 
• Upset stomach, vomiting, nausea, loose or watery stools 
• 
Pancreatitis (inflammation of the pancreas), which may cause death. If you develop 
pancreatitis, you may have one or more of the following: stomach pain, nausea, and 
vomiting 
• Abnormal pancreatic and liver function blood tests 
 
Persons who are living with both hepatitis B and HIV should be warned that their liver function 
may be affected, and symptoms associated with hepatitis (an acute inflammation of the liver) 
may worsen after lamivudine has been stopped. Although most of these cases have resolved 
without treatment, some deaths have been reported. 
 


 
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Lamivudine (3TC)/Abacavir (ABC), Epzicom® 
No new or unexpected side effects are observed with the ABC 600 mg/3TC 300 mg 
combination tablet than those observed when each drug is given separately. 
 
Risks Associated with Procedures and Other Risks 
 
Electrocardiogram (ECG) 
You may have local skin irritation and redness where the adhesive patches are placed on your 
skin. 
 
Blood Draw or Intravenous (IV) Placement 
Taking blood may cause some discomfort, bleeding, bruising, and/or swelling where the needle 
enters the body, and in rare cases it may result in fainting. There is a small risk of infection. 
Placement of an intravenous catheter can cause bleeding, swelling, or bruising where the 
needle enters the body. 
 
Intramuscular Injections 
Although trained study staff will administer the CAB LA injections, it is possible that the person 
giving you your injection could accidentally give the injection too deeply or not deeply enough, 
missing the muscle and entering your skin, blood stream or a nerve. The risks of injecting a long 
acting drug outside of the muscle are not well understood but could include having drug levels 
that are either too low or too high. The risk of having levels that are too low is that the drug may 
not work well to control your HIV virus. The risks of having high levels of CAB LA in your body 
are not well known at this time. 
 
Social Harm 
Although the study site will make every effort to protect your privacy and confidentiality, it is 
possible that your involvement in the study as a participant could become known to others if it is 
not already and that social harms may result (because you could become labeled as being 
infected with HIV). For example, you could be treated unfairly or discriminated against by family 
members, friends, and/or the community. 
 
Other Non-study Medicines 
There is a risk of serious and/or life-threatening side effects when non-study medicines are 
taken with study drugs. For your safety, you must tell your study doctor or the study nurse 
about all medicines you are taking before you start the study and also before starting any new 
medicines while on the study. Also, you must tell your study doctor or the study nurse before 
enrolling in any other clinical trials while on this study. 
 
Unforseen Risks 
Since the study drug is investigational, there may be other risks that are unknown. 
 
Virologic Failure 
CAB LA and VRC07-523LS may not control your viral load levels as well as your current ART. 
 


 
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Drug Resistance 
Although the study team does not think it likely, you may develop resistance to CAB or other 
integrase inhibitors as a consequence of participating in this study. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have 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. 
 
Your records may be reviewed by the U.S. Food and Drug Administration (FDA), the ACTG, the 
U.S. Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties, the study site, Advarra IRB (a committee that 
protects the rights and safety of participants in research), National Institutes of Health (NIH), 
study staff, study monitors, drug companies supporting this study, and their designees. Having a 
Certificate of Confidentiality does not prevent you from releasing information about yourself and 
your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by US 
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. 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study-provided drugs, CAB (oral and LA injections) and 
VRC07-523LS, study-related visits, physical examinations, required laboratory tests, or other 
procedures. This study will not provide you with other ARV drugs. If you are not able to obtain 
the two NRTIs that are required in Part 1 of the study, then the study will reimburse you if you 
have to purchase these drugs. You, your insurance company, or your health care system may 
need to assume the cost of drugs not provided by the study. 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. 
 
 
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 could be charged to you or your insurance 
company. There is no program for compensation either through this institution or the National 


 
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Institutes of Health (NIH). You will not be giving up any of your legal rights by signing and 
dating this consent form. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
«Compensation» 
You may be reimbursed for your time and travel expenses as part of your participation in 
this study. [If applicable:] We will reimburse you for the cost of [describe: e.g., traveling 
to your study visits]. You will be reimbursed approximately [e.g., 2 weeks, 1 month, etc.] 
after you submit your travel receipts to the study staff. 
 
 
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. You will still be able to receive drugs to treat your HIV outside this study. 
 
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. 
 
 
WHOM TO CONTACT ABOUT THIS STUDY? 
 
During the study, if you experience any medical problems, suffer a research-related 
injury, or have questions, concerns or complaints about the study, please contact the 
study doctor at the telephone number listed on the first page of this consent document. If 
you seek emergency care, or hospitalization is required, alert the treating physician that 
you are participating in this research study. 
 
An institutional review board (IRB) is an independent committee established to help 
protect the rights of research participant. If you have any questions about your rights as 
a research participant, and/or concerns or complaints regarding this research study, 
contact: 
 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
Or call toll free: 877-992-4724 
• 
Or by email: adviser@advarra.com 
 


 
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Please reference the following number when contacting the Study Subject Adviser: 
Pro00057341. 


 
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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 and date it. 
 
 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
 
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 


 
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APPENDIX I: STUDY VISITS 
 
I. 
Schedule for Clinic Visits 
 
The study staff can answer any questions you have about individual study visits, the 
evaluations that will occur, or how long each visit will be. The tables below can be used as 
a quick reference. 
 
A. Appendix Table 1A-1: Schedule for Part 1 
 
Evaluation or Test 
Screen 
Study 
Entry 
Post-Entry 
Visits 
Early 
Discontinuation 
Start SOC 
Treatment 
(follow-up 
every 2 weeks 
for 1 month) 
Oral CAB and 
NRTIs (week 4 
&, if needed, 
week 5) 
Consent 
√ 
 
 
 
 
HIV documentation 
√ 
 
 
 
 
Pre-ART HIV-1 RNA and Nadir 
CD4+ T-cell count 
documentation 
 
√ 
 
 
 
Clinical Assessments 
√ 
√ 
√ 
√ 
√ 
Complete physical examination 
√ 
 
 
 
 
Brief physical examination 
 
√ 
√ 
√ 
√ 
Medical/medication history 
√ 
√ 
 
 
 
Hepatitis screen 
√ 
 
 
 
 
CD4+/CD8+ T-cells 
√ 
 
 
 
 
Plasma HIV-1 RNA 
√ 
√ 
√ 
 
√ (Wk 7) 
Blood sample (for  VRC07-
523LS susceptibility test) 
√ 
 
 
 
 
Blood sample collection (for 
routine safety tests) 
√ 
√ 
√ 
√ 
 
Urinalysis 
 
√ 
 
 
 
Pregnancy test 
√ 
√ 
√ 
√ 
√ 
Study medications dispensed 
 
√ 
√(Wk 4) 
 
 
Non-study provided medications 
dispensed 
 
 
 
 
√ 
Confirm availability of pre-ART 
sample and store, if available 
 
√ 
 
 
 
Electrocardiogram (ECG) 
√ 
 
 
 
 
Genotype testing 
 
 
√ (Wk 5) 
 
 
Adherence questionnaire 
 
√ 
√ 
 
 
Stored blood samples (for future 
studies) 
 
√ 
√ (Wk 4) 
 
 


 
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B. Appendix Table 1A-2: Schedule for Part 2 
Evaluation or Test 
Part 2 
Entry 
Post-Entry Visits 
Confirm 
Virologic 
Failure 
Early 
Discontinuation 
Most 
Visits 
Some 
Visits 
End of CAB 
LA and 
VRC07-
523LS 
(week 44) 
Week 
48 
Brief physical 
examination 
√ 
√ 
 
√ 
√ 
√ 
√ 
Clinical 
assessments 
√ 
√ 
 
√ 
√ 
√ 
√ 
Blood sample 
collection (for 
routine safety tests) 
√ 
√ 
 
√ 
√ 
 
√ 
Urinalysis 
√ 
 
 
 
√ 
 
√ 
Pregnancy test 
√ 
All visits 
 
√ 
CD4+/CD8+ T-cells 
√ 
 
√ 
 
√ 
 
√ 
Plasma HIV-1 RNA 
√ 
√ 
 
√ 
If 
needed 
√ 
√ 
Study medications 
administered 
√ 
√ 
 
√ 
 
 
 
Stored blood 
samples (for future 
studies) 
√ 
 
√ 
 
√ 
√ 
√ 
Genotype testing 
 
 
 
 
√ 
√ 
 
Stored plasma (for 
PK of CAB LA) 
√ 
 
√ 
 
√ 
 
 
Serum collection 
(for VRC07-523LS  
PK) 
 
√ 
 
√ 
√ 
√ 
 
Serum collection 
(for antibody to 
VRC07-523LS) 
 
√ 
 
√ 
√ 
√ 
 
Stored plasma (for 
additional PK 
studies) 
 
√ 
 
√ 
√ 
√ 
 
Infusion report card 
distribution 
√ 
√ 
 
 
 
 
 
Infusion report 
card collection 
 
√ 
 
√ 
 
 
 
 
 
 


 
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C. Appendix Table 1A-3: Schedule for Part 3 
Evaluation or test 
Part 3 
Entry 
Post-Entry Visits 
(SOC ART) 
Confirm 
Virologic 
Failure 
Early 
Discontinuation 
Weeks 4, 
12, 24, 36 
Final 
Visit 
(week 
48) 
Brief physical exam 
√ 
√ 
√ 
√ 
√ 
Blood sample 
collection (for routine 
safety tests) 
√ 
√ 
√ 
 
√ 
CD4+/CD8+ T-cells 
√ 
√ 
√ 
√ 
√ 
Plasma HIV-1 RNA 
√ 
√ 
√ 
√ 
√ 
Genotype testing 
 
 
 
√ 
 
Stored PBMC and 
plasma 
 
 
√ 
√ 
√ 
Stored plasma and 
serum (for additional 
PK studies) 
 
√ 
√ 
√ 
 
Adherence 
questionnaire 
 
√ 
√ 
√ 
√ 
 


 
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II. 
Description of Visits 
 
Screening Visit: After you have read and signed the consent form, you will have several 
evaluations done to make sure that you meet the requirements for joining the study. You 
will have a special procedure done called an ECG that will measure the electrical activity of 
your heart. This is a simple and painless test to show how the heart is doing. 
 
Entry (Part 1 of study): If you are eligible to join the study, you will enter the study. As part 
of the entry visit, you will switch to the study-provided drug (oral CAB) and continue your 
current NRTIs. You will be seen at the clinic at 4 weeks (and possibly at 5 weeks) after you 
enter the study. If the level of HIV in your blood (also known as viral load) goes up to a 
higher level than what is required while on study, you will be seen at the clinic every 2 
weeks for a month (about 30 days) and then will be taken off the study. 
 
Part 2 of study: If the study drugs are working well for you at the end of week 4 or week 5 in 
Part 1, you will start Part 2 (about 5 weeks after you enter the study). When you enter Part 
2 of the study, you will have routine safety labs done only if these tests were not done at the 
final visit on Part 1 of the study. 
 
You will stop taking the anti-HIV drugs you were on during Part 1 of the study and start 
taking CAB LA every 4 weeks for 44 weeks and VRC07-523LS every 8 weeks for 40 weeks 
on Part 2 of the study. You will be seen in the clinic every 2 weeks until week 8, and then 
every 4 weeks until week 48. If your viral load is over 200 copies/mL, you will have a repeat 
test done. If the repeat test is still over 200 copies/mL, you will be required to stop the study 
drugs and your doctor will select a new regimen for you. However, you will be followed on 
study but off study treatment until the final study visit. Your viral load will be checked at 
week 48 only if it is not suppressed at week 44. 
 
If you received one dose of CAB LA or VRC07-523LS in Part 2, you will enter Part 3 (the 
SOC follow-up, see below) at the final visit on Part 2 of the study. 
 
Part 3: In Part 3 of the study, the anti-HIV drugs you received on Part 2 will no longer be 
provided to you. You will need to start taking the anti-HIV drugs that you were on before 
you entered this study or another ART depending on the results of the resistance testing. 
When you enter Part 3 of the study, you will have routine safety labs done only if these 
tests were not done at the final visit on Part 2 of the study. After you enter Part 3, you will 
be seen in the clinic at 1 month, 3 months, and then every 3 months for 48 weeks. 
 
Early Discontinuation: If you leave the study before you have been told that your time in the 
study is ended, you will be asked to return for one final visit. 


 
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III. Explanation of Evaluations 
 
Consent and contact information collected 
After you read the consent form and have had a chance to ask questions about the study, 
you will sign and date the consent form if you want to continue to be evaluated for study 
participation. You will also be asked how to be contacted in case you miss a visit or there 
are problems with your tests, and whether you give the study team permission to contact 
you. 
 
HIV infection confirmed 
If an HIV test has to be done, you may have to sign a separate consent form before this is 
done. You will be told the results of the HIV test as soon as it is available. 
 
Physical examination 
You will have a physical exam and will be asked questions about your health and about any 
medicines you have taken or are taking now. 
 
Electrocardiogram (ECG) 
ECG is a test to measure heart activity. Small adhesive pads connected to wires from the 
ECG machine will be painlessly placed on your chest and arms. You will be asked to lie 
down, remain still, and breathe normally for a few minutes during the test. 
 
Blood collected  
Blood will be collected from you for various tests during the study. These include: routine 
safety laboratory tests, HIV-1 viral load (a test that shows how much HIV is in your blood), 
CD4 count (a test that shows how many infection-fighting cells you have in your blood), liver 
function tests, and levels of study drugs. Blood will be collected and stored at some other 
visits. 
 
The site staff can tell you how much blood will be collected at any visit. 
 
Pregnancy test 
If you are able to become pregnant, you will be asked to give a small urine or blood sample 
for a pregnancy test. 
 
HIV-1 Resistance testing 
Your blood will be used to see which anti-HIV drugs might work best for you. 
 
Urine collection 
You will be asked to provide a small amount of urine that will be used in safety tests. 
 
Adherence Questionnaire 
You will be asked how you are feeling when you were taking the anti-HIV drugs and if there 
were any changes in your medicines since your last visit. 
 


 
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Infusion Report Card (IRC) 
You will receive an IRC to take home and use as a memory aid for side effects, on which 
you will record temperature and symptoms daily, starting on the day of VRC07-523LS 
infusion, after you leave the clinic, and continue for 3 days until the IRC is completed. 
 
IV. Consent for Use of Samples in Other Studies 
 
Use of Your Other Stored Samples 
Some blood that is collected from you during the study might be left over after all required 
study testing is done. This blood will be stored and, if you give your consent below, may be 
used for future ACTG-approved research that is not yet planned. This means that 
researchers who are not part of the protocol team may use your information and samples in 
different types of future ACTG research to fight HIV and other related diseases without 
asking you again for your consent. 
 
Some of these research studies may include testing of your genes or your DNA (your own 
genetic information), as described below. We do not know whether a type of testing called 
whole genome sequencing, or WGS, might be done. In WGS, researchers look at all of 
your genes and at almost all of your DNA. In “standard” genetic testing, researchers look at 
specific genes or subsets of genes, but not at all genes. It is hard to predict the exact 
amount of blood that will be left over after all required study testing is completed, but it will 
be no more than 10 tablespoons. 
 
As noted above, none of your samples will have any private information about you on their 
labels. You may decide whether this “extra” blood may be stored and, if so, whether 
additional testing may be performed on it. You may withdraw your consent for research on 
your extra samples at any time and the specimens will be discarded. 
 
You will not be paid for your samples. Also, a researcher may make a new scientific 
discovery or product based on the use of your samples. If this happens, there is no plan to 
share any money with you. The researcher is not likely to ever know who you are. 
 
Your blood will be kept frozen for an indefinite length of time. We cannot ensure that you 
will be told of the results of the research done on your blood. 
 
For each of the questions below, choose the response that matches what you want by 
putting your initials in the space provided. Please ask the staff any questions that you have 
before you indicate your selections. 
 
Research Without Human Genetic Testing – OPTIONAL (Research on leftover blood; no 
human genetic testing) 
 
If you agree, some of your blood that is left over after all required study testing is done may 
be stored (with usual protection of your identity) and used for ACTG-approved HIV-related 
research that does not include human genetic testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my blood. 


 
118 
A5357 
FINAL VERSION 4.0 
11Mar2022 
 
OR 
 
____ (initials) I understand but I do not agree to this storage or possible use of my blood. 
 
Research With Human Genetic Testing – OPTIONAL (Human genetic research on leftover 
blood) 
 
The ACTG has two studies that collect samples and consent for genetic testing. 
 
In the US, this study is A5128, Plan for Obtaining Informed Consent to use Stored 
Human Biological Materials (HBM) for Currently Unspecified Analysis 
 
Outside the US, this study is A5243, Plan for Obtaining Human Biological Samples at 
Non-U.S. Clinical Research Sites for Currently Unspecified Genetic Analyses 
 
Your site might ask you if you would like to participate in the study that is being 
done where you live. If you would like to participate, you will sign and date a 
separate consent form. 
 
Your extra samples will not be used for human genetic testing unless you sign and 
date a consent form for A5128 or A5243. 
 
If you agree, some of your blood will be saved (with protectors of identity that will not have 
your name on the sample) and tested in the future (after the study is done) to help 
understand how CAB and VRC07-523LS and methods of preventing HIV work. Some 
genetic tests may be done (after the study has been completed) to see if different types of 
immune responses to CAB LA and VRC07-523LS are related to genetic differences in 
people. You will not receive the results of these studies because they are experimental 
tests. 
 
Please initial below if you agree to have any of your blood used for ACTG-approved HIV-
related research that includes human genetic testing, and may include whole genome 
sequencing (WGS). 
 
____ (initials) I understand and I agree to this storage and possible use of my blood. 
 
OR 
 
____ (initials) I understand but I do not agree to this storage or possible use of my blood. 
 
If you decide now that your samples can be stored for research to be done at a later date, 
you may change your mind at any time. If you change your mind, you must contact your 
study doctor or nurse and let them know that you do not want your samples used for 
research to be done at a later date. Every effort will then be made to destroy your left-over 
samples. 
 


 
119 
A5357 
FINAL VERSION 4.0 
11Mar2022 
 
Sharing Genetic Data - OPTIONAL 
Genetic Research Databases: If you agreed to possible genetic testing of your blood above, 
researchers may want to share genetic information (with protection of your identity) with 
other researchers around the world, so that they can learn more about the causes and 
treatment of diseases. They may store this information in dbGaP, a genetic database 
maintained by the National Institutes of Health, as well as in other protected databases. 
 
____ (initials) I understand and I agree to this possible sharing of my genetic data. 
 
OR 
 
____ (initials) I understand but I do not agree to this possible sharing of my genetic data. 
 
 

SAP_001.pdf: 
 
Approvals 


ACTG A5357  
Primary Statistical Analysis Plan 
Version 4.0 
 
 
A Study of Long-Acting Cabotegravir Plus VRC-HIVMAB075-00-AB 
(VRC07-523LS) to Maintain Viral Suppression in Adults Living with HIV-1 
Protocol v4.0 
 
ClinicalTrials.gov Identifier: NCT03739996 
 
August 22, 2023 
 
This is the ACTG A5357 SAP Version 4.0 with names of authors, names of publication 
writing team members, and analysis timelines redacted. 
 
 


ACTG A5357 Protocol Version 4.0 
Primary Statistical Analysis Plan  v4.0 
 
 
      
        
 
August 22, 2023 
 
 
 
 
1 of 14 
Table of Contents 
1 
Introduction ............................................................................................................................................. 2 
1.1 
Purpose ......................................................................................................................................... 2 
1.2 
Key SAP Updates .......................................................................................................................... 2 
2 
Study Overview....................................................................................................................................... 3 
2.1 
Study design .................................................................................................................................. 3 
2.2 
Hypotheses .................................................................................................................................... 4 
2.3 
Sample Size Considerations ......................................................................................................... 4 
2.4 
Study Monitoring ............................................................................................................................ 4 
2.5 
Study Objectives ............................................................................................................................ 6 
2.5.1 
Primary objectives: ............................................................................................................ 6 
2.5.2 
Secondary Objectives: ....................................................................................................... 6 
2.6 
Study Outcome Measures ............................................................................................................. 7 
2.6.1 
Primary Outcome Measures .............................................................................................. 7 
2.6.2 
Secondary Outcome Measures ......................................................................................... 7 
3 
Definitions ............................................................................................................................................... 8 
3.1 
Baseline ......................................................................................................................................... 8 
3.2 
Analysis populations ...................................................................................................................... 8 
4 
Statistical methods.................................................................................................................................. 9 
4.1 
General considerations.................................................................................................................. 9 
4.2 
Visit schedule and analysis windows ............................................................................................ 9 
4.3 
Primary Analyses ......................................................................................................................... 10 
4.3.1 
Primary Safety Analyses .................................................................................................. 10 
4.3.2 
Primary Efficacy Analyses ............................................................................................... 10 
4.4 
Secondary Analyses .................................................................................................................... 10 
5 
Report components .............................................................................................................................. 12 
 
 


 
 
 
 
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1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary outcome measures of 
ACTG A5357 that will be included in the primary manuscript, and which address, at 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 Statistical 
Analysis Report are included in the (separate) Analysis Implementation Plan (AIP).  A separate Statistical 
Analysis Plan for other objectives and outcome measures will be developed once results for the Primary 
and Secondary Objectives are known, and analyses will be presented in a separate report.   
Analyses for the Primary Analysis Report will begin  once the last participant has completed the week 
R2+48 study visit, all adverse events (through Step 2) have been adjudicated by the core team, all 
queries have been resolved to the statistician’s satisfaction in order to conduct the intended analyses.  A 
preliminary version of this report will be produced containing analysis of all outcomes observable 
once all participants have completed Step 2 and with preliminary looks at primary and secondary 
safety outcomes 10.2.1.1 and 10.2.2.11.  
The Primary Statistical Analysis Report will be used for submission of results to ClinicalTrials.gov. Results 
for primary outcomes are required to be submitted within one year of the primary completion date (PCD), 
which is the date the last participant is examined for the purposes of data collection for the latest 
observed primary outcome measure.  For this study, the PCD is based on 101 weeks of follow-up (5 
weeks in Step 1, 48 weeks in Step 2 and 48 weeks in Step 3), as adverse events observed on Step 3 
are still being adjudicated with respect to CAB LA and VRC07-523LS.   A submission to 
ClinicalTrials.gov will be done once all follow-up (through Step 3) is complete.    
1.2 
Key SAP Updates 
This is the initial version of the statistical analysis plan and there have yet to be any key updates. This 
section will be updated in future versions of the analysis plan. 
Version 
Changes Made 
Effective Date 
1.0 
Original Version 
13JAN2020 
2.0 
Letter of amendment review by Evelyn Zheng (LOA #1 and #2 for 
Protocol Version 3.0). Changes were minor and are bolded. 
9/10/2020 


 
 
 
 
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2.1 
Letter of amendment review by Evelyn Zheng (LOA #3 for 
Protocol Version 3.0). No changes were required. 
7/21/2021 
3.0 
Protocol version 4.0 review by Evelyn Zheng. 
The word “oral” was removed when describing the SOC ART 
regimen participants begin in Step 3.  
6/29/2022 
4.0 
Updates were made to capture extending the PCD to 
appropriately capture Step 3 adverse events which may contribute 
to outcome measures 10.2.1.1 and 10.2.2.11. Major changes are 
bolded. 
August 22, 2023 
2 
Study Overview 
2.1 
Study design 
Protocol Version 1.0 was finalized on October 2, 2018.  Due to recommendations made by the FDA, the 
protocol was intended to open to enrollment under version 2.0 and not version 1.0. Protocol Version 2.0 
was finalized on February 27, 2019.  Due to new results in the field, VRC01LS was replaced by VRC07-
523LS in protocol v3.0. The protocol will open to enrollment under version 3.0 and not version 2.0.  
Protocol Version 3.0 was finalized on October 18, 2019.  
A5357 is a Phase II, single arm, open-label switch study to assess the safety, tolerability, 
pharmacokinetics, and antiviral activity of long-acting cabotegravir (CAB LA) plus the broadly neutralizing 
monoclonal antibody, VRC-HIVMAB075-00-AB (VRC07-523LS) in HIV-1-infected adults with suppressed 
plasma viremia.  
 
At Step 1 entry, all participants will discontinue their current ART regimen except for nucleoside reverse 
transcriptase inhibitors (NRTIs), and initiate oral CAB (30 mg).  Viral load monitoring will occur at entry 
and week 4 (and also at week 5 if HIV-1 RNA is 50-199 copies/mL at week 4). Participants tolerating oral 
CAB plus their current two NRTIs with HIV-1 RNA <50 copies/mL at week 4, or HIV-1 RNA of 50-199 
copies/mL at week 4 followed by HIV-1 RNA <50 copies/mL at week 5, will register to Step 2 and receive 
CAB LA every 4 weeks through week R2+44 plus VRC07-523LS every 8 weeks through week R2+40. 
Participants in Step 1 who are not eligible for Step 2 entry will be switched to a standard of care (SOC) 
regimen and followed on study every 2 weeks for a total of 4 weeks and then be taken off study. 
Viral load monitoring in Step 2 will occur every 2 weeks until week R2+8 and then every 4 weeks until 
week 48. All participants will complete the week R2+48 visit in Step 2, and this visit will be used to confirm 
virologic rebound in those with HIV-1 RNA ≥50 copies/mL at week R2+44.  
For participants who have a confirmed HIV-1 RNA ≥200 copies/mL during Step 2 or confirmed HIV-1 RNA 
≥50 copies/mL at week R2+44 and ≥200 copies/mL at week R2+48, genotypic testing will be performed 


 
 
 
 
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for protease/reverse transcriptase (PR/RT) and integrase resistance. In addition, samples from the failure 
confirmation visit and pre-ART or entry (if available) will be tested for viral clonality, integrase resistance, 
and VRC07-523LS neutralization resistance. These participants will be switched back to an SOC  ART 
regimen, guided by resistance testing (Step 3). 
All participants who receive any dose of CAB LA or VRC07-523LS or prematurely discontinue study 
treatment in Step 2 will register to Step 3 (the 48-week follow up on an SOC regimen) at the final study 
visit in Step 2 or at premature treatment discontinuation.   
2.2 
Hypotheses 
The combination of long-acting cabotegravir (CAB LA) and VRC-HIVMAB075-00-AB (VRC07-523LS) is 
safe and will prevent viral rebound (confirmed HIV-1 RNA ≥200 copies/mL) in individuals who have 
achieved suppression with conventional antiretroviral therapy (ART).  
2.3 
Sample Size Considerations 
Assuming 74 participants are enrolled, 70 initiate CAB LA plus VRC07-523LS, 10% are lost to follow-up 
and 5% subsequently discontinue CAB LA plus VRC07-523LS, there will be 60 analyzable participants. 
With 60 analyzable participants, if the observed virologic failure probability is 5.0%, the 95% CI will be 
[1.7%, 13.7%]. This 95% CI is estimated using the Wilson score method. A 95% CI of [1.7%, 13.7%] 
would provide proof of concept in support of the investigational strategy.  Assuming the true rate of failure 
is 5%, the sample size will provide >90% power to reject a null failure rate of 20%.  Regarding the 
assessment of safety and tolerability, a sample size of 70 CAB LA plus VRC07-523LS treated participants 
will provide a 94% probability of observing a CAB LA plus VRC07-523LS related AE or CAB LA plus 
VRC07-523LS related treatment discontinuation that would occur in 4% of treated participants. 
Overall, the study aims to enroll at least 15 (20% of 74) female participants. The core team will also 
monitor accrual to ensure that ≥70 participants enroll in Step 2. Additional participants will be enrolled into 
the study if >4 Step 1 participants are ineligible for Step 2. 
2.4 
Study Monitoring 
Accrual, baseline characteristics, study conduct (including premature treatment and study 
discontinuations), virologic failures, and all AEs will be monitored during the trial on a regular basis by the 
protocol core team. The protocol core team will review the individual safety data frequently to assess the 
relation of all reported AEs to oral CAB, CAB LA, and VRC07-523LS. 
The DAIDS clinical representative will review and assess select EAE reports for potential impact on the 
study participant safety and protocol conduct as per DAIDS policies, guidance documents, and SOPs as 
applicable.  
To ensure the safety of the participants, the study will be reviewed routinely by an independent ACTG 
appointed study monitoring committee (SMC) at the earlier of (i) the 25th enrolled participant has reached 
week 24 in Step 2 of the CAB LA plus VRC07-523LS combination or discontinued the study or study 


 
 
 
 
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treatment prior to this, or (ii) 1 year after the study is open for enrollment.  After the first interim review, the 
study will be routinely monitored annually by the SMC.   
An interim review may be triggered prior to this if (i) three or more participants have virologic failures while 
adhering to Step 2 treatment (see below for definition of virologic failures considered in the stopping 
guideline), (ii) one or more participant(s) experience a death that is assessed by the protocol core team 
as possibly, probably, or definitely related to CAB LA and/or VRC07-523LS at any time, (iii) two or more 
participants experience a Grade 4 AE that is assessed by the protocol core team as possibly, probably, or 
definitely related to CAB LA and/or VRC07-523LS before 25 participants are enrolled and have reached 
week 24 of Step 2, or (iv) four or more participants experience a Grade 4 AE that is assessed by the 
protocol core team as possibly, probably, or definitely related to CAB LA and/or VRC07-523LS at any 
time. If an interim review is triggered, enrollment into Step 1 and Step 2 will be paused pending SMC 
consultation and participants in Step 1 or Step 2 will continue to follow the intended study design 
including continuing the step-specific study treatment regimen until the SMC has been consulted. An 
interim review may also be convened if a concern is identified by the DAIDS clinical representative, the 
study chairs, or study statisticians in consultation with the team. 
To protect participants if virologic failure on the experimental regimen turns out to be higher than what 
may be clinically acceptable, a stringent stopping rule has been put into place. However, to guard against 
premature study stoppage or modification due to virologic failures that may be attributed to non-
adherence or deviations from the specified dosing of the study treatments, virologic failures contributing 
to the stopping criteria must meet additional criteria to ensure that the pure treatment efficacy is 
evaluated. Specifically, virologic failure for the study’s stopping guideline will be defined as two 
consecutive HIV-1 RNA levels ≥200 copies/mL on Step 2, while adhering to study treatment (i.e., no 
missed dose of CAB LA or VRC07-523LS). A missed dose is defined as an unadministered dose, 
inadequate dose, or any dose outside the window specified in the protocol. Initial HIV-1 RNA 
measurements ≥200 copies/mL taken prior to Step 2 treatment initiation will be excluded from the 
evaluation of virologic failure for the stopping guideline.  Under this definition of virologic failure, a true 
failure rate ≤2% is considered to be acceptable. The reference for the threshold is the recent result from 
the LATTE-2 trial, where the virologic failure rate was 1% through week 96 for the combination of CAB LA 
plus RPV LA as a maintenance therapy for participants suppressed on ART.  
Note that the virologic failure definition considered for the stopping guideline has more stringent 
adherence criteria than the virologic failure definition for the primary outcome, with the intention that the 
stopping guideline serves the purpose of protecting participants if available data indicate that efficacy of 
the experimental regimen may be lower than what is clinically acceptable. Table 10.5-1 (in the protocol) 
estimates the choices of the stopping guideline associated with different sample sizes and the probability 
that the guideline will be met under various true probabilities of failure. At any time during Step 2, if three 
or more participants are observed to experience virologic failures defined for the stopping guideline, 
enrollment into Step 1 and Step 2 will be paused, and SMC will be promptly convened. The SMC, in such 
an event, is expected to require all participants in Step 1 and Step 2 to enter Step 3 immediately. The 
stopping criteria will ensure that the trial has a high probability (≥85%) to continue when the true failure 


 
 
 
 
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rate is ≤2%, and is likely to stop when the true failure rate is unacceptably high (e.g., when the true failure 
rate is 10%, the trial will stop with a probability of 58%-95% when the sample size is ≥30). 
The SMC safety triggers assume 95% of participants will initiate CAB LA plus VRC07-523LS, and have a 
low chance (9%) to be triggered if there is a low probability of a treatment related death (0.1%) and Grade 
4 AE (1%), but a higher chance (97%) to be triggered if there is a high probability of a treatment related 
death (1%) and Grade 4 AE (10%). 
2.5 
Study Objectives  
This Primary SAP addresses the following primary and secondary objectives listed in the study protocol. 
Other study objectives in the protocol will be addressed in subsequent analysis plans.  
2.5.1 
Primary objectives: 
• 
To evaluate the safety and tolerability of the combination of parenteral VRC07-523LS plus CAB 
LA in HIV-1 infected adults with well-controlled viral replication  
• 
To evaluate the virologic efficacy of the combination of parenteral VRC07-523LS plus CAB LA to 
prevent viral rebound (confirmed HIV-1 RNA ≥200 copies/mL) in HIV-1 infected adults with well-
controlled viral replication 
2.5.2 
Secondary Objectives:  
• 
To determine the pharmacokinetic (PK) parameters of the combination of VRC07-523LS and 
CAB LA and their associations with viral rebound in HIV-1-infected adults 
• 
To evaluate evidence of anti-idiotype antibodies against VRC07-523LS in samples collected from 
representative time points throughout the study 
• 
To evaluate the safety and tolerability of oral CAB 
2.6 
Study Outcome Measures  
This Primary SAP addresses the following primary and secondary outcome measures listed in the study 
protocol. Other study outcome measures in the protocol will be addressed in subsequent analysis plans. 
2.6.1 
Primary Outcome Measures 
• 
Either the occurrence of a Grade 3 or higher AE that is possibly, probably, or definitely related (as 
judged by the core team) to the CAB LA plus VRC07-523LS combination or premature study 
treatment discontinuation due to an AE (regardless of grade) that is possibly, probably, or 
definitely related (as judged by the core team) to the CAB LA plus VRC07-523LS combination 
• 
Virologic failure defined as confirmed HIV-1 RNA ≥200 copies/mL at or prior to week R2+44 of 
the CAB LA plus VRC07-523LS combination 


 
 
 
 
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2.6.2 
Secondary Outcome Measures 
2.6.2.1 
PK parameters of the combination of VRC07-523LS and CAB LA 
2.6.2.2 
Viral resistance of breakthrough isolates 
2.6.2.3 
Virologic failure (confirmed HIV-1 RNA ≥200 copies/mL) at or prior to week R2+24 of the CAB 
LA plus VRC07-523LS combination 
2.6.2.4 
Virologic failure (confirmed HIV-1 RNA ≥200 copies/mL) or premature discontinuation of the 
CAB LA plus VRC07-523LS combination at or prior to week R2+44 
2.6.2.5 
Confirmed HIV-1 RNA ≥50 copies/mL at or prior to week R2+24 and R2+44 of the CAB LA 
plus VRC07-523LS combination 
2.6.2.6 
Confirmed HIV-1 RNA ≥50 copies/mL or premature discontinuation of the CAB LA plus 
VRC07-523LS combination at or prior to week R2+44 
2.6.2.7 
Virologic failure (defined by FDA snapshot algorithm) at week R2+44 of the CAB LA plus 
VRC07-523LS combination. 
2.6.2.8 
Measurable levels of anti-idiotype antibodies against VRC07-523LS in samples collected from 
representative time points throughout the study 
2.6.2.9 
Either the occurrence of a Grade 3 or higher AE that is possibly, probably, or definitely related 
(as judged by the core team) to oral CAB or premature oral CAB discontinuation due to an AE 
(regardless of grade) that is possibly, probably, or definitely related (as judged by the core 
team) to oral CAB 
2.6.2.10 Premature discontinuation of oral CAB or the CAB LA plus VRC07-523LS combination 
2.6.2.11 Occurrence of a Grade 3 or higher AE that is possibly, probably, or definitely related (as 
judged by the core team) to oral CAB or the CAB LA plus VRC07-523LS combination 
 
3 
Definitions 
3.1 
Baseline 
“Study entry” or “baseline” is defined as the study registration date.  The value used for baseline (Week 0) 
will be the last evaluation on or before the study registration date.  Although the protocol intended for 
the study/step entry visits to occur on the day of registration, this did not always occur. In these 
instances, the value used for baseline of “Step X Entry” will be the last evaluation on or before the 
study/step entry visit date. Note: Target dates for subsequent study visits are determined by step 
registration date, regardless of the date of the entry visit.  
Adverse events with an onset date on the study treatment initiation date and assessed by the site to have 
started before the administration of oral CAB, will be included as baseline.   


 
 
 
 
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3.2 
Analysis populations 
Participants found to be ineligible and who the study team determines should not be included in any 
analyses will be included in screening, accrual and eligibility summaries only.   
Safety Analyses:  
The primary  safety analyses (10.2.1.1) will include all participants who have been exposed to CAB LA 
and VRC07-523LS.  All events observed on Step 2 and Step 3 (when the CMC assigned a 
relationship to Step 2 treatment) will be considered.  
The secondary safety outcomes (10.2.2.9, 10.2.2.10, and 10.2.2.11) will include all participants who 
have been exposed to oral CAB, as this population naturally encompasses all participants who 
were later exposed to CAB LA and VRC07-523LS.  
Efficacy Analyses:  
Primary and secondary virologic efficacy outcome (10.2.1.2, 10.2.2.3, 10.2.2.5) analyses will utilize the  
as-treated (i.e., per protocol) population, only including participant follow-up on the CAB LA plus VRC07-
523LS combination. Participants who prematurely discontinue the CAB LA plus VRC07-523LS 
combination will be censored at the time of discontinuation.  
Participants who have a single HIV-1 RNA ≥200 copies/mL at or prior week R2+44, who subsequently are 
lost to follow-up or discontinue study treatment, will be treated as virologic failure. 
Analyses of the secondary virologic failure/premature treatment discontinuation outcomes (CAB LA plus 
VRC07-523LS) will include all participants initiating CAB LA plus VRC07-523LS. 
4 
Statistical methods  
4.1 
General considerations 
Baseline characteristics will be summarized for the entire study population (i.e. participants that receive 
any dose of oral CAB, CAB LA or VRC07-523LS).  
Statistical tests (all two-sided) will not be adjusted for interim monitoring.  Significance levels where the   
p-value < 0.05 will be highlighted in the text, but must be interpreted with caution, since there will be 
multiple statistical tests which will increase the chance of spuriously significant p-values.   
Categorical data will be summarized using N (%), and continuous data using N, min, Q1, median, Q3, 
max, and mean (standard deviation (SD)) (when appropriate).  Any modifications to outcome measures 
after the team has seen data that were collected after entry will be identified as such in the analysis 
report. 


 
 
 
 
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4.2 
Visit schedule and analysis windows 
The study treatment administration and clinic visit schedules are summarized in Figure 1.   
Figure 1: Study treatment administration and clinic visit schedules 
 
For the purposes of analysis, visit windows will be formed around each study visit using the midpoints 
between adjacent weeks as cutoffs, and potentially including assessments collected outside the 
recommended visit windows described above.  If there are multiple evaluations within the analysis 
window for a given visit, the evaluation closest to the scheduled study week will be used, and the earlier 
measurement will be used if there are two measurements which are equally distant from the scheduled 
week.   
4.3 
Primary Analyses 
4.3.1 
Primary Safety Analyses  
Outcome measure: Either the occurrence of a Grade 3 or higher AE that is possibly, probably, or 
definitely related (as judged by the core team) to the CAB LA plus VRC07-523LS combination or 
premature study treatment discontinuation due to an AE (regardless of grade) that is possibly, probably, 
or definitely related (as judged by the core team) to the CAB LA plus VRC07-523LS combination 


 
 
 
 
10 of 14 
For the primary safety and tolerability analysis, all participants who have been exposed to CAB LA and 
VRC07-523LS will be included and summaries will include the number and percentage of participants 
experiencing a grade 3 or higher treatment-related AE or premature treatment discontinuation with a two-
sided Wilson score 95% CI.   
4.3.2 
Primary Efficacy Analyses 
Outcome measure: Virologic failure defined as confirmed HIV-1 RNA ≥200 copies/mL at or prior to week 
R2+44 of the CAB LA plus VRC07-523LS combination (where the starting time is the date of treatment 
initiation on Step 2). 
For the primary virologic efficacy analysis, the cumulative probability of participants experiencing virologic 
failure at or prior to week R2+44 of the CAB LA plus VRC07-523LS combination will be estimated using 
Kaplan-Meier methods.  If the probability is high, a standard two-sided 95% CI around the true virologic 
failure probability will be calculated using the adaption of Greenwood’s variance estimate with a log(-log) 
transformation.  However, if the probability is low, Rothman-Wilson two-sided 95% CIs will be estimated.  
Primary virologic efficacy analysis will be as-treated (i.e. per protocol) only including participant follow-up 
on the CAB LA plus VRC07-523LS combination. Participants who prematurely discontinue the CAB LA 
plus VRC07-523LS combination will be censored at the time of discontinuation (as described in Section 
3.2.)  
4.4 
Secondary Analyses 
The secondary safety and tolerability outcome for the oral CAB (2.6.2.9) will be analyzed in a similar 
manner to the primary safety and tolerability outcome.  
A similar approach will also be taken for the secondary safety outcome describing Grade 3 or higher AEs 
related to oral CAB or the CAB LA plus VRC07-523LS combination, overall and separately (2.6.2.11). In 
addition, all reported grade 3 or 4 AEs (regardless of study treatment relatedness) on oral CAB or the 
CAB LA plus VRC07-523LS combination will be summarized and tabulated. 
Secondary intent-to-treat (ITT) sensitivity analyses will be conducted for the primary virologic efficacy 
outcome measure. Participants who initiate but then prematurely discontinue LA CAB plus VRC07-523LS 
will only be censored if lost to follow-up prior to virologic failure (defined as confirmed virologic failure or 
last available HIV-1 RNA ≥ 200 copies/mL). If not lost to follow up, HIV-1 RNA measures on Step 3 (SOC  
ART regimen) will be used to determine if the participant had virologic failure.   
The secondary virologic efficacy outcomes will be analyzed in a similar manner to the primary efficacy 
outcome, but with respect to week R2+24 and/or ≥50 copies/mL (2.6.2.3, 2.6.2.5).   
The secondary virologic failure/premature treatment discontinuation outcome will include all participants 
initiating CAB LA plus VRC07-523LS and consider both virologic failure and premature discontinuation of 
LA CAB plus VRC07-523LS as failure, whichever occurs first (2.6.2.4, 2.5.2.6).  


 
 
 
 
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The secondary premature treatment discontinuation outcome will include all participants initiating oral 
CAB and consider premature discontinuation of oral CAB, LA CAB or VRC07-523LS as failure, and will 
summarize them overall and separately with reasons for the discontinuation (2.6.2.10).  
For the secondary analysis defining the virologic failure at week R2+44 endpoint using the FDA Snapshot 
Algorithm, see attachment #3 in the appendix for the derivation of virologic success and failure based on 
the decision tree algorithm. The FDA snapshot algorithm accounts for missing data by including a 
categorization of missed visits and study discontinuations; therefore, no special missing data methods will 
be used (2.6.2.7). 
The percentage of participants with measurable levels of anti-idiotype antibodies will be presented along 
with a two-sided Wilson score 95% CI (2.6.2.8). Neutralization resistance and diversity of viral rebound 
quasispecies will be summarized pre-ART and at virologic failure (2.6.2.2). 
For details on the determination of the PK parameters of the combination of VRC07-523LS and CAB LA, 
see the Pharmacology Plan in the protocol.  Selected PK parameters will be summarized for all 
participants, and possibly by subgroup with viral rebound vs. maintaining viral suppression (2.6.2.1).  
5 
Report components 
Detailed descriptions of the content of each of the following sections are provided in the Analysis 
Implementation Plan (AIP).   
1. Study entry 
a. Screening 
b. Enrollment 
c. Eligibility errors 
2. Baseline characteristics 
3. VRC07-523LS susceptibility test results 
4. Study status by Step 
5. Study treatment status by Step 
6. Changes/interruptions to study treatment during study follow-up by Step 
7. Safety: 
a. Primary safety outcome 
b. Local injection and infusion site reactions  
c. Deaths 
d. Overall safety 
8. Primary efficacy outcome (HIV-1 RNA) 
a. Evaluability  
b. Primary efficacy outcome 
c. Sensitivity analyses 
d. Secondary efficacy outcome 
9.  Virologic Failure and Viral Resistance  


 
 
 
 
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10. CD4 counts during study follow-up 
11. HIV-1 RNA during study follow-up 
12. CAB LA PK concentrations 
13. VRC07-523LS PK concentrations 
14. VRC07-523LS ADA