Clinical trial NCT03239483
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2017-10-26; Completion date: 2018-09-20
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and pharmacokinetics (PK) of dapivirine gel (0.05%) administered rectally to HIV-1 seronegative adults.

Detailed description:
This study will evaluate the safety and pharmacokinetics (PK) of dapivirine gel (0.05%) administered rectally to HIV-1 seronegative adults.

Participants will be randomized to receive a single dose of either rectally administered dapivirine gel (0.05%) or placebo gel at study entry (Day 0). Following a minimum 2-week washout period, participants or study staff will administer daily rectal doses of the assigned gel for 7 consecutive days under direct observation in the clinic.

Participants will be in the study for approximately 40 days, and they will attend 16 study visits. Study visits may include behavioral assessments, physical examinations, blood and urine collection, and pelvic and anorectal sample collection. Some visits will include intensive PK sampling. Study staff will contact participants 1 week after Visit 16 for follow-up safety monitoring.

Arms: arm 1: Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic. arm 2: Participants will receive a single dose of placebo gel rectally, followed by 7 daily doses of placebo gel to be administered under direct observation in the clinic.
Interventions: intervention 1: Dapivirine gel intervention 2: Placebo gel
Intervention descriptions: intervention 1: Dapivirine gel (0.05%); administered rectally intervention 2: Universal HEC placebo gel; administered rectally

Protocol documents:
Prot_000.pdf: 
MTN-026 
 
 
A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and 
Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally  
to HIV-1 Seronegative Adults 
 
 
 
Microbicide Trials Network 
 
 
 
Funding Agencies: 
Division of AIDS, US National Institute of Allergy and Infectious Diseases 
US Eunice Kennedy Shriver National Institute of  
Child Health and Human Development 
US National Institute of Mental Health 
US National Institutes of Health 
 
 
 
Grant Numbers: 
UM1AI068633, UM1AI068615, UM1AI106707 
 
 
DAIDS Protocol ID: 
12021 
 
 
IND Sponsor: 
DAIDS 
 
 
IND#: [XXXXX] 
 
 
Protocol Chair: 
Ross D. Cranston, MD, FRCP 
 
 
 
Version 2.0 
 
July 21, 2017 
 
NCT03239483


 
 
  
MTN-026, Version 2.0 
2 
July 21, 2017 
 
MTN-026 
 
A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and 
Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 
Seronegative Adults 
 
TABLE OF CONTENTS 
 
PROTOCOL SUMMARY ........................................................................................................... 19 
1 KEY ROLES ........................................................................................................................ 22 
1.1 
Protocol Identification .................................................................................................. 22 
1.2 
Funding Agencies, Sponsor and Monitor Identification ............................................... 22 
1.3 
Medical Officer ............................................................................................................ 23 
1.4 
Clinical Laboratories ................................................................................................... 23 
1.5 
Data Center ................................................................................................................. 23 
1.6 
Study Implementation ................................................................................................. 23 
2 INTRODUCTION ................................................................................................................. 24 
2.1 
Dapivirine Gel ............................................................................................................. 24 
2.2 
Universal Placebo gel ................................................................................................. 25 
2.3 
Non-Clinical Studies .................................................................................................... 26 
2.4 
Clinical Studies ........................................................................................................... 30 
2.5 
Other Clinical Studies of Dapivirine ............................................................................. 38 
2.6 
Study Hypotheses and Rationale for Study Design .................................................... 40 
3 OBJECTIVES....................................................................................................................... 41 
3.1 
Primary Objectives ...................................................................................................... 41 
3.2 
Secondary Objectives ................................................................................................. 41 
3.3 
Exploratory Objectives ................................................................................................ 41 
4 STUDY DESIGN .................................................................................................................. 42 
4.1 
Identification of Study Design ...................................................................................... 42 
4.2 
Summary of Major Endpoints ...................................................................................... 42 
4.3 
Description of Study Population .................................................................................. 43 
4.4 
Time to Complete Accrual ........................................................................................... 43 
4.5 
Study Groups .............................................................................................................. 43 
4.6 
Expected Duration of Participation .............................................................................. 43 
4.7 
Sites ............................................................................................................................ 43 
5 STUDY POPULATION ......................................................................................................... 44 
5.1 
Selection of the Study Population ............................................................................... 44 
5.2 
Inclusion Criteria ......................................................................................................... 44 
5.3 
Exclusion Criteria ........................................................................................................ 45 
5.4 
Co-enrollment Guidelines ........................................................................................... 48 
6 STUDY PRODUCT .............................................................................................................. 48 
6.1 
Regimen...................................................................................................................... 48 
6.2 
Administration ............................................................................................................. 49 
6.3 
Study Product Formulation.......................................................................................... 49 
6.4 
Study Applicator .......................................................................................................... 49 
6.5 
Study Product Supply and Accountability ................................................................... 50 
6.6 
Study Product Dispensing ........................................................................................... 50 


 
 
  
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6.7 
Retrieval of Unused Study Products ........................................................................... 50 
6.8 
Ancillary Study Supplies ............................................................................................. 51 
6.9 
Concomitant Medications ............................................................................................ 51 
6.10 
Prohibited Medications and Practices ......................................................................... 51 
7 STUDY PROCEDURES ...................................................................................................... 52 
7.1 
Pre-screening .............................................................................................................. 52 
7.2 
Visit 1: Screening ........................................................................................................ 53 
7.3 
Visit 2: Enrollment (Day 0) .......................................................................................... 54 
7.4 
Visit 3: Single Dose Administration Visit ..................................................................... 55 
7.5 
Visits 4-6 (~24, 48, 72 Hours After Application of Study Product) ............................... 56 
7.6 
Visits 7-12: Study Product Administration Visits .......................................................... 57 
7.7 
Visit 13: Last Study Product Administration Visit/Early Termination Visit .................... 58 
7.8 
Visits 14-16: PK Visits (~24, 48, 72 Hours After Last Application of Study 
Product) ...................................................................................................................... 59 
7.9 
Visit 17:  Follow-Up Safety Contact and Termination Visit .......................................... 60 
7.10 
Follow-up Procedures for Participants Who Permanently Discontinue Study 
Product ....................................................................................................................... 60 
7.11 
Interim Visits ............................................................................................................... 61 
7.12 
Study Product Use / Adherence Counseling ............................................................... 61 
7.13 
Clinical Evaluations and Procedures ........................................................................... 61 
7.14 
Behavioral Assessments ............................................................................................. 62 
7.15 
Pharmacokinetics, Pharmacodynamics and Mucosal Safety ...................................... 63 
7.16 
Laboratory Evaluations ............................................................................................... 64 
7.17 
Specimen Collection and Processing .......................................................................... 65 
7.18 
Specimen Handling ..................................................................................................... 66 
7.19 
Biohazard Containment .............................................................................................. 66 
8 ASSESSMENT OF SAFETY ............................................................................................... 66 
8.1 
Safety Monitoring ........................................................................................................ 66 
8.2 
Clinical Data and Safety Review ................................................................................. 66 
8.3 
Adverse Events Definitions and Reporting Requirements .......................................... 67 
8.4 
Adverse Event Reporting Requirements ..................................................................... 70 
8.5 
Pregnancy and Pregnancy Outcomes ........................................................................ 71 
8.6 
Regulatory Requirements ........................................................................................... 71 
8.7 
Social Harms Reporting .............................................................................................. 71 
9 CLINICAL MANAGEMENT .................................................................................................. 71 
9.1 
Grading System .......................................................................................................... 71 
9.2 
Dose Modification Instructions .................................................................................... 72 
9.3 
General Criteria for Permanent Discontinuation of Study Product .............................. 72 
9.4 
Follow-up in Response to Observed Adverse Events ................................................. 72 
9.5 
Pregnancy ................................................................................................................... 73 
9.6 
Criteria for Early Termination of Study Participation ................................................... 73 
10 STATISTICAL CONSIDERATIONS ..................................................................................... 74 
10.1 
Overview and Summary of Design .............................................................................. 74 
10.2 
Study Endpoints .......................................................................................................... 74 
10.3 
Primary Study Hypotheses.......................................................................................... 74 
10.4 
Sample Size and Power Calculations ......................................................................... 74 
10.5 
Participant Accrual, Follow-up and Retention ............................................................. 76 


 
 
  
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10.6 
Randomization ............................................................................................................ 76 
10.7 
Blinding ....................................................................................................................... 76 
10.8 
Data and Safety Monitoring and Analysis ................................................................... 76 
11 DATA HANDLING AND RECORDKEEPING ....................................................................... 78 
11.1 
Data Management Responsibilities ............................................................................. 78 
11.2 
Source Documents and Access to Source Data/Documents ...................................... 78 
11.3 
Quality Control and Quality Assurance ....................................................................... 78 
12 CLINICAL SITE MONITORING............................................................................................ 79 
13 HUMAN SUBJECTS PROTECTIONS ................................................................................. 79 
13.1 
Institutional Review Boards/Ethics Committees .......................................................... 79 
13.2 
Protocol Registration ................................................................................................... 80 
13.3 
Study Coordination ..................................................................................................... 80 
13.4 
Risk Benefit Statement ............................................................................................... 81 
13.5 
Informed Consent Process.......................................................................................... 84 
13.6 
Participant Confidentiality............................................................................................ 85 
13.7 
Special Populations .................................................................................................... 85 
13.8 
Compensation ............................................................................................................. 86 
13.9 
Communicable Disease Reporting .............................................................................. 86 
13.10 Access to HIV-related Care......................................................................................... 86 
13.11 Study Discontinuation ................................................................................................. 86 
14 PUBLICATION POLICY ....................................................................................................... 87 
15 APPENDICES ...................................................................................................................... 88 
APPENDIX I:  SCHEDULE OF STUDY VISITS AND EVALUATIONS ...................................... 89 
APPENDIX II:  ALGORITHM FOR HIV ANTIBODY TESTING FOR SCREENING AND 
FOLLOW-UP ............................................................................................................................. 91 
APPENDIX III: SAMPLE INFORMED CONSENT FORM (SCREENING, 
ENROLLMENT, LONG-TERM STORAGE AND FUTURE TESTING) ...................................... 92 
 
TABLE OF FIGURES 
Figure 1: Study Visit Schedule ............................................................................................ 20 
Figure 2:  MTN-026 Study Visit Schedule ........................................................................... 52 
 
TABLE OF TABLES 
 
Table 1: Dapivirine Gel 4759, 0.05%, 2.5 g Formulation ..................................................... 25 
Table 2: Universal HEC Placebo Gel Formulation .............................................................. 25 
Table 3: Treatment-Emergent AEs from Gel 4750 Use ....................................................... 33 
Table 4: Treatment-Emergent AEs from Dapivirine Gels across Vaginal Gel Trials* 
(Regardless of Causality) .................................................................................................... 35 
Table 5: Clinical Studies of Dapivirine ................................................................................. 38 
Table 6: Study Product Regimen ........................................................................................ 48 
Table 7: Visit 1:  Screening Visit .......................................................................................... 53 
Table 8: Visit 2:  Enrollment (Day 0) .................................................................................... 54 
Table 9: Visit 3: Single Dose Administration Visit ................................................................ 55 
Table 10: Visits 4-6:  PK Visits (~24, 48, 72 Hours After Application of Study 
Product) ............................................................................................................................... 56 
Table 11: Visits 7-12: Study Product Administration Visits .................................................. 57 


 
 
  
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Table 12:  Visit 13: Last Study Product Administration Visit/Early Termination Visit ........... 58 
Table 13:  Visits 14-16: PK Visits (~24, 48, 72 Hours After Last Application of Study 
Product) ............................................................................................................................... 59 
Table 14: Visit 17: Follow-up Safety Contact and Termination Visit .................................... 60 
Table 15: PK, PD, and Mucosal Safety Sampling Table ..................................................... 63 
Table 16: Analysis of Safety Event Frequency .................................................................... 75 
Table 17: Exact 2-sided 95% Confidence Intervals Based on Observing a Particular 
Rate of Safety Endpoints for Arms of Size 18 ..................................................................... 75 
Table 18: Difference in the Rates of Safety Events ............................................................. 75 
 
 
 


 
 
  
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MTN-026 
 
A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and 
Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 
Seronegative Adults 
 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE 
adverse event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
alanine transaminase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BAT 
Dosing Before and After Sex </= Two doses in 24h 
BRWG 
Behavioral Research Working Group 
BV 
CASI 
bacterial vaginosis 
computer assisted self-interview 
CBC 
complete blood count 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
maximum concentration 
CNS 
central nervous system 
CRF 
case report form 
CRS 
Clinical Research Site 
CT 
Chlamydia trachomatis, Chlamydia 
CTA 
Clinical Trial Agreement 
CVL 
cervicovaginal lavage 
CWG 
Community Working Group 
CYP3A 
cytochrome P450, family 3, subfamily A genetic locus 
DAERS 
DAIDS Adverse Event Reporting System 
DAIDS 
Division of AIDS 
DAPY 
di-amino-pyrimidine 
DLV 
delavirdine 
DNA 
deoxyribonucleic acid 
DOD 
directly observed dosing 
DPV 
dapivirine 
EAE 
expedited adverse event 
EC 
ethics committees 
EC50 
EFV 
50% effective concentration 
efavirenz 
ENR 
enrollment 
FDA 
(US) Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
g 
grams 
GC 
Neisseria gonorrhoeae, gonorrhea 


 
 
  
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GCP 
Good Clinical Practices 
GEE 
generalized estimating equations 
GMP 
Good Manufacturing Practices 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HEC 
hydroxyethylcellulose 
HEENT 
Head, Eye, Ear, Nose and Throat Examination 
HHS 
(U.S.) Department of Health and Human Services 
HIV 
Human Immunodeficiency Virus 
HIV-1 
Human Immunodeficiency Virus type 1 
HIV-1 IIIB 
Human Immunodeficiency Virus type 1, IIIB strain 
HPTN 
HIV Prevention Trials Network 
HPV 
human papillomavirus 
HSV 
herpes simplex virus 
HSV-1/2 
herpes simplex virus type 1/2 
hu-PBL 
human peripheral blood lymphocytes 
hu-SCID 
humanized severe combined immunodeficient 
IATA 
International Air Transport Association 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDI 
In-Depth Interview 
IL 
interleukin 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IoR 
Investigator of Record 
IPM 
International Partnership for Microbicides 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
kg 
kilogram 
LC 
Laboratory Center 
LDMS 
Laboratory Data Management System 
LOC 
Leadership and Operations Center 
μg 
microgram 
MDP 
Microbicides Development Programme 
mg 
milligram 
mL 
milliliter 
mM 
millimolar 
MO 
Medical Officer 
mOsm 
milliosmole 
MPA 
medroxyprogesterone acetate 
MT-2 
human melatonin receptor 2 
MTN 
Microbicide Trials Network 
MTT 
(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a 
tetrazole) 
n 
number 
N-9 
nonoxynol-9 
NAAT 
nucleic acid amplification test 


 
 
  
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NF 
National Formulary 
ng 
nanogram 
nM 
nanomolar 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NL 
network laboratory 
NNRTI 
non-nucleoside reverse transcriptase inhibitor 
NOAEL 
no observed adverse effect level 
NOEL 
no observed effect level 
NSAIDS 
non-steroidal anti-inflammatory drugs 
NVP 
nevirapine 
OHRP 
Office for Human Research Protections 
PBL 
peripheral blood lymphocytes 
PBS 
phosphate-buffered saline 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PEP 
post-exposure prophylaxis 
pH 
potential of hydrogen 
PK 
pharmacokinetics 
PoR 
Pharmacist of Record 
PPD 
Pharmaceutical Product Development, Inc. 
PrEP 
pre-exposure prophylaxis 
PRO 
Protocol Registration Office 
PSP 
Prevention Sciences Program 
PSRT 
Protocol Safety Review Team 
PSS 
polystyrene sulfonate 
PT 
prothrombin time 
PTID 
participant identification 
RAI 
receptive anal intercourse 
RE 
regulatory entity 
RG 
reduced-glycerin 
RNA 
ribonucleic acid 
RSC 
Regulatory Support Center 
RT 
reverse transcriptase 
RTI 
reproductive tract infection 
RT-PCR 
real-time polymerase chain reaction 
Rx 
treatment 
SAE 
serious adverse event 
SCHARP 
Statistical Center for HIV/AIDS Research & Prevention 
SCID 
severe combined immunodeficient 
SCR 
screening 
SDMC 
Statistical Data Management Center 
SHIV 
simian human immunodeficiency virus 
SMC 
Study Monitoring Committee 
SOP 
standard operating procedure 
SSP 
Study-specific procedures 
STI 
sexually transmitted infection 


 
 
  
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SUSAR 
suspected, unexpected serious adverse reaction 
TCID 
tissue culture infective dose 
TEAE 
treatment-emergent adverse events 
TFV 
tenofovir 
TFV-DP 
tenofovir-diphosphate 
Tmax 
time at which Cmax is observed 
TPGS 
tocopheryl polyethylene glycol succinate 
UA 
urinalysis 
ULN 
upper limit of normal 
UPMC 
University of Pittsburgh Medical Center 
USA 
United States of America 
USP 
United States Pharmacopoeia 
UTI 
urinary tract infection 
WHO 
World Health Organization 
w/w 
weight/weight 
wt 
wild type 


 
 
  
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MTN-026 
 
A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and 
Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 
Seronegative Adults 
 
PROTOCOL TEAM ROSTER 
 
 
 
Protocol Chair  
 
Ross D. Cranston, MD, FRCP 
Protocol Chair 
Fundació Lluita Contra la Sida 
Hospital Universitari Germans Trias I Pujol 
Caratera de Canyet 
Badalona 
Barcelona, Spain 08916 
Phone: 34-934-657-897 
Fax: 34-934-657-602 
E mail: rdcranston@outlook.com  


 
 
  
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Site Investigators  
 
Ken Ho, MD 
Site Investigator 
UPMC, Keystone Building, Suite 533 
3520 Fifth Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-383-7178 
Fax: 412-383-2900 
Email: hok2@upmc.edu 
 
Eileen F. Dunne, MD, MPH 
Site Investigator 
Thailand MOPH-U.S. CDC Collaboration 
DDC 7 Building, 4th floor  
Ministry of Public Health, Soi 4 
Nonthaburi 11000 Thailand  
Phone: 66 02-580-0669 ext 454 
Fax: 66 02-580-0712 
Email: dde9@cdc.gov  
 
Craig Hoesley, MD 
Site Investigator 
University of Alabama at Birmingham 
1530 3rd Avenue South, VH 201 
Birmingham, AL 35294 USA 
Phone: 205-934-3365 
Fax: 205-975-3232 
Email: choesley@uab.edu 


 
 
  
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US National Institutes of Health (NIH) 
 
Roberta Black, PhD 
Chief, Clinical Microbicide Research Branch 
Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), 
National Institutes of Health (NIH) - U.S. Department of Health and Human Services (HHS) 
5601 Fishers Lane, Room 8B62, MSC 9831 
Rockville, MD 20852 USA 
Phone: 301-496-8199 
Email: rblack@niaid.nih.gov 
 
Naana Cleland, MHCA 
Health Specialist, Clinical Microbicide Research Branch (CMRB)  
Prevention Sciences Program (PSP) DAIDS, NIAID  
NIH- U.S. Department of Health and Human Services (HHS) 
5601 Fishers Lane, Room 8B27, MSC 9831 
Rockville, MD 20852 USA 
Phone: 240-292-4779 
Email: clelandn@niaid.nih.gov   
 
Jeanna Piper, MD 
DAIDS Senior Medical Officer 
DAIDS/NIAID 
5601 Fishers Lane, Room 8B68, MSC 9831 
Rockville, MD 20852 USA 
Phone: 240-292-4798 
Email: piperj@niaid.nih.gov  
 
Dianne M. Rausch, PhD 
Director 
DAIDS Research, NIMH 
5601 Fishers Lane, Room 8D20, MSC 9831 
Rockville, MD 20852 USA 
Phone: 240-627-3874 
Fax: 240-627-3467 
Email: drausch@mail.nih.gov 
 
 


 
 
  
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Microbicide Trials Network (MTN) Leadership and Operations Center (LOC) - Pitt 
 
Jose A. Bauermeister, MPH, PhD 
BRWG Representative 
University of Pennsylvania 
418 Curie Blvd., Suite 402 
Philadelphia, PA 19104 
Phone: 215-898-9993 
Email: bjose@upenn.edu     
 
Ian McGowan, MD, PhD, DPhil, FRCP 
Director, Rectal Microbicide Program 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8999 
Fax: 412-641-6170 
Email: imcgowan@pitt.edu  
 
Katherine Bunge, MD 
Protocol Safety Physician 
Magee-Womens Hospital of UPMC 
300 Halket Street 
Pittsburgh, PA 15213 USA 
Phone: 412-641-3464 
Fax: 412-641-1133 
Email: kbunge@mail.magee.edu 
 
Sharon A. Riddler, MD, MPH 
Protocol Physician 
UPMC, Keystone Building, Suite 510 
3520 Fifth Avenue 
Pittsburgh, PA 15213 USA 
Phone:  412-383-1741 or 412-383-1675 
Fax: 412-383-2900 
Email: riddler@dom.pitt.edu 
 
Sharon Hillier, PhD 
MTN Principal Investigator 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8933 
Fax: 412-641-6170 
Email: shillier@mail.magee.edu 
Devika Singh, MD, MPH 
Protocol Safety Physician 
Box 359927, Dept. of Global Health, ICRC 
325 Ninth Ave. 
Seattle WA 98104 USA 
Phone: 206-744-8311 
Fax: 206-520-3831 
Email: dsingh@u.washington.edu 
 
Cindy Jacobson, PharmD 
Director of Pharmacy Affairs 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA  15213 USA 
Phone: 412-641-8913 
Fax: 412-641-6170 
Email: cjacobson@mail.magee.edu    
 
Jennifer Thomas, MSc 
Protocol Development Manager 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-5579 
Fax: 412-641-6170 
Email: thomasj15@mwri.magee.edu 
 
 
 


 
 
  
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MTN Laboratory Center (LC) 
 
Charlene S. Dezzutti, PhD 
LC Director/BSWG Representative 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-3462 
Fax: 412-641-6170 
Email: dezzuttics@upmc.edu 
 
 
Craig Hendrix, MD 
Pharmacology LC Principal Investigator 
Johns Hopkins University 
600 North Wolfe Street, Harvey 502 
Baltimore, MD 21287 USA 
Phone: 410-955-9707 
Fax: 410-955-9708 
Email: cwhendrix@jhmi.edu  
 
Ratiya Pamela Kunjara Na Ayudhya, BSMT, ASCP 
Laboratory Manager 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-6393  
Fax: 412-641-6170 
Email: pkunjara@mwri.magee.edu  
 
Mark Marzinke, PhD, DABCC 
Johns Hopkins University School of Medicine  
1800 Orleans Street, Sheikh Zayed Tower, 
Room B1-1020G 
Baltimore, MD 21287  
Office: 443-287-7516 
CPAL Office:  410-550-9702 
Fax: 410-955-0767 
Email: mmarzin1@jhmi.edu 
 


 
 
  
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MTN LOC – FHI 360 
 
Sherri Johnson, MPH 
Sr. Clinical Research Manager 
FHI 360 
1825 Connecticut Avenue, NW  
Washington, DC 20009 USA 
Phone: 202-884-8000 Ext. 18677 
Fax: 202-884-8844 
Email: sjohnson@fhi360.org 
 
Jonathan Lucas, MPH 
Sr. Community Program Manager 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27703 USA 
Phone: 919-544-7040, Ext. 11458 
Fax: 919-544-0207 
Email: jlucas@fhi360.org 


 
 
  
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MTN Statistical Data Management Center (SDMC) 
 
Elizabeth Brown, ScD 
SDMC Principal Investigator 
Fred Hutchinson Cancer Research Center (FHCRC)- Statistical Center for HIV/AIDS Research & 
Prevention (SCHARP) 
1100 Fairview Avenue North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-1731 
Fax: 206-667-4812 
Email: erbrown@fhcrc.org 
 
Holly Gundacker, MS 
Statistical Research Associate  
FHCRC-SCHARP 
1100 Fairview Ave North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024  USA  
Phone: 206-667-6480 
Email: hgundack@scharp.org  
 
Melissa A. Peda, MPA 
SDMC Clinical Data Manager 
1100 Fairview Avenue North, E3-129 
PO Box 19024 
Seattle, WA  98109-1024 USA 
Phone: 206-667-7672  
Work Mobile: 206-295-5843 
Email: mapeda@scharp.org 
 
 


 
 
  
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MTN Community Working Group (CWG) Representative 
 
Sherri Karas, MEd 
CWG Representative 
University of Pittsburgh 
Presbyterian University Hospital 
3520 Fifth Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-383-1313 
Fax: 412-383-2900 
Email: sjk91@pitt.edu  


 
 
  
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MTN-026 
 
A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and 
Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 
Seronegative Adults 
 
INVESTIGATOR SIGNATURE FORM 
Version 2.0; July 21, 2017 
A Study of the Microbicide Trials Network 
 
Funded by: 
Division of AIDS (DAIDS), US National Institute of Allergy and Infectious Diseases 
US Eunice Kennedy Shriver National Institute of Child Health and Human Development 
US National Institute of Mental Health 
US National Institutes of Health 
 
IND Sponsor: 
DAIDS (DAIDS Protocol ID: 12021) 
 
I, the Investigator of Record, agree to conduct this study in full 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 for 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., NIH, DAIDS) and institutional policies. 
 
I agree to maintain all study documentation for at least two years after the last approval 
of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least two years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. These documents should be retained for a longer period, however, if required 
by the applicable regulatory requirements or by an agreement with the sponsor. DAIDS 
will inform the investigator/institution as to when these documents no longer need to be 
retained 
 
I have read and understand the information in the Investigator's Brochure(s), including 
the potential risks and side effects of the products under investigation, and will ensure 
that all associates, colleagues, and employees assisting in the conduct of the study are 
informed about the obligations incurred by their contribution to the study. 
 
___________________________ 
Name of Investigator of Record (print) 
 
____________________________ 
______________________________ 
Signature of Investigator of Record  
Date 


 
 
  
MTN-026, Version 2.0 
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July 21, 2017 
 
MTN-026 
 
A Randomized, Double Blind, Placebo-Controlled Phase 1 Safety and 
Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 
Seronegative Adults 
 
PROTOCOL SUMMARY 
 
Short Title:   
Dapivirine Gel Rectal Safety and PK Study 
 
Clinical Phase: 
Phase 1 
 
IND Sponsor: 
DAIDS 
 
Protocol Chair:  
Ross D. Cranston, MD, FRCP 
 
Sample Size: 
MTN-026 will enroll approximately 27 participants.   
 
Study Population:  HIV-uninfected men and women between the ages of 18 and 45 
years (inclusive) 
 
Study site(s): 
Sites selected by MTN leadership 
 
Study Design: 
Phase 1, multi-site, randomized (2:1), double-blind, placebo-
controlled trial 
 
Study Duration: 
Approximately 40 days of follow-up per participant is planned with a 
projected accrual period of 6-8 months 
 
Study Products: 
Dapivirine gel (0.05%) 
Universal HEC placebo gel 
 
Study Regimen:  
Participants will be randomized to receive a single dose of either 
dapivirine gel or universal HEC placebo gel rectally, followed by 7 
daily doses of the same product to be administered under direct 
observation in the clinic.  
 
Study specific visits and an overview of procedures are illustrated in 
Figure 1. 


 
 
  
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Figure 1: Study Visit Schedule 
 
 
Primary Objectives:  
 
Safety 
x 
To evaluate the safety of dapivirine gel formulation when applied rectally. 
 
Pharmacokinetics 
x 
To characterize the systemic and compartmental pharmacokinetics of dapivirine gel 
following rectal application. 
 
Primary Endpoints: 
 
Safety 
x 
Grade 2 or higher AEs as defined by the Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 
and/or Addenda 1, 2 and 3 (Female Genital [Dated November 2007], Male Genital 
[Dated November 2007] and Rectal [Clarification Dated May 2012] Grading Tables 
for Use in Microbicide Studies). 
 
Pharmacokinetics 
x 
Dapivirine concentrations 
o Blood  
o Rectal fluid 
o Rectal mucosal tissue homogenates 
 
Secondary Objectives:  
 
Acceptability 
x 
To identify product attributes considered likely to challenge and facilitate future 
sustained use of rectally applied dapivirine gel. 
 
Mucosal Safety 
x 
To evaluate the mucosal safety of dapivirine gel when applied rectally.  
 


 
 
  
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Secondary Endpoints:  
 
Acceptability 
x 
Product attributes considered likely to challenge future sustained use. 
 
Mucosal Safety 
x 
Rectal proteomics 
x 
Rectal transcriptome  
x 
Rectal microflora 
x 
Rectal histology 
x 
Rectal tissue flow cytometry 
 
Exploratory Objectives:  
 
Ex Vivo Efficacy 
x 
To assess the preliminary (ex vivo) efficacy of dapivirine gel formulation after 
product is applied rectally.  
 
Pharmacokinetics 
x To characterize the vaginal pharmacokinetics of dapivirine gel following rectal 
application in women. 
 
Exploratory Endpoints:  
 
Ex Vivo Efficacy 
x 
Changes in HIV-1 p24 levels in colorectal explant culture supernatant  
x 
Anti-HIV activity in rectal fluid 
x 
Anti-HIV activity in cervicovaginal fluid♀ 
 
Pharmacokinetics 
x 
Dapivirine concentrations 
o Cervicovaginal fluid♀ 
o Cervical tissue♀ 
 
♀Female participants only 
 
 


 
 
  
MTN-026, Version 2.0 
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July 21, 2017 
 
1 
KEY ROLES 
 
1.1 Protocol Identification 
 
Protocol Title:   
A Randomized, Double Blind, Placebo-Controlled, Phase 1 
Safety and Pharmacokinetic Study of Dapivirine Gel (0.05%) 
Administered Rectally to HIV-1 Seronegative Adults 
 
 
Protocol Number: 
MTN-026 
 
Short Title: 
Dapivirine Gel Rectal Safety and PK Study 
 
Date:  
July 21, 2017 
 
1.2 Funding Agencies, Sponsor and Monitor Identification 
 
Funding Agencies:  
US Division of AIDS (DAIDS)/National Institute of Allergy 
and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
5601 Fishers Lane 
Rockville, MD  20852 USA 
 
 
 
 
 
US National Institute of Mental Health (NIMH) 
6001 Executive Boulevard 
Rockville, MD  20852 USA 
 
 
US Eunice Kennedy Shriver National Institute of Child Health 
and Human Development (NICHD)  
 
Maternal and Pediatric Infectious Diseases (MPID) Branch 
6100 Executive Boulevard 
Bethesda, MD  20892 USA 
 
IND Sponsor:  
US Division of AIDS (DAIDS)/National Institute of Allergy 
and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
5601 Fishers Lane 
 
 
Rockville, MD  20852 USA 
 
Monitor: 
Pharmaceutical Product Development (PPD), Inc.  
929 North Front St.  
Wilmington, NC  28401-3331 USA 
 


 
 
  
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July 21, 2017 
 
1.3 Medical Officer 
 
Medical Officer: 
 Jeanna Piper, MD 
DAIDS/NIAID 
5601 Fishers Lane, Room 8B68, MSC 9831 
Rockville, MD 20852 USA 
 
1.4 Clinical Laboratories 
 
Network: 
 
MTN Laboratory Center (LC) 
 
 
 
204 Craft Ave. 
 
 
 
Pittsburgh, PA  15213 USA 
 
Pharmacology: 
 
MTN Pharmacology LC 
 
 
 
600 N. Wolfe Street, Osler 527 
 
 
Johns Hopkins University 
Baltimore, MD  21287 USA 
1.5 Data Center 
Statistical Center for HIV/AIDS Research & Prevention 
(SCHARP)/Fred 
Hutchinson 
Cancer Research 
Center 
(FHCRC) 
 
 
 
1100 Fairview Avenue N., LE-400 
 
 
 
PO Box 19024 
 
 
 
Seattle, WA 98109-1024 USA 
 
1.6 Study Implementation 
 
 
 
 
FHI 360 
 
 
 
359 Blackwell Street, Suite 200 
 
 
 
Durham, NC 27701 USA 
 
 


 
 
  
MTN-026, Version 2.0 
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July 21, 2017 
 
 
2 
INTRODUCTION 
 
2.1 Dapivirine Gel 
 
 
Dapivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is a substituted di-
amino-pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1.  
Dapivirine was initially developed as an oral antiretroviral drug for treatment of 
HIV/AIDS, and many animal studies and several clinical trials were performed using the 
oral route of administration. Following the subsequent switch to the microbicide 
indication, additional preclinical animal studies and clinical trials were performed to 
evaluate vaginal administration of dapivirine gel and vaginal ring formulations.1 More 
recently, a study in rabbits was conducted to evaluate the rectal administration of 
dapivirine gel. 
 
The preclinical safety studies and clinical trials performed to date support the favorable 
safety profile and tolerability of microbicide dapivirine dosage forms. The highest daily 
dose of dapivirine delivered from a vaginal gel to date (approximately 1250 μg/day) is 
280 times lower than the maximum tolerated single dose for oral dapivirine (350 mg) 
and 480 times lower than the maximum tolerated multiple dose for oral dapivirine (300 
mg twice a day for 14 days).  The same dose of dapivirine gel is proposed for rectal 
administration. MTN-026 is the first study to assess the safety of dapivirine gel applied 
rectally. 
 
Multiple gel formulations of dapivirine have been developed for vaginal use.  Dapivirine 
Gel 4759 (Gel 4759) is the gel formulation planned for this trial. The Gel 4759 is highly 
viscous and opaque.  Dapivirine 0.05% gel has an osmolality of approximately 870 
mOsm/kg, similar to the safe and acceptable reduced glycerin 1% tenofovir formulation 
that was used in MTN-007, which had an osmolality of approximately 850 mOsmol/kg2 
(see Section 2.4.2 for additional information regarding the MTN-007 study). Please refer 
to Section 2.4.1 for further evidence of safety and acceptability of dapivirine gel.   
 
2.1.1 
Description and Mechanism of Action 
 
NNRTIs bind to the HIV reverse transcriptase (RT) enzyme preventing viral replication 
and consequently production of infectious virus.  The primary ingredient of dapivirine gel 
is water, with hydroxyethylcellulose (HEC) and polycarbophil used as thickening agents.  
Other ingredients of the gel include methyl- and propylparaben, as preservatives, 
propylene glycol as solvent, and sodium hydroxide for pH adjustment.  The excipients 
contained in the drug product formula are United States Pharmacopoeia (USP) grade 
components (e.g., propylene glycol) with a history of use in currently approved vaginal 
products.   


 
 
  
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Table 1: Dapivirine Gel 4759, 0.05%, 2.5 g Formulation 
Name  
Quality Standard  
Function  
% Composition/Dose 
(dose = 2.5 g  gel  
[2.5 mL])  
Dapivirine  
Manufacturer’s 
Certificate of Analysis 
Active pharmaceutical 
ingredient (API) 
0.05 
Purified water  
USP 
Solvent 
90.99 
HEC  
National Formulary 
(NF) 
Thickening/binding agent 
3.50 
Polycarbophil  
USP 
Thickening agent 
0.20 
Propylene Glycol  
NF 
Solvent 
5.00 
Methylparaben  
NF 
Preservative 
0.20 
Propylparaben  
NF 
Preservative 
0.05 
Sodium Hydroxide  
NF 
pH adjustment 
0.01 
 
2.1.2 
Strength of Study Product 
 
The dapivirine gel strength proposed for use in MTN-026 is 0.05%.  
 
2.2 Universal Placebo gel 
 
2.2.1 
Description  
 
The “Universal Placebo” is a HEC-based gel that was developed for use in clinical 
evaluations of investigational microbicides.  This formulation is sufficiently stable as a 
vaginal gel formulation, is safe and is sufficiently inactive for use in the clinical study of 
investigational microbicides. The gel is isotonic and clear in color. 
 
Table 2: Universal HEC Placebo Gel Formulation 
Ingredient 
Quality 
Standard 
Function 
Amount (w/w) 
Purified Water 
USP 
Solvent 
96.3 
HEC 
NF 
Tonicity agent 
2.7 
Sodium Chloride 
USP 
Preservative 
0.85 
Sorbic Acid 
NF 
Thickening/binding agent 
0.1 
Sodium Hydroxide 
NF 
pH adjustment 
As needed for pH 
adjusted to 4.4 (+0.2) 
 
2.2.2 
Strength of Study Product 
 
There is no active ingredient in the Universal Placebo gel. 
 


 
 
  
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2.3 Non-Clinical Studies 
 
2.3.1 
Virology and Pharmacology  
 
Dapivirine 
 
Anti-HIV-1 Activity 
The activity of dapivirine against wild-type (wt) HIV-1, African isolates of HIV-1 
(including subtype C virus), and a panel of NNRTI-resistant viruses has been 
established using in vitro models, with 50% effective concentration (EC50) values 
ranging from 0.3 ng/mL (0.9 nM) against laboratory isolates to <33 ng/mL (<100 nM) for 
HIV-1 isolates encoding one or more known NNRTI resistance mutations.  The anti-HIV 
activity was also confirmed in an ex vivo model of human cervical explant cultures and a 
humanized severe combined immunodeficient (hu-SCID) mouse model.3,4  
 
Resistance 
A panel of recombinant viruses was constructed from clinical isolates derived from 
different geographical origins, representing strains from HIV-1 group M subtypes A, B, 
C, D, F and H as well as circulating recombinant forms: CRF01_AE, CRF02_AG, 
CRF05_DF and HIV-1 group O.  All group M viruses tested were sensitive to dapivirine 
with EC50 values below 1.0 ng/mL and fold change in EC50 values below 4.  Eight of the 
group M viruses carried mutations in the RT coding region at positions associated with 
NNRTI resistance (positions 98, 101, 106, and 179). The group O virus tested 
(V029524) naturally harbored amino acids at positions 98 (G), 179 (E) and 181 (C), 
which are associated with NNRTI resistance in HIV-1 strains from group M.  This virus 
displayed significantly reduced sensitivity to nevirapine (NVP) (89-fold change), 
delavirdine (140-fold change), efavirenz (EFV) (42-fold change), and dapivirine (150-
fold change, which is typical of Type O strains treated with NNRTI).1  
 
Cross-resistance 
In comparison with NVP, delavirdine (DLV), emivirine, and EFV, dapivirine showed 
significantly better in vitro activity against laboratory and recombinant HIV strains 
resistant to one or more drugs of the same class.  The EC50 was below 32.9 ng/mL (100 
nM) for 80% of the strains, compared with only 56% of the strains for efavirenz.  
 
When tested against 433 clinical isolates with phenotypic resistance to at least one of 
the NNRTIs NVP, delavirdine, EFV or dapivirine, dapivirine was able to inhibit 46% 
(202/433) of the samples including 41% (142/350) of the strains resistant to EFV. In 
contrast, only 10% (24/231) of the dapivirine-resistant strains were inhibited by EFV.1  
 
Spermatozoa Motility  
Assays using human semen samples from normal, healthy, male donors showed that 
dapivirine did not affect the motility of spermatozoa at a concentration of up to 2 mM 
(659 μg/mL), which exceeded the limit of solubility. 
 


 
 
  
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Safety Pharmacology  
In a series of preclinical safety pharmacology studies, dapivirine was generally devoid of 
adverse effects on overt behavior, reflexes and other body functions.  Although these 
studies revealed no cardiovascular effects, there was evidence of an increase in QT 
interval during the 1- and 6-month oral toxicity studies in dogs. However, this was only 
seen at 30 mg/kg/day at which Cmax and area under the curve (AUC) values were more 
than 1600 and 850 times greater, respectively, than the values achieved in women 
following daily use of dapivirine gels 4750 and 4789.  
 
Universal Placebo Gel 
 
Anti-HIV-1 Activity 
In vitro analyses of anti-HIV-1 activity were performed on Universal Placebo gel 
following a viral binding assay that consisted of a 2-hour incubation of test compound, 
HIV-1lllB, and MT-2 cells.  Cell culture followed by further assessments performed after 
this incubation period showed no significant antiviral or cytotoxic activity.  The Universal 
Placebo gel had negligible effect on virus-induced cytopathic effect at a 1:5 dilution, the 
highest concentration tested.  Additional in vitro studies on potential HIV-1 infection of 
neoplastic T cell lines concluded the Universal Placebo gel had little or no effect on the 
infection and replication of HIV in human target cells, or the specific replication steps of 
virus attachment or cell-to-cell fusion.5  
 
Cytotoxicity 
Dilutions of the Universal Placebo gel in culture medium exhibited negligible toxicity to 
human vaginal epithelial cells (standard [1-(4,5-dimethylthiazol-2-yl)-3,5 diphenylform- 
azan (MTT)] assay), even at the lowest dilution tested (1:2).5 Exposure of human 
vaginal epithelial cells to the Universal Placebo gel resulted in minimal IL-1α induction, 
even at the lowest dilutions tested (1:2).6  
 
Transmission of SHIV 
The effect of the Universal Placebo gel on vaginal transmission of simian human 
immunodeficiency virus (SHIV)162p3 (103TCID50) to rhesus monkeys (n=5, n=3, 
respectively) was determined in two separate studies.3  Macaques pretreated with MPA 
were vaginally administered 1 mL of the Universal Placebo gel formulation 15 minutes 
prior to challenge with 0.5 mL SHIV162p3.  Investigators monitored total ribonucleic acid 
(RNA) load in the animal plasma for a total of 8 weeks by means of a standard 
quantitative reverse transcriptase polymerase chain reaction (RT-PCR).  The first study 
utilized the Universal Placebo gel formulation at pH 6.5; the second study utilized a 
formulation of pH 4.4.  In both studies, all monkeys were infected, as determined by the 
presence of viral RNA in circulation blood, regardless of the pH of the formulation.6 
 
Anti-Herpes Simplex Virus (HSV) Activity 
CF-1 mice (n=10 per group) pretreated with medroxyprogesterone acetate (MPA) were 
administered 0.02 mL of Universal Placebo gel or phosphate-buffered saline (PBS) 
vaginally, followed by a 0.01 mL of HSV-2 viral inoculum of 10 ID50 0.3 minutes later.7  
On Day 3, vaginal lavage was cultured on human foreskin fibroblasts, and mice were 


 
 
  
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considered infected if a cytopathic effect was observed after 3 days of incubation.  
Infection rate following pretreatment with Universal Placebo gel (90%) was not 
significantly different from pretreatment with PBS (80%) or from mice given no treatment 
(80%).  Universal Placebo gel did not enhance susceptibility of mice to HSV-2 when 
administered 12 hours before vaginal challenge.7  
 
Spermatozoa Motility  
Analyses of pH (Universal Placebo gel mixed with human seminal plasma, pH 8.03± 
0.26) found the HEC formulation did not show significant buffering capacity and could 
not acidify the alkaline pH of seminal plasma, a favorable result in a placebo 
formulation.6  In vitro assessments of spermicidal activity utilizing human semen from 
healthy donors showed the Universal Placebo gel had no significant deleterious effects 
on sperm motility, even after 60-minute incubation. 
 
2.3.2 
Pharmacokinetics  
 
Dapivirine 
 
Systemic exposure to dapivirine was low following vaginal administration of dapivirine 
gels to rabbits.1  Much higher systemic exposures were obtained in single-dose oral and 
subcutaneous toxicity studies in mice and rats, and in repeat dose oral toxicity studies in 
rats, dogs and monkeys.  The free fraction of dapivirine in plasma was 0.19-0.34% in 
the male rat, 0.18-0.39% in the female rat, 0.21-0.22% in the dog and 0.15% in humans.  
In rats, tissue to plasma AUC0-24 ratios following a single oral dose were 11 in liver, 7-8 
in lung, kidney and adrenals, about 4 in spleen and lymph nodes, and 2-3 in brain, heart 
and muscle.  Plasma/tissue equilibrium was rapid, and there was no undue retention of 
dapivirine in tissues.  Following a single oral or vaginal dose of 14C-dapivirine, 
absorption and distribution of drug-related material to the tissues was moderate in non-
pregnant and slow in pregnant female rats.  Vaginal dosing did not result in greater 
distribution to the reproductive tissues (except the vaginal wall) than oral dosing.  For 
virtually all tissues, maximal concentrations after vaginal dosing were <1% of those after 
oral dosing.  Drug-related material was shown to freely cross the placenta to the fetus. 
In dogs, dapivirine concentrations following oral administration for 14 days were about 9 
times higher in liver and muscle, and about 5 times higher in lymph nodes and brain 
than in plasma.  Preliminary metabolism studies demonstrated the presence of free and 
conjugated metabolites in rats, dogs, monkeys and humans, but the molecular 
structures have not been elucidated.  There was evidence of extensive cytochrome 
P450 (particularly CYP3A4) mediated metabolism.1  
 
2.3.3 
Toxicology 
 
Dapivirine 
 
General toxicity  
The gel formulation to be used in this trial was evaluated in a study in rabbits in which 
dapivirine concentrations of 0.05%, 0.2%, and 0.5% (w/w) were administered rectally 


 
 
  
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once daily for 14 days using a dose volume of 1 mL.  Three animals died or were killed 
prematurely during the study but none of the deaths were attributed to treatment.  The 
no observable effect level (NOEL) was considered to be 0.5% (w/w).  In addition, this 
formulation was evaluated in two intravaginal studies in female rats.  In a 13-week study 
in which gels containing 0.2% and 0.5% (w/w) dapivirine were administered 
intravaginally using a daily dose volume of 0.2 mL, no evidence of local or systemic 
toxicity was observed. The carcinogenic potential of dapivirine was also evaluated when 
administered intravaginally at concentrations of 0.05, 0.2 and 0.5% (w/w) using a dose 
volume of 0.2 mL for 104 weeks.  There were no neoplastic or non-neoplastic findings 
that were attributable to treatment with dapivirine.  It was concluded that the NOEL was 
0.5%.  Furthermore, in other intravaginal studies in rabbits using various formulations of 
dapivirine gel, there were no significant local or systemic findings following repeat 
administration at up to 20 mg/mL for 14 days, up to 5 mg/mL for 13 weeks or up to 
2 mg/mL for 39 weeks. In studies conducted via the oral route of administration, a no 
observed adverse effect level (NOAEL) was not established in the rat.  However, the 
main findings (effects on liver, thyroid, and pituitary) were considered adaptive rather 
than adverse responses, and therefore the NOAEL was considered to be 20 mg/kg/day.  
This dosage was also the NOAEL in the dog.  At higher dose levels, hepatotoxicity was 
observed in dogs and slight hematological and clinical chemistry changes were 
observed in rats. In the guinea pig, dapivirine (2 mg/mL) did not demonstrate any 
potential to cause contact sensitization when evaluated using a maximization test.1  
 
Mutagenicity 
Dapivirine was considered to be non-genotoxic based on the results from a range of in 
vitro and in vivo mutagenicity assays, including the Ames Test, L5178Y Mouse 
Lymphoma Test, Human Peripheral Lymphocyte Test, Mouse Micronucleus Test, and 
Unscheduled DNA Synthesis Test.  
 
Reproductive Toxicity 
In rats, some effects on the developing fetus were observed following oral 
administration at maternally toxic doses (80 and 320 mg/kg) of dapivirine. However, 
there were no effects in rats at the maternally non-toxic dose of 20 mg/kg/day, or in 
rabbits at up to 90 mg/kg. No toxicity to maternal animals or the developing 
embryo/fetus was seen in embryo-fetal development studies performed via the vaginal 
route in rats (up to 3.3 mg/mL using a dose volume of 0.2 mL/kg) and rabbits (up to 2 
mg/mL using a dose volume of 1.0 mL).  
 
2.3.4 
Animal Studies of Universal Placebo Gel 
 
Intravenous Administration 
Up to 55 intravenous injections of HEC were given to dogs (dose and n not specified) 
without causing injury other than that typical of the other water-soluble cellulose ethers.5  
Only transitory changes in the blood picture and the deposition of the material on the 
intima of the blood vessels were noted.  Groups of rats maintained for two years on 
diets containing HEC (n not specified, up to 5%) did not exhibit any adverse effects.5  
HEC has also been administered to rats in single oral doses as high as 23,000 mg/kg 
without observed toxic effects (n not specified). 


 
 
  
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Local Tolerance 
A 10-day rabbit vaginal irritation study (10 per arm, 2 arms, placebo gel vs. 0.9% saline 
control) found the HEC-based placebo gel was not irritating to the vaginal mucosa of 
rabbits when dosed daily for 10 days.5, 7  One animal in the HEC-based placebo gel 
group had an instance of vaginal redness (compared to four animals in the saline 
group), which did not persist and was not evident at the end of the study.  Diarrhea, few 
feces, and soiling of the anogenital area were noted in that animal.  Body weight 
changes were noted to be normal.  In 9 of 10 animals, necropsy results were normal.  
Histopathologic changes observed were similar to those seen in the control group and 
likely attributable to those that occur because of the repeated insertion of a catheter, 
rather than due to any effect of the test samples. 
 
Universal Placebo gel was also used as the placebo comparator in a rectal safety study 
of a combination microbicide in a macaque model.8  A third study arm received no 
product and served as a negative control.  Rectal safety of the active product and 
Universal Placebo gel was evaluated following four daily applications of study 
products.  Rectal flora, pH, and rectal lavage samples were assessed pre- and post-
dosing and showed no evidence of toxicity in the macaques that received Universal 
Placebo gel.  The infrequent evidence of epithelial sloughing and rare incidence of 
associated blood cells in rectal lavage samples was similar in the Universal Placebo 
and negative control arm of this study. 
 
Reproductive Toxicity 
Intraperitoneal administration of unformulated HEC to pregnant mice in a 1% and 4% 
concentration caused an increase in resorption, but no detectable increase in birth 
defects.9  While no epidemiological studies of congenital anomalies in infants born to 
women exposed to HEC during pregnancy have been reported, the Teratogen 
Information System considers the magnitude of teratogenic risk to a child born after 
exposure during gestation to be none. 
 
2.4 Clinical Studies 
2.4.1 Clinical Studies of Dapivirine Gel 
 
To date, 28 Phase 1 and Phase 1/2 clinical trials of dapivirine have been conducted: 
nine trials in which 501 participants used dapivirine gel, eight trials in which 298 
participants used dapivirine rings, and 11 trials in which 211 participants used oral 
dapivirine.1 In addition, one Phase 1 clinical trial has been conducted in 48 male 
participants to evaluate the safety and tolerability of dapivirine vaginal gel (Gel 4759) 
following multiple topical penile exposures.10, 11 Three Phase 1 clinical trials that 
evaluated the vaginal film formulation of dapivirine in 81 women have been 
conducted.12-14 
 
Importantly, recent results from two Phase 3 trials demonstrate the safety and efficacy 
of dapivirine delivered through vaginal rings (VRs). In the Phase 3 trial, MTN-020 


 
 
  
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(ASPIRE), there was no significant difference detected between the dapivirine and 
placebo treatment groups in frequency of the primary safety endpoint 15, defined as the 
incidence of any SAE, any Grade 3 or 4 AE, and any Grade 2 AE that was assessed by 
the investigator as being related to the investigational product. The primary safety 
endpoint was observed in 180/1313 (14%) of the dapivirine VR arm compared to 
186/1316 (14%) in the placebo arm (P=0.80 for the overall comparison by chi-square 
test)15. The DPV VR resulted in a 27% (95% CI: 1-46%, p=0.05) relative reduction in 
HIV-1 incidence overall, a 37% (95% CI: 12-56%, p=0.007) reduction in an analysis 
defined early in the study, excluding data from two study sites with lower retention and 
adherence, and a 56% (95% CI: 31-71%, p<0.001) reduction in a post-hoc analysis 
among women older than 21 years of age15. In the Phase 3 trial, IPM 027 (The Ring 
Study), no clinically significant differences in the frequency of treatment emergent 
adverse events between the DPV and placebo groups were detected16. In The Ring 
Study, dapivirine VR use reduced the risk of HIV-1 infection by 30.7% relative to 
placebo, and a 37.5% reduction in HIV-1 infection was observed in a subgroup analysis 
of women older than 21 years of age17. 
 
Pharmacokinetics 
 
Dapivirine Gels 4759 and 4789 
The particular formulation of dapivirine gel planned for this trial was tested in IPM 02018, 
IPM 014A19, MTN-012/IPM 0101, 20, and FAME-02B21.  IPM 020 was a double-blind, 
randomized, placebo-controlled Phase 1/2 expanded safety study conducted in the 
USA.  The trial enrolled 128 healthy, sexually active, HIV-negative women to assess the 
safety of Dapivirine Gel 4759, 0.05% 2.5g and Dapivirine Gel 4789, 0.05% 2.5g as 
compared to the HEC-based Universal Placebo gel. Three SAEs were reported during 
the trial, one by a participant in the Dapivirine Gel 4759 group and two by participants in 
the Universal placebo gel group. In the Gel 4759 group, one woman was reported with 
Grade 3 (severe) breast cellulitis. In the Universal placebo gel arm, one woman was 
reported with Grade 3 abdominal pain of unclear origin and one woman with Grade 3 
asthma. None of these events were assessed by the Investigator as related to product 
use. Two TEAEs resulted in early trial discontinuation of two participants, both from the 
Dapivirine Gel 4759 group: worsening of a cervicovaginal human papillomavirus (HPV) 
infection that was reported by the Investigator as Grade 1 (mild), and Grade 1 (mild) 
hypersensitivity (reported as an allergic response; symptoms reported included vaginal 
burning, itching and erythema); both events were regarded by the Investigator as 
probably related to IP. Three TEAEs led to the permanent discontinuation of gel use in 
two participants assigned to the Gel 4789 and one participant in the placebo gel group, 
who in return withdrew their consent due to these TEAEs. In the Gel 4789 group, one 
participant was reported with vulvovaginal pruritus (Grade 2) which was assessed by 
the Investigator as probably not related to IP. Another participant, also in the Gel 4789 
group, was reported with vulvovaginal discomfort (Grade 2) and vulvovaginal pruritus 
(Grade 2) which were both assessed by the Investigator as probably related to IP. In the 
placebo gel group, one woman experienced a mild (Grade 1) ulcer on the clitoral hood 
and discontinued gel use permanently; however, she completed all trial visits. The event 
was regarded by the Investigator as possibly related to the placebo gel.  
 


 
 
  
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In addition to IPM 020, the safety of Gel 4759 was also tested in IPM 014A, conducted 
in 280 healthy, sexually active, HIV-negative women in South Africa, Rwanda, Malawi 
and Kenya.19 IPM 014A was a double-blind, randomized, placebo-controlled Phase 1/2 
study to evaluate the safety and acceptability of Dapivirine Gel 4759, 0.05%, 2.5g, 
administered daily over a 6-week period. The trial was conducted using daily monitored 
adherence. No SAEs were reported and no participants were discontinued from the trial. 
Additionally, there were no permanent discontinuations from dapivirine or placebo gel 
use due to TEAEs during the trial. 
 
MTN-012/IPM 010 was a penile tolerance study conducted in Pittsburgh, PA USA with 
twenty-four circumcised and 24 uncircumcised (N=48) healthy HIV-negative male 
participants aged 18 years or older.20  The males were randomized 2:1:1 to apply 
dapivirine 0.05% gel (Gel 4759), matched placebo gel, or Universal Placebo gel, 
respectively, to their penis once daily for 7 sequential days. The safety, acceptability, 
and pharmacokinetic (PK) profile of DPV 0.05% gel were assessed by the presence of 
Grade 2 or higher genitourinary adverse events (AEs) and systemic AEs, a behavioral 
questionnaire, and PK plasma blood draw, respectively, at the final clinic visit. Topical 
seven-day penile application of dapivirine 0.05% gel was locally and systemically safe, 
was acceptable to male participants, and resulted in systemic exposure to the drug.  
There were no Grade 2 genitourinary AEs in 47 participants completing the final clinic 
visit. There were 13 AEs reported; all were Grade 1 except one Grade 2 corneal 
laceration unrelated to study product. Dapivirine was detectable in plasma in all 23 
dapivirine arm study participants at the final clinic visit, as one participant failed to 
present to the clinic for the final study visit. On average, the circumcised participants’ 
dapivirine concentrations were 54% of those in uncircumcised participants (p = 0.07). 
 
FAME-02B was a Phase 1, two-arm, randomized crossover study conducted in 
Baltimore, MD that compared the multi-compartment PK and ex vivo PD characteristics 
between the Gel 4579 and vaginal film formulations of dapivirine.21 Ten healthy, HIV-
uninfected women ages 18-45 years old were randomized (1:1) to receive either a 
single dose of dapivirine Gel 4579 followed by a single dose of dapivirine vaginal film 
one week later, or to receive a single dose of vaginal film followed by a single dose of 
Gel 4579 a week later. PK was assessed in blood, cervical tissue and CVF, while PD 
was assessed via HIV tissue explant challenge. No SAEs were recorded, and 75% (18 
of 24) of AEs were Grade 1. No AEs were determined to be related to study product, 
and the AEs that occurred during the dosing intervals were evenly distributed between 
the two study products (10 with film and 11 with gel). There were no statistically 
significant PK or PD differences between the film and gel study products for plasma, 
CVF or tissue, except for a greater dapivirine concentration in mid-vaginal CVF for film 
as compared to gel. CVF DPV concentrations 5 hr after dosing were greater than tissue 
concentrations, and both were greater than plasma concentrations. Plasma half-life was 
significantly greater than estimated maximum half-life for both CVF and cervical tissue, 
which were similar to each other. 
 
Dapivirine Gel 4750 
A similar formulation (Gel 4750) was studied in IPM 012.  Gel 4750 contained dapivirine 
drug substance, purified water, HEC, Vitamin E TPGS, polycarbophil, propylene glycol, 


 
 
  
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methyl paraben, and sodium hydroxide.  Gel 4750 and the gel being tested in this study, 
Gel 4759 are essentially the same except 4750 included the Vitamin E TPGS 
(dispersing agent, 0.50).1  In IPM 012, the safety and pharmacokinetics of two 
formulations of dapivirine vaginal gel were compared with the HEC-based Universal 
Placebo gel in 36 healthy, HIV-negative, sexually abstinent women 18 to 40 years of 
age.  This Phase 1, randomized, double-blind, placebo-controlled trial was conducted at 
one research center in Belgium.  Women were randomized in a 1:1:1 ratio to once daily 
applications of Gel 4750 (0.05%, 2.5 g), Gel 4789 (0.05%, 2.5 g), or placebo gel for 11 
days (Day 1 followed by a 3-day washout period and then for 10 consecutive days, 
Days 5-14).  Dapivirine concentrations were measured in cervicovaginal fluids and 
plasma on Days 1, 2, 5, 9, 11, 14-17, 19, 21, and 24.   
 
Systemic absorption of dapivirine was low.22  Cmax and AUC0-24h values for dapivirine in 
plasma were slightly higher for Gel 4750 than Gel 4789 on Days 1 and 14; however, the 
differences did not achieve statistical significance.  For both gels, Day 14 values were 2- 
to 4-fold higher than values on Day 1.  Tmax was variable; on Day 1 the mean was 23.5 
hours for both gels, whereas by Day 14 means were 10-12 hours.  Terminal half-life 
was much longer in plasma (73-90 hours) than in cervicovaginal fluids (15-17 hours). 23  
 
Table 3: Treatment-Emergent AEs from Gel 4750 Use 
 
Dapivirine Gel 
MedDRA SOC/Preferred Term 
 
Gel 4750 
(N=12) 
 
(%) 
Participants with at least one TEAE 
83.3 
Gastrointestinal Disorders 
41.7 
Nausea 
8.3 
Vomiting 
8.3 
Abdominal pain 
16.7 
Diarrhea  
16.7 
General Disorders and Administration Site Conditions 
16.7 
Catheter site pain 
8.3 
Pyrexia 
8.3 
Malaise 
8.3 
Injury, Poisoning and Procedural Complications 
8.3 
Procedural pain 
8.3 
Musculoskeletal and Connective Tissue Disorders 
16.7 
Neck pain 
8.3 
Back pain 
8.3 
Nervous System Disorders 
41.7 
Headache 
41.7 
Reproductive Disorders and Breast Disorders 
25.0 
Breast discomfort 
8.3 
Vaginal hemorrhage  
8.3 
Cervix erythema 
8.3 
Respiratory, Thoracic and Mediastinal Disorders 
16.7 
Nasal congestion 
8.3 
Phayrngolaryngeal pain 
8.3 
Nasophayngitis 
8.3 
Skin and Subcutaneous Tissue Disorders 
8.3 
Dermatitis contact 
8.3 
 


 
 
  
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Safety  
 
Dapivirine Vaginal Gels 
 
Gel 001 and 002 
Vaginal application of Gel 001 and 002 were found to be well-tolerated by healthy 
participants.  Details regarding treatment-emergent AEs with incidence ≥5% are 
summarized along with other safety data in Table 4. Additional information can be found 
in the Investigator’s Brochure. 
 
Dapivirine Gels 4750 and 4789 
The pharmacokinetics of candidates Gel 4750 (the gel formulation most similar to the 
gel planned for this trial) and Gel 4789 (both 0.05%, 2.5 g) were tested in IPM 012, 
which was conducted in Belgium in 36 women who applied the vaginal gel once daily for 
11 days.1, 22 There were no SAEs or discontinuations due to treatment-emergent 
adverse events (TEAEs) in the trial. Most subjects (83-100%) in each group had at least 
one TEAE during the trial. Headache was the event that occurred most often; 42-67% of 
subjects in the dapivirine gel groups and 42% of subjects in the placebo gel group 
reported at least one headache.  For most subjects with headaches (13/18; 72%), the 
event was assessed as possibly related to the investigational product.  
 
All but two TEAEs were assessed as Grade 1 (mild). One subject in the Gel 4789 group 
had a Grade 2 (moderate) headache assessed as possibly related to the investigational 
product, and a different subject in the same group had Grade 2 pyrexia assessed as not 
related to the investigational product. Thirty-four percent (36/105) of TEAEs were 
assessed as possibly related to the investigational product, and one subject in the Gel 
4789 group had two episodes of vulvovaginal pruritus that were assessed as probably 
related.  Among participants using Gel 4750 (the gel formulation most similar to the one 
planned for this trial), the other TEAEs deemed related to the gel included malaise 
(1/12) and cervix erythema (1/12). 
 
Of the treatment-emergent adverse events with incidence >5% in the Gel-001, Gel-002, 
Gel 4750, and Gel 4789 dapivirine trials involving HIV-negative participants the 
following were reported: 
 


 
 
  
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Table 4: Treatment-Emergent AEs from Dapivirine Gels across Vaginal Gel Trials* (Regardless of 
Causality) 
  
MedDRA SOC/Preferred Term 
 
Gel-001**, Gel-002, Gel 4750, Gel 4789 
N=295 
Gel 4759 
N=184 
N (%) 
N(%) 
Metrorrhagia 
28 (9.5) 
41 (22.3) 
Headache 
45 (15.3) 
13 (7.1) 
Vaginitis Bacterial 
38 (12.9) 
13 (7.1) 
Vaginal Candidiasis 
18 (6.1) 
10 (5.4) 
Abdominal Pain Lower 
17 (5.8) 
5 (2.7) 
Vulvovaginal Pruritus 
7 (2.4) 
14 (7.6) 
Upper Respiratory Tract Infection 
2 (0.7) 
13 (7.1) 
Blood Urine Present 
14 (4.7) 
0 (0.0) 
Gynaecological Chlamydia Infection 
6 (2.0) 
7 (3.8) 
Nasopharyngitis 
10 (3.4) 
3 (1.6) 
Neutropenia 
12 (4.1) 
1 (0.5) 
Oligomenorrhoea 
8 (2.7) 
5 (2.7) 
Influenza 
11 (3.7) 
1 (0.5) 
Urinary Tract Infection 
6 (2.0) 
6 (3.3) 
Vaginal Discharge 
9 (3.1) 
3 (1.6) 
 
* For comparisons across gel trials it should, however, be noted that these trials were conducted in  
different trial populations in Africa, Europe and the USA, and with different gel formulations.  
** To compare results with those obtained for trials using Gel 002, Gel 4750, Gel 4789, and Gel 4759, 
only data for HIV-1 negative participants (Part A and Part B Group 1) are included here. 
 
Oral Dapivirine 
There have been 11 oral administration trials in which a total of 211 participants have 
been dosed with dapivirine. The maximum tolerated dose established was 350 mg for a 
single dose, and for multiple doses, 300 mg twice a day for 14 days.  There were no 
deaths during clinical trials of oral dapivirine, and no trials were stopped for safety 
reasons.  A total of 10 participants stopped dapivirine treatment prior to trial completion 
for safety reasons, six of whom stopped due to a clear dose dependent increase in 
central nervous system (CNS) and gastrointestinal TEAEs, thereby establishing the 
maximum tolerated dose at 300 mg twice a day. These TEAEs resolved within 1-2 days 
after discontinuation of use of oral dapivirine. One of the discontinuations was classified 
as an SAE, with hospitalization due to elevated liver function tests.  This participant was 
also infected with hepatitis C virus.  The only other SAE noted in these trials was a 
hospitalization due to a bicycle accident.  
 
2.4.2 
Clinical Studies of Universal Placebo Gel 
 
Unformulated HEC is known to be a non-irritating substance in humans (skin 
sensitization is unusual), with doses less than 2 g/kg by ingestion not expected to be 
toxic.24  No inhalation studies have been conducted, but exposure of humans to the dust 
in manufacturing operations over many years has not led to any known adverse effects. 
 


 
 
  
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Safety – Vaginal Administration 
 
The HEC placebo formulation was developed and adopted for use in the HPTN 035 
microbicide study, the Phase II/IIb Safety and Effectiveness Study of the Vaginal 
Microbicides Buffer Gel and 0.5% PRO2000/5 Gel (P) for the Prevention of HIV 
Infection in Women. 
 
A randomized, closed label, Phase I study of daily vaginal Universal HEC Placebo Gel 
exposure was conducted in 2003.25  In this trial, 30 women were randomized to twice-
daily vaginal applications of 3.5 mL of the Universal HEC Placebo Gel or polystyrene 
sulfonate (PSS) vehicle. The primary objective of this study was to assess and compare 
the effects of the test articles on symptoms and signs of irritation of the external 
genitalia, cervix, and vagina as seen on naked eye exam after 7 and 14 days of use 
including disruption of the epithelium and blood vessels as seen on colposcopy after 14 
days of use.  Secondary objectives included: an assessment and comparison of 
differences in vaginal health by evaluating the results of wet mounts, pH, and Gram-
stained vaginal smears (Nugent score and neutrophil counts) after 7 and 14 days of use 
and vaginal cultures after 14 days of use; and an assessment of acceptability of the 
study products after 14 days of use among participants. 
 
Results of this trial indicated that both gels appear safe for vaginal use twice a day for 
14 days in sexually abstinent women. Two out of 14 women (14.3%) randomized to the 
HEC group reported at least one symptom of mild severity of genital irritation, which 
included genital burning, soreness and pelvic pain. Three out of 14 women in the HEC 
group (21.4%) had colposcopic findings that included erythema, petechiae and 
peeling.25  No deep genital disruption was observed in either product group. Minimal 
changes in wet mounts, pH, Nugent scores, neutrophils, and vaginal flora were 
observed in both product groups. 
 
Safety – Rectal Administration 
 
In several rectal microbicide trials, the Universal HEC Placebo Gel has served as the 
placebo arm. RMP-01 using topical UC781 enrolled 36 subjects with 12 randomized to 
the HEC placebo arm. Following single topical rectal HEC exposure, four Grade 2 AEs 
were reported in 1 individual, shown to be in the placebo group. As this individual had 
no complaints during the subsequent 7-day exposure, the symptoms of fever, cramps, 
flatulence, and diarrhea were likely not related to the HEC gel.  There were no other 
Grade 2 or Grade 3 AEs associated with HEC gel.26   
 
In the second rectal microbicide Phase 1 safety trial, RMP-02/MTN-006, 18 subjects 
were studied with 6 randomized to the HEC placebo arm in the topical-exposed portion 
of the trial. With regards to gastrointestinal-related AEs following single-dose topical 
HEC exposure, no Grade 2 or Grade 3 AEs were reported.  Following 7-day exposure, 
one Grade 2 event was reported in one subject receiving HEC gel (abdominal pain); 
three events were reported in 2 subjects in the tenofovir-treated group. None of the five 
gastrointestinal Grade 3 AEs reported in 2 subjects (all during 7-day exposure) were 


 
 
  
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July 21, 2017 
 
related to HEC placebo; all were in the tenofovir-product group. No SAEs were 
reported.27  
 
MTN-007 was a Phase 1, randomized, double-blinded, placebo-controlled safety and 
acceptability study of reduced glycerin tenofovir 1% gel when applied rectally.28 
Secondary objectives of MTN-007 were to evaluate the safety of HEC placebo gel when 
applied rectally.  Participants were randomized to receive a single dose of reduced 
glycerin tenofovir 1% gel, 2% N-9 gel, placebo gel, or no treatment. A total of 65 
participants were enrolled and randomized in the study; 16 participants were 
randomized to HEC. A single dose of the study gel was self-administered under 
observation. Within approximately 30 minutes, lavage, stool, and rectal biopsy 
specimens were collected. After a one-week recovery period, participants returned to 
the clinic for assessment. If no significant adverse events were reported, participants 
began to self-administer once-daily doses of the study gel for 7 days on an outpatient 
basis. Participants returned to the clinic for evaluation and specimen collection after 
completion of 7 days of daily dosing. HEC was found to be safe and well tolerated. 
There were no significant differences in the proportion of participants with > Grade 2 or 
higher adverse events across the arms of the study: 3/16 (19%) in the TFV arm, 7/17 
(41%) in the N-9 arm, 5/16 (31%) in the HEC arm, and 6/16 (38%) in the No Rx arm; 
when compared to the No Rx arm, one sided Fisher exact test yielded p-value 0.94 for 
the TFV arm, 0.56 for the N-9 arm, and 0.77 for the HEC arm.  Likelihood of future 
product use (acceptability) was high for the HEC gel (93.3%).  
 


 
 
  
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2.5 Other Clinical Studies of Dapivirine  
 
Several other studies of the safety and/or effectiveness of dapivirine for HIV prevention have been completed, are ongoing or 
are in development.  These studies are included in the table below. 
 
Table 5: Clinical Studies of Dapivirine  
Trial 
Number 
Description 
Country 
Gel-
4759 
(2.5 g) 
Gel-
4789 
(2.5 g) 
Gel-4759 & 
Gel-4789 
(2.5 g) 
Ring-001 
reservoir 
(200 mg) 
Ring-002 
reservoir (25 
mg) 
Ring-003 
matrix* 
(25mg) 
Ring-004 
matrix** 
(25mg) 
Ring-004 
matrix*** 
(25mg) 
Ring-102 
matrix** 
(200mg DPV/ 
320 mg LNG) 
Ring-104 
matrix** 
(200 mg) 
Placebo Ring 
or Gel 
IPM 001 
Safety and PK in 
women; 7 days 
Belgium 
 
-- 
-- 
-- 
12 
-- 
-- 
-- 
-- 
-- 
-- 
12 (crossover) 
IPM 008 
Safety and PK in 
women; 7 days 
Belgium 
-- 
-- 
-- 
-- 
10 
-- 
-- 
-- 
-- 
-- 
3 
IPM 013 
Safety and PK in 
women; 56/57 days 
Belgium 
-- 
-- 
-- 
-- 
-- 
-- 
36 
-- 
-- 
-- 
12 
IPM 014A 
Safety and 
acceptability in 
women; 42 days 
Kenya, 
Rwanda, South 
Africa, Malawi 
141 
-- 
141 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
139 
IPM 014B19 
Safety and 
acceptability in 
women; 42 days 
South Africa 
-- 
50 
50 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
50 
IPM 015 
Safety and PK in 
women; 84 days 
Multiple 
Countries in 
Sub-Saharan 
Africa 
-- 
-- 
-- 
-- 
-- 
-- 
140 
-- 
-- 
-- 
140 
IPM 018 
Safety and PK in 
women; 28 days 
Belgium 
-- 
-- 
-- 
-- 
8 
8 
-- 
-- 
-- 
-- 
8 
IPM 020 
Safety; 84 days 
United States 
43 
43 
86 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
42 
IPM 024 
Safety and PK in 
women; 28 days 
Belgium 
-- 
-- 
-- 
-- 
-- 
-- 
8 
-- 
-- 
-- 
8 
IPM 027 
Safety and efficacy; 2 
years 
South Africa, 
Uganda 
-- 
-- 
-- 
-- 
-- 
-- 
1307 
-- 
-- 
-- 
652 
IPM 028 
Safety and PK in 
women, Drug-drug 
interaction; 112 days 
Belgium 
-- 
-- 
-- 
-- 
-- 
-- 
36 
-- 
-- 
-- 
-- 
IPM 034 
Safety and PK in 
women; 7 to 84 days 
Belgium 
-- 
-- 
-- 
-- 
-- 
-- 
40 
-- 
-- 
-- 
-- 
MTN-
012/IPM 010 
Male tolerance; 7 
days 
United States 
24 
-- 
24 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
MTN-
013/IPM 
02629 
Safety and PK in 
women; 52 days 
United States 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
12 
-- 
-- 
12 
MTN-020 
Safety and efficacy in 
women; median 1.6 
years 
Malawi, South 
Africa, Uganda, 
Zimbabwe 
-- 
-- 
-- 
-- 
-- 
-- 
1313 
-- 
-- 
-- 
1316 
MTN-
023/IPM 030 
Safety in adolescent 
females; 24 weeks 
United States 
-- 
-- 
-- 
-- 
-- 
-- 
73 
-- 
-- 
-- 
23 


 
 
  
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Trial 
Number 
Description 
Country 
Gel-
4759 
(2.5 g) 
Gel-
4789 
(2.5 g) 
Gel-4759 & 
Gel-4789 
(2.5 g) 
Ring-001 
reservoir 
(200 mg) 
Ring-002 
reservoir (25 
mg) 
Ring-003 
matrix* 
(25mg) 
Ring-004 
matrix** 
(25mg) 
Ring-004 
matrix*** 
(25mg) 
Ring-102 
matrix** 
(200mg DPV/ 
320 mg LNG) 
Ring-104 
matrix** 
(200 mg) 
Placebo Ring 
or Gel 
MTN-
024/IPM 031 
Safety in 
postmenopausal 
women; 12 weeks 
United States 
-- 
-- 
-- 
-- 
-- 
-- 
72 
-- 
-- 
-- 
24 
MTN-025 
Safety and 
adherence in women; 
1 year 
Malawi, South 
Africa, Uganda, 
Zimbabwe 
-- 
-- 
-- 
-- 
-- 
-- 
(Former MTN-
020 
participants) 
-- 
-- 
-- 
-- 
MTN-
029/IPM 039 
PK in lactating 
women; 14 days 
United States 
-- 
-- 
-- 
-- 
-- 
-- 
16 
-- 
-- 
-- 
-- 
MTN-
030/IPM 041 
(Enrollment 
not started) 
Safety and PK in 
women; 14 days 
United States 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
12 
12 
-- 
MTN-033 
(Enrollment 
not started) 
PK in males; two 
doses over 30 days 
United States 
16 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
MTN-
034/IPM 045 
(Enrollment 
not started) 
Safety and 
adherence in 
adolescent & young 
adult females; 24-48 
weeks 
Kenya, South 
Africa, 
Zimbabwe 
-- 
-- 
-- 
-- 
-- 
-- 
300 
-- 
-- 
-- 
-- 
TOTAL participants 
224 
93 
301 
12 
18 
8 
3333 
12 
12 
12 
2441 
 
 
*Tin-catalyzed matrix ring 
**Platinum-catalyzed matrix ring 
***Platinum-catalyzed matrix ring Ring-004, but did not contain the silicone oil MED360 - only silicone elastomer and the API(s). 
 


 
 
  
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2.6 Study Hypotheses and Rationale for Study Design 
 
2.6.1 
Study Primary Hypotheses 
 
It is hypothesized that dapivirine gel (0.05%) will be safe when applied to the rectum 
and well-tolerated among healthy men and women who have a history of receptive anal 
intercourse. 
 
2.6.2 
Rationale for Study Design 
 
Rectal microbicides are needed for individuals at risk of acquiring HIV infection through 
unprotected receptive anal intercourse (RAI). It will be important to expand the rectal 
microbicide pipeline with the addition of products from different classes such as 
dapivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI). 
 
Rationale for the Dosing and PK Sampling Schedule 
MTN-026 is the first study to assess the safety of dapivirine gel applied rectally.  A 
single dose exposure for each participant will allow for the identification of any safety 
concerns following single dose gel application.  An additional benefit of this design is 
that it will collect valuable PK and pharmacodynamic (PD) data from men and women 
who have been exposed to a single dose of dapivirine gel rectally (which may be 
representative of episodic or coital dosing) as well as to 7 daily rectal doses (daily 
dosing).  While the ideal dosing regimen for dapivirine gel applied rectally is not yet 
known (coital-dosing vs. daily dosing), this design will provide critical PK and PD data, 
while controlling for inter-personal variability.   
 
Regarding the washout period, based on several prior dapivirine studies, the plasma 
half-life is ~72 hours and the vaginal tissue half-life is ~15 hours. In several prior 
studies, tissue dapivirine concentrations fall between 2 and 4 log10 over a 2 week 
period, often to undetectable levels. During the MTN-026 2-week washout, plasma 
concentrations will fall to less than 5% of peak concentrations and contribute negligibly 
to the concentrations in plasma during the repeated daily rectal dosing phase. After the 
week of repeated daily rectal dosing, concentrations due to the single dose phase will 
drop another 95% to undetectable levels, and visit 13 sampling will be influenced only 
by the multiple dose period.   
 
 


 
 
  
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3 
OBJECTIVES  
 
3.1 Primary Objectives 
 
Safety 
x To evaluate the safety of dapivirine gel formulation when applied rectally. 
 
Pharmacokinetics 
x To characterize the systemic and compartmental pharmacokinetics of dapivirine 
gel following rectal application. 
 
3.2 Secondary Objectives 
 
Acceptability 
x To identify product attributes considered likely to challenge and facilitate future 
sustained use of rectally applied dapivirine gel. 
 
Mucosal Safety 
x To evaluate the mucosal safety of dapivirine gel when applied rectally. 
 
3.3 Exploratory Objectives 
 
Ex Vivo Efficacy 
x To assess the preliminary (ex vivo) efficacy of dapivirine gel formulation after 
product is applied rectally. 
 
Pharmacokinetics 
x To characterize the vaginal pharmacokinetics of dapivirine gel following rectal 
application in women. 
 
 


 
 
  
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4 
STUDY DESIGN 
 
4.1 Identification of Study Design 
 
MTN-026 is a Phase 1, multi-site, randomized (2:1), double-blind, placebo-controlled 
trial. 
 
4.2 Summary of Major Endpoints 
 
Primary Endpoints: 
 
Safety 
x 
Grade 2 or higher AEs as defined by the Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 
and/or Addenda 1, 2 and 3 (Female Genital [Dated November 2007], Male Genital 
[Dated November 2007] and Rectal [Clarification Dated May 2012] Grading Tables 
for Use in Microbicide Studies). 
 
Pharmacokinetics 
x 
Dapivirine concentrations 
o Blood 
o Rectal fluid 
o Rectal mucosal tissue homogenates 
 
Secondary Endpoints:  
 
Acceptability 
x 
Product attributes considered likely to challenge future sustained use. 
 
Mucosal Safety 
x 
Rectal proteomics 
x 
Rectal transcriptome  
x 
Rectal microflora 
x 
Rectal histology 
x 
Rectal tissue flow cytometry 
 
Exploratory Endpoints: 
 
Ex Vivo Efficacy 
x 
Changes in HIV-1 p24 levels in colorectal explant culture supernatant  
x 
Anti-HIV activity in rectal fluid 
x 
Anti-HIV activity in cervicovaginal fluid♀ 
 


 
 
  
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Pharmacokinetics 
x 
Dapivirine concentrations 
o Cervicovaginal fluid♀ 
o Cervical tissue♀ 
♀Female participants only 
 
4.3 Description of Study Population 
 
The study population will consist of HIV-uninfected men and women who are between 
the ages of 18 and 45 years (inclusive) at Screening and meet the criteria outlined in 
Sections 5.2 and 5.3.  Only sites with the capacity to enroll female participants will do 
so.  
 
4.4 Time to Complete Accrual 
 
The time to complete accrual is anticipated to be approximately 6-8 months at each site.   
 
4.5 Study Groups  
 
MTN-026 will enroll up to 27 participants.  Randomized (2:1) to dose rectally with either 
dapivirine gel (0.05%) or placebo gel. 
 
4.6 Expected Duration of Participation 
 
Each participant will be on study for approximately 40 days.  The total duration of the 
study will be approximately 9-12 months. 
 
4.7 Sites 
 
Sites selected by the MTN Executive Committee. 


 
 
  
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5 
STUDY POPULATION 
 
5.1 Selection of the Study Population 
 
The inclusion and exclusion criteria in Sections 5.2 and 5.3 will be used to ensure the 
appropriate selection of study participants.  
 
5.1.1 
Recruitment 
 
Participants will be recruited from a variety of sources across sites, including outpatient 
clinics, universities and community-based locations.  Recruitment materials will be 
approved by site Institutional Review Boards/Ethics Committees (IRBs/ECs) prior to 
use.   
 
5.1.2 
Retention 
 
Once a participant is enrolled and randomized in MTN-026, the study site will make 
every effort to retain the participant in follow-up to minimize possible bias associated 
with loss-to-follow-up. A retention rate of 95% will be targeted at each site. Each study 
site will be responsible for developing and implementing local Standard Operating 
Procedures (SOPs) to target and ensure high rates of retention. 
 
5.2 Inclusion Criteria 
 
Individuals who meet the following criteria are eligible for study inclusion: 
1. Age of 18 – 45 years (inclusive) at Screening, verified per site SOP 
 
2. Able and willing to provide written informed consent 
 
3. HIV-1/2 uninfected at Screening and Enrollment, per applicable algorithm in 
Appendix II and willing to receive HIV test results 
 
4. Able and willing to provide adequate locator information, as defined in site SOP 
 
5. Available to return for all study visits and willing to comply with study participation 
requirements 
 
6. In general good health at Screening and Enrollment, as determined by the site 
IoR or designee 
 
7. Per participant report, a history of consensual RAI at least once in the past 
calendar year 
 
8. Willing to not take part in other research studies involving drugs, medical devices, 
genital or rectal products, or vaccines for the duration of study participation, 
including the time between Screening and Enrollment 


 
 
  
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9. Willing to be sexually abstinent for 72 hours prior to each study visit, during the 
study product use periods and for 72 hours after biopsy collection 
 
Note: See Criteria 12 and 13 for additional restrictions for female participants  
 
10. Willing to abstain from inserting any non-study products into the rectum for 72 
hours prior to each study visit and during the study product use periods 
 
Note: See Criteria 12 and 13 for additional restrictions for female participants 
 
Females must also meet the following additional inclusion criteria to be eligible for 
study inclusion:  
 
11. Women over the age of 21 (inclusive) must have documentation of a satisfactory 
Pap within the past 3 years prior to Enrollment consistent with Grade 0 according 
to the Female Genital Grading Table for Use in Microbicide Studies Addendum 1 
(dated November 2007) to the DAIDS Table for Grading Adult and Pediatric 
Adverse Events, Corrected Version 2.1, July 2017, or satisfactory evaluation with 
no treatment required of Grade 1 or higher Pap result  
 
12. Willing to be sexually abstinent for 72 hours prior to each study visit and during 
the study product use periods and for 7 days after biopsy collection 
 
13. Willing to abstain from inserting any non-study products into the vagina for 72 
hours prior to each study visit, during the study product use periods and for 7 
days after biopsy collection 
 
14. Willing to use an effective method of contraception for at least 30 days (inclusive) 
prior to Enrollment and intending to continue use of an effective method for the 
duration of study participation; effective methods include: hormonal methods 
(except contraceptive ring), intrauterine device (IUD), sterilization (of participant 
and/or partner, as defined in site SOPs), or sexually abstinent for 90 days prior to 
Screening 
 
5.3 Exclusion Criteria 
 
Individuals who meet any of the following criteria will be excluded from the study:   
 
1. At Screening: 
i. 
Hemoglobin Grade 1 or higher* 
ii. 
Platelet count Grade 1 or higher*  
iii. 
White blood count Grade 2 or higher* 
iv. 
Serum creatinine >1.3× the site laboratory upper limit of normal (ULN) 
v. 
International normalized ratio (INR) >1.5× the site laboratory ULN 
vi. 
Aspartate aminotransferase (AST) or alanine transaminase (ALT) 
Grade 1 or higher* 
vii. 
Positive for hepatitis C antibody 
viii. 
Positive for hepatitis B surface antigen 
ix. 
History of inflammatory bowel disease by participant report 


 
 
  
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*As per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
Corrected Version 2.1, July 2017 
 
Note: Otherwise eligible participants with an exclusionary test result (other than HIV, 
HBV or HCV) can be re-tested during the screening process. If a participant is re-tested 
and a non-exclusionary result is documented within 45 days of providing informed 
consent for screening, the participant may be enrolled.  
 
2. Anticipated use of and/or unwillingness to abstain from the following medications 
during study participation: 
i. 
Heparin, including Lovenox® 
ii. 
Warfarin 
iii. 
Plavix® (clopidogrel bisulfate) 
iv. 
Aspirin (greater than 81 mg) 
v. 
Non-steroidal anti-inflammatory drugs (NSAIDS) 
vi. 
Any other drugs that are associated with increased likelihood of 
bleeding 
vii. 
CYP3A inducer(s) and/or inhibitor(s) as specified in the MTN-026 
Study-Specific Procedures (SSP) Manual 
viii. 
Hormone-replacement therapy in tablet, injectable or gel form 
 
3. Known adverse reaction to any of the components of the study products  
 
4. Use of post-exposure prophylaxis (PEP) for potential HIV exposure within the 6 
months prior to Enrollment 
 
5. Use of pre-exposure prophylaxis (PrEP) for HIV prevention within the 6 months 
prior to Enrollment, and/or anticipated use during trial participation 
  
6. Use of systemic immunomodulatory medications within the 6 months prior to 
Enrollment, and/or anticipated use during trial participation 
 
7. RAI without a condom and/or penile-vaginal intercourse with a partner who is 
known to be HIV-positive in the past 6 months 
 
8. Non-therapeutic injection drug use in the 12 months prior to Screening and 
Enrollment 
 
9. Participation in research studies involving drugs, medical devices, genital or 
rectal products, or vaccines within 45 days of the Enrollment Visit 
 
10. At Screening, participant report of treatment for an anogenital STI within the past 
3 months  
 
11. At Screening, participant-reported symptoms and/or clinical or laboratory 
diagnosis of active anorectal or reproductive tract infection requiring treatment 


 
 
  
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per 
current 
World 
Health 
Organization 
(WHO) 
guidelines 
(http://www.who.int/hiv/pub/sti/pub6/en/) or symptomatic urinary tract infection 
(UTI). Infections requiring treatment include symptomatic Neisseria gonorrhea 
(GC), Chlamydia trachomatis (CT) infection, syphilis, active herpes simplex virus 
(HSV) lesions, anogenital sores or ulcers, or symptomatic genital warts, 
cervicitis, chancroid, pelvic inflammatory disease (PID), bacterial vaginosis (BV), 
symptomatic vaginal candidiasis, other vaginitis, trichomoniasis. 
 
Note:  Otherwise eligible participants with an exclusionary UTI, BV and/or 
candida finding may be re-tested during the screening process. 
 
12. At Enrollment, active anorectal or reproductive tract infection requiring treatment 
per 
current 
WHO 
guidelines 
(http://www.who.int/hiv/pub/sti/pub6/en/) 
or 
symptomatic urinary tract infection (UTI). Infections requiring treatment include 
symptomatic GC, CT, syphilis, active HSV lesions, anogenital sores or ulcers, 
symptomatic genital warts, bacterial vaginosis, symptomatic vaginal candidiasis, 
other vaginitis, trichomoniasis, chancroid, cervicitis and PID. 
 
Note: HSV-1 or HSV-2 seropositive diagnosis with no active lesions is permitted since 
treatment is not required 
 
13. Has any other condition that, in the opinion of the IoR/designee, would preclude 
informed consent, make study participation unsafe, complicate interpretation of 
study outcome data, or otherwise interfere with achieving study objectives. 
 
Females who meet any of the following additional criteria will be excluded from the 
study:   
 
14. Pregnant or breastfeeding at either Screening or Enrollment or intends to 
become pregnant or start breastfeeding during study participation 
 
Note:  A documented negative pregnancy test performed by study staff is required for 
inclusion; however, a self-reported pregnancy is adequate for exclusion from 
screening/enrollment into the study. 
 
15. Last pregnancy outcome 90 days or less prior to Screening 
 
16. Has had a hysterectomy  
 
17. At Enrollment, has a clinically apparent Grade 1 or higher pelvic exam finding 
(observed by study clinician or designee) per the Female Genital Grading Table 
for Use in Microbicide Studies [Addendum 1,  Dated November 2007] 
 
Note: Cervical friability bleeding associated with speculum insertion and/or specimen 
collection judged to be within the range of normal according to the clinical judgment of 
the IoR/designee is considered expected non-menstrual bleeding and is not 
exclusionary. 
 


 
 
  
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5.4 Co-enrollment Guidelines 
 
As indicated in Sections 5.2 and 5.3, participants must not take part in other research 
studies involving drugs, medical devices, genital or rectal products, or vaccines after the 
Screening Visit and while taking part in MTN-026, unless approved by the Protocol 
Safety Review Team (PSRT).  Participation in the following types of studies may be 
allowed at the discretion of the IoR/designee: 
 
x Participants may take part in ancillary studies if approved by MTN-026 PSRT  
x Participants who become infected with HIV may take part in observational and/or 
interventional studies for HIV-positive persons 
x Participants who become pregnant may take part in observational studies, 
including pregnancy registries 
 
Should any participant report concurrent participation in contraindicated studies after 
enrolling in MTN-026, the IoR/designee will consult the PSRT regarding ongoing 
product use and other potential safety considerations associated with co-enrollment. 
   
 
6 
STUDY PRODUCT 
 
6.1 Regimen 
 
Twenty-seven participants will be randomized (2:1) to receive rectally administered 
dapivirine gel (0.05%) or placebo gel.  Participants will receive a single dose of the gel 
administered by the study staff.  Following a minimum two week washout period 
participants or study staff will administer daily rectal doses of study gel for 7 consecutive 
days under direct observation in the clinic.  
 
Table 6: Study Product Regimen 
Study 
Study Products 
Number of Participants 
Frequency and Route 
MTN-026 
0.05% Dapivirine Gel  
Universal Placebo Gel  
27 
Single dose followed by 
washout period and then 7 
consecutive doses rectally 
administered  
 


 
 
  
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6.2 Administration 
 
Study staff will administer the single dose of study gel in the clinic to randomized 
participants. Study staff will observe each administration of the 7 daily doses of study 
gel. Participants will be instructed to present to the clinic daily for the 7-day period for 
directly observed dosing (DOD). Administration of study product during the 7-day period 
will be performed either by participants or by study staff, depending upon site and/or 
participant preference.  Study staff who apply gel rectally are not to be the same staff 
who assess the participant’s safety.  If a participant is not able to attend a clinic visit, the 
participant will be instructed to administer a dose at home at approximately the same 
time of day as all other daily doses, unless the next dose is due within 6 hours. If the 
next dose is due within 6 hours, the dose will be skipped and the next dose will be 
administered as originally scheduled. Participants who miss more than one application 
of the product will be instructed to contact the site for further direction. Participants will 
receive one pre-filled applicator of dapivirine gel (0.05%) or placebo gel at Visit 7 in the 
event that they cannot attend one of their seven daily dosing clinic visits. Participants 
will be informed of the ideal storage conditions for this single dose. Participants will also 
be instructed on how to properly dispose of the used applicator at home in the event 
they insert a dose at home. 
 
Additional detail on administration and participant education will be provided in the 
MTN-026 SSP Manual. 
 
6.3 Study Product Formulation  
 
Dapivirine Gel (0.05%) 
Dapivirine gel (0.05%) is formulated as an aqueous semi-solid (gel). The excipients in 
the drug product formula are pharmacopoeia grade components that have a history of 
use in currently approved vaginal products.  Dapivirine gel has a pH of 4.7. Each pre-
filled applicator will contain approximately 2.5 g (2.5 mL) of 0.05% dapivirine gel. 
 
Dapivirine gel should be stored at room temperature 25°C (77°F).  Excursions are 
permitted between 15°C to 30°C (59°F to 86°F). 
 
Universal Placebo Gel 
The Universal Placebo gel contains HEC as the gel thickener, purified water, sodium 
chloride, sorbic acid and sodium hydroxide.  The gel is isotonic and formulated at a pH 
of 4.4.  HEC, the gelling agent, is used to approximate the viscosity of other microbicide 
gel candidates.  Each pre-filled applicator will contain approximately 2.5 g (2.5 mL).4  
 
Universal Placebo gel should be stored at room temperature 25°C (77°F).  Excursions 
are permitted between 15°C to 30°C (59°F to 86°F). 
 
6.4 Study Applicator 
 
MTN-026 will use the HTI pre-filled applicator, the same applicator that has been 
utilized in other rectal studies, including RMP02/MTN-006, MTN-007, Project GEL and 


 
 
  
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CHARM 01, and is currently being used in MTN-017 and CHARM 03. The applicator is 
manufactured by HTI Plastics, Lincoln NE, USA, in accordance with HTI’s quality 
assurance procedures and the Good Manufacturing Practices as established by the 
Food and Drug Administration.  Participants will be advised on proper storage 
conditions while at home. 
 
6.5 Study Product Supply and Accountability 
 
6.5.1 
Study Product Supply 
 
MTN (Pittsburgh, PA) will supply the 0.05% dapivirine gel and Universal Placebo gel 
prefilled applicators.  MTN will ensure the manufacture of dapivirine gel (0.05%) and 
Universal Placebo gel and analyze/release the gels under Good Manufacturing 
Practices (GMP).  Study product will ship directly to the Pharmacist of Record (PoR) at 
each study site.   
 
6.5.2 
Study Product Accountability 
 
The Clinical Research Site (CRS) Pharmacist of Record (PoR) is required to maintain 
complete records of the study product received and subsequently dispensed. 
 
6.6 Study Product Dispensing  
 
Following receipt of a written prescription from an authorized prescriber, one pre-filled 
applicator of study product (0.05% dapivirine gel or Universal Placebo gel) will be 
dispensed to enrolled study participants or to study staff on behalf of the participant at 
each study product administration visit for DOD. An authorized prescriber includes the 
IoR or a licensed clinician directly responsible to the IoR as noted on the United States 
(US) Food and Drug Administration (FDA) 1572 Form. 
 
Additionally, participants will receive one pre-filled applicator of 0.05% dapivirine gel or 
Universal Placebo gel for at home use in the event that they are unable to attend a 
scheduled observed dosing visit at the clinic.  This dose will be dispensed and provided 
to the participant at the first administration of the 7 consecutive daily doses, Visit 7. 
 
6.7 Retrieval of Unused Study Products 
 
Study participants will be instructed to return the unused applicator of dapivirine gel 
(0.05%) or Universal Placebo gel at Visit 14: 24 hour PK Visit. In the event that unused 
study products are not returned at Visit 14: 24 hour PK Visit, site staff members will 
make every effort to encourage participants to return study product as soon as possible. 
Attempts by study staff to retrieve unused study product from the participant must be 
documented. If study product is not returned within the time frames outlined below the 
MTN-026 PSRT must be notified. 
 


 
 
  
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Study product must be retrieved (optimally within 24 hours) and returned to the study 
site pharmacy when study product use is permanently discontinued. If the study 
product(s) is not retrieved within 24 hours, the MTN-026 PSRT must be informed. 
 
It is expected that participants will return any unused study product not previously 
returned at their Final Clinic Visit (Visit 16). If a participant does not bring his/her unused 
study product to the Final Clinic Visit (Visit 16), study staff must attempt to retrieve the 
unused study product within 7 days.  If the study product(s) are not retrieved within that 
timeframe, the MTN-026 PSRT must be informed. 
 
6.8 Ancillary Study Supplies 
 
All participants will be offered study-provided lubricant to facilitate the insertion of the 
applicator.  Lubricant will be dispensed by the clinic staff and made available in the 
clinic. 
 
Study provided condoms will be offered to participants at Visit 6. 
 
6.9 Concomitant Medications 
 
With the exception of those not permitted under inclusion and exclusion criteria, and 
listed below, concomitant medications will be permitted.  Throughout the course of the 
study, all concomitant medications, including those used to treat AEs, will be recorded 
on forms designed for that purpose.  Prescription medications, over-the-counter 
preparations, vitamins and nutritional supplements, and herbal preparations all will be 
recorded as concomitant medications. Sexual lubricants may be recorded on a separate 
form. 
 
6.10 Prohibited Medications and Practices 
 
Use of Heparin, including Lovenox®, Warfarin, Plavix® (clopidogrel bisulfate), hormone-
replacement therapy in tablet, injectable or gel form is prohibited during study 
participation. See Section 9.3 for additional details regarding permanent discontinuation 
for reported use of these medications. 
 
Participants will be counseled to abstain from using aspirin (greater than 81 mg) and 
other non-steroidal anti-inflammatory drugs (NSAIDS), CYP3A inducer(s) and/or 
inhibitor(s) and any other drugs that are associated with increased likelihood of 
bleeding.  Should a participant report the use of such drugs within 72 hours prior to a 
PK sample collection visit, collection of biopsies at that visit would be performed at IoR 
discretion. Participants will be appropriately counseled regarding the potential risks 
associated with biopsy collection and documentation of the decision process will be 
included in the participants’ study documents. Rapid PSRT consultation can be 
requested at IoR discretion, if needed.  Participants who report use of prohibited 
products and/or products to avoid during study product use period will be counseled 
regarding the use of alternative methods.  


 
 
  
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Participants are to abstain from inserting any non-study products into the rectum or 
vagina for 72 hours prior to clinic visits and during the study product use periods. Male 
participants are to abstain from the following sexual activities for 72 hours after biopsy 
collection: receptive anal intercourse (RAI), receptive oral anogenital stimulation, rectal 
stimulation via fingers, and rectal insertion of sex toys. Further, female participants are 
to abstain from inserting anything into their vagina and rectum for 7 days following 
biopsy collection, including the following sexual activities: RAI, penile-vaginal 
intercourse, receptive oral anogenital stimulation, vaginal or rectal stimulation via 
fingers, and vaginal or rectal insertion of sex toys.  Participants will be appropriately 
counseled regarding the potential risks associated with biopsy collection and 
documentation of the decision process will be included in the participants’ study 
documents. Rapid PSRT consultation can be requested at IoR discretion, if needed. 
 
 
7 
STUDY PROCEDURES 
 
An overview of the study visit and evaluations schedule is presented in Appendix I.  
Presented in this section is additional information on visit-specific study procedures.  
Detailed instructions to guide and standardize procedures across sites are provided in 
the MTN-026 SSP Manual available at www.mtnstopshiv.org.   
 
Figure 2:  MTN-026 Study Visit Schedule 
 
  
 
7.1 Pre-screening 
 
As part of participant outreach and recruitment strategies, study staff can pre-screen 
potential study participants at either on-site or off-site locations. During these 
interactions, study staff may explain the study to potential participants and ascertain 
elements of presumptive eligibility (e.g., willingness to use the study product in a directly 
observed fashion, willingness to adhere to the study rules, etc.), to be confirmed at an 
on-site screening visit. Process information (e.g., number of potential participants 
contacted, number presumptively eligible) may be recorded and stored at the study site 
in the absence of written informed consent from potential participants, provided the 
information is collected in such a manner that it cannot be linked to participant 


 
 
  
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identifiers, unless a waiver is granted from the local IRB/EC. Procedures and 
documentation will comply with local IRB/EC requirements.  
 
7.2 Visit 1: Screening  
 
A Screening Visit will take place up to 45 days prior to the Enrollment Visit (Day 0).  
Multiple visits may be conducted to complete all required screening procedures, if 
necessary.  Written informed consent for Screening/Enrollment will be obtained before 
any screening procedures are initiated.  For participants who do not meet the eligibility 
criteria, Screening will be discontinued once ineligibility is determined.   
 
Table 7: Visit 1:  Screening Visit  
Visit 1:  Screening Visit  
Component 
Procedures 
Administrative and 
Regulatory 
x 
Obtain written informed consent 
x 
Assess consent form comprehension 
x 
Assign participant ID (PTID) 
x 
Collect locator information 
x 
Collect demographic information 
x 
Assess eligibility  
x 
Provide reimbursement for study visit 
x 
Schedule next visit* 
Behavioral 
x 
Provide counseling  
 
HIV pre- and post-test  
 
HIV/STI risk reduction 
 
Protocol requirements  
Clinical 
x 
Collect medical history 
x 
Collect menstrual history♀ 
x 
Collect concomitant medications 
x 
Perform physical examinationӨ  
x 
Perform pelvic examinationӨ ♀ 
x 
Perform rectal examinationӨ 
x 
Provide available test results 
x 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for other findings* 
Laboratory 
 
Urine 
x 
Collect urine 
 
Qualitative hCG♀ 
 
Dipstick urinary analysis (UA)* 
 
Urine culture* 
 
NAAT for GC/CT 
Blood 
x 
Collect blood 
 
Complete blood count (CBC) with differential and platelets 
 
Chemistries (AST, ALT, Creatinine) 
 
Syphilis serology 
 
HIV-1/2 test 
 
HSV-1/2 serology 
 
HBsAg 
 
HCV serology 
 
Coagulation (PT/INR) 
Pelvic 
Samples 
x 
Collect pelvic specimens 
 
Vaginal NAAT for GC/CT♀ 
 
Pap test♀* 
Anorectal 
Samples 
x 
Collect rectal specimens 
 
Rectal NAAT for GC/CT 
 
Anal HSV-1/2 detection* 
♀Female participants *if indicated Ө See Section 7.13 for examination details 
 


 
 
  
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7.3 Visit 2: Enrollment (Day 0) 
 
Menses must not coincide with Study Visits 2-6, therefore participant’s menstrual cycle 
must be considered when scheduling the Enrollment Visit (Visit 2). 
 
Table 8: Visit 2:  Enrollment (Day 0) 
Visit 2:  Enrollment  
Component 
Procedures 
Administrative and 
Regulatory 
x 
Review informed consent and confirm participant’s willingness to continue 
in the study 
x 
Confirm eligibility  
x 
Review/update locator information 
x 
Randomization 
x 
Provide reimbursement for study visit  
x 
Schedule next visit* 
Behavioral 
x 
Behavioral assessment  
x 
Provide counseling  
 
HIV pre- and post-test  
 
HIV/STI risk reduction 
 
Protocol requirements 
Clinical 
x 
Review/update medical history 
x 
Review/update menstrual history♀ 
x 
Review/update concomitant medications 
x 
Perform targeted physical examination  
x 
Perform pelvic examination♀ 
x 
Perform rectal examination 
x 
Provide available test results 
x 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for other findings* 
Laboratory 
 
Urine 
x 
Collect urine 
 
Qualitative hCG ♀ 
 
Dipstick UA* 
 
Urine culture* 
 
Urine NAAT for GC/CT* 
Blood 
x 
Collect blood  
 
CBC with differential and platelets* 
 
Chemistries (AST, ALT, Creatinine)* 
 
Syphilis serology* 
 
HIV-1/2 test 
 
Plasma for archive 
Pelvic 
Samples 
x 
Cervicovaginal lavage (CVL) for PD baseline prior to biopsy collection♀ 
Anorectal 
Samples 
x 
Rectal NAAT for GC/CT*  
x 
Anal HSV-1/2 detection* 
x 
Rectal enema effluent for PD baseline prior to biopsy collection 
x 
Rectal tissue for PD baseline 
x 
Rectal tissue for mucosal safety baseline 
x 
Rectal fluid for mucosal safety baseline 
♀Female participants *If indicated 
 


 
 
  
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7.4 Visit 3: Single Dose Administration Visit 
 
Table 9: Visit 3: Single Dose Administration Visit 
Visit 3:  Single Dose Administration Visit 
Component 
Procedures 
Administrative and 
Regulatory 
x 
Review/update locator information 
x 
Provide reimbursement for study visit 
x 
Schedule next visit 
Behavioral 
x 
Behavioral assessment 
x 
In-depth interview (IDI) 
x 
Provide counseling  
 
Protocol requirements 
 
Product use 
Clinical 
x 
Review/update medical history 
x 
Review/update menstrual history♀ 
x 
Review/update concomitant medications 
x 
Perform targeted physical examination*  
x 
Perform pelvic examination♀* 
x 
Perform rectal examination 
x 
Provide available test results 
x 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for other findings* 
x 
Record/update AEs 
Laboratory 
 
Urine 
x 
Collect urine 
 
Dipstick UA* 
 
Urine culture* 
 
Urine NAAT for GC/CT* 
Blood 
x 
Collect blood  
 
CBC with differential and platelets* 
 
Chemistries (AST, ALT, Creatinine)* 
 
Syphilis Serology* 
 
PK levels ● 
Anorectal 
Samples 
x 
Collect rectal specimens 
 
Rectal NAAT for GC/CT* 
 
Anal HSV-1/2 detection* 
 
Rectal fluid for PK levels ● 
 
Rectal fluid for mucosal safety ● 
 
Rectal tissue for PD ● 
 
Rectal tissue for PK ● 
 
Rectal tissue for mucosal safety ● 
Study Product Supply 
x 
Provision of study product 
x 
Provision of lubricant 
x 
Observe dose application  
♀Female participants *if indicated   ● = Participants will be assigned to provide samples at either 30-60 or 120 minutes.  In 
addition, all participants will provide blood for PK at hr 0. Blood collection times are matched to fluid/tissue sample collection 
times. 
 


 
 
  
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7.5 Visits 4-6 (~24, 48, 72 Hours After Application of Study Product) 
 
All participants attend Visits 4, 5, and 6.  Participants will only provide intensive PK 
samples at Visit 4, 5 or 6. 
 
Table 10: Visits 4-6:  PK Visits (~24, 48, 72 Hours After Application of Study Product) 
Visits 4-6  (~24, 48, 72 Hours After Application of Study Product) 
Component 
Procedures 
Administrative and 
Regulatory 
x 
Review/update locator information 
x 
Provide reimbursement for study visit 
x 
Schedule next visit/contact 
Behavioral 
x 
Provide counseling  
 
Protocol requirements 
Clinical 
x 
Review/update medical history 
x 
Review/update menstrual history♀ 
x 
Review/update concomitant medications 
x 
Perform targeted physical examination * 
x 
Perform pelvic examination ●♀ 
x 
Perform rectal examination ● 
x 
Provide available test results 
x 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for other findings* 
x 
Record/update AEs 
Laboratory 
 
Urine 
x 
Collect urine 
 
Dipstick UA* 
 
Urine culture* 
 
Urine NAAT for GC/CT* 
Blood 
x 
Collect blood  
 
CBC with differential and platelets* 
 
Chemistries (AST, ALT, Creatinine)* 
 
Syphilis Serology*  
 
PK levels 
Pelvic 
Samples 
x 
Collect pelvic specimens 
 
Cervicovaginal fluid for PK levels ●♀  
 
CVL for PK and PD prior to biopsy collection ●♀ 
 
Cervical tissue for PK levels ●♀ 
Anorectal 
Samples 
x 
Collect rectal specimens 
 
Rectal NAAT for GC/CT* 
 
Anal HSV-1/2 detection* 
 
Rectal fluid for PK levels ● 
 
Rectal enema effluent for PK and PD prior to biopsy collection ● 
 
Rectal tissue for PK levels ●  
 
Rectal tissue for PD ●  
Study Product Supply 
x 
Offer condoms□ 
♀Female participants *If indicated ● Participants will be assigned to provide intensive PK samples at either Visit 4, 5 or 6 □Visit 
6 only 
 


 
 
  
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July 21, 2017 
 
7.6 Visits 7-12: Study Product Administration Visits   
 
After a minimum 14 day washout period, participants will return to the clinic to initiate 
the application of 7 daily doses.    
 
Note: The washout period should be timed to coincide with female participants’ menses. 
 
Table 11: Visits 7-12: Study Product Administration Visits 
Visits 7-12:  Study Product Administration Visits  
Component 
Procedures 
Administrative and 
Regulatory 
 
x 
Review/update locator information 
x 
Provide reimbursement for study visit 
x 
Schedule next visit 
Behavioral  
x 
Provide counseling  
 
Protocol requirements  
 
Product use  
 
HIV pre- and post-test (Required at Visit 7)* 
 
HIV/STI risk reduction (Required at Visit 7)* 
Clinical 
x 
Review/update medical history 
x 
Review/update menstrual history♀ 
x 
Review/update concomitant medications 
x 
Perform targeted physical examination*  
x 
Perform pelvic examination♀* 
x 
Perform rectal examination (Required at Visit 7 & 8)* 
x 
Provide available test results 
x 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for other findings* 
x 
Record/update AEs 
Laboratory 
 
Urine 
x 
Collect urine 
 
Qualitative hCG (Required at Visit 7)♀* 
 
Dipstick UA* 
 
Urine culture* 
 
Urine NAAT for GC/CT* 
Blood 
x 
Collect blood  
 
CBC with differential and platelets* 
 
Chemistries (AST, ALT, Creatinine)* 
 
HIV-1/2 test (Required at Visit 7)* 
 
Plasma for storage (Visit 7 only) 
 
Syphilis serology* 
 
PK levels (Visits 7 & 8 only) 
 
Anorectal 
Samples 
x 
Collect rectal specimens 
 
Rectal NAAT for GC/CT* 
 
Anal HSV 1/2 detection* 
 
Rectal fluid for PK levels (Visits 7 & 8 only) 
Study Product Supply 
x 
Provision of study product  
Note: At Visit 7 one additional pre-filled applicator of study product will be 
dispensed in the event a participant cannot attend one of their seven daily 
dosing visits, See Section 6.2 
x 
Provision of lubricant 
x 
Observe dose application  
♀Female participants *if indicated  
 
 


 
 
  
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7.7 Visit 13: Last Study Product Administration Visit/Early Termination Visit 
 
Table 12:  Visit 13: Last Study Product Administration Visit/Early Termination Visit 
Visit 13: Last Study Product Administration Visit 
Component 
Procedures 
Administrative and 
Regulatory 
 
x 
Review/update locator information 
x 
Provide reimbursement for study visit 
x 
Schedule next visit/contact 
Behavioral  
x 
Behavioral assessment□ 
x 
In-Depth Interview□ 
x 
Provide counseling  
 
Protocol requirements  
 
Product use  
Clinical 
x 
Review/update medical history 
x 
Review/update menstrual history♀ 
x 
Review/update concomitant medications 
x 
Perform targeted physical examination*  
x 
Perform pelvic examination♀ 
x 
Perform rectal examination 
x 
Provide available test results 
x 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for other findings* 
x 
Record/update AEs 
Laboratory 
 
Urine 
x 
Collect urine 
 
Dipstick UA* 
 
Urine culture* 
 
Urine NAAT for GC/CT* 
Blood 
x 
Collect blood  
 
CBC with differential and platelets* 
 
Chemistries (AST, ALT, Creatinine)* 
 
Syphilis Serology*  
 
PK levels ● 
Pelvic 
Samples 
x 
Collect pelvic specimens 
 
Cervicovaginal fluid for PK levels ●♀  
 
CVL for PK and PD prior to biopsy collection for PD ●♀ 
 
Cervical tissue for PK levels ●♀  
Anorectal 
Samples 
x 
Collect rectal specimens 
 
Rectal NAAT for GC/CT* 
 
Anal HSV 1/2 detection* 
 
Rectal enema effluent for PK and PD prior to biopsy collection ● 
 
Rectal fluid for PK levels ● 
 
Rectal fluid for mucosal safety ● 
 
Rectal tissue for PK levels ● 
 
Rectal tissue for PD ● 
 
Rectal tissue for mucosal safety ● 
Study Product Supply 
x 
Provision of study product Ө 
x 
Provision of lubricant Ө 
x 
Observe dose application Ө 
x 
Collect unused study product 
♀Female participants *if indicated ● Participants will be assigned to provide samples at either 30-60 or 120 minutes.  In addition, 
all participants will provide blood for PK at hr 0. Blood collection times are matched to fluid/tissue sample collection times. 
□Required at Early Termination only Ө Omit at Early Termination  
Note: If Visit 13 is serving as the Early Termination Visit- PK and PD sample collection will be at the discretion of the MTN-026 
Management Team. 
 


 
 
  
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7.8 Visits 14-16: PK Visits (~24, 48, 72 Hours After Last Application of Study 
Product) 
 
All participants attend Visits 14, 15, 16.  Participants only provide intensive PK samples 
at Visit 14, 15 or 16.   
 
Table 13:  Visits 14-16: PK Visits (~24, 48, 72 Hours After Last Application of Study Product) 
Visits 14-16:  PK Visits  (~24, 48, 72 Hours After Last Application of Study Product) 
Component 
Procedures 
Administrative and 
Regulatory 
 
x 
Review/update locator information 
x 
Provide reimbursement for study visit 
x 
Schedule next visit/contact 
Behavioral  
x 
Behavioral assessment∞ 
x 
IDI∞  
x 
Provide counseling  
 
HIV pre- and post-test (Required at Visit 16)* 
 
HIV/STI risk reduction (Required at Visit 16)* 
 
Protocol requirements 
Clinical 
x 
Review/update medical history 
x 
Review/update menstrual history♀ 
x 
Review/update concomitant medications 
x 
Perform targeted physical examination*  
x 
Perform pelvic examination●♀ 
x 
Perform rectal examination● 
x 
Provide available test results 
x 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for other findings* 
x 
Record/update AEs 
Laboratory 
 
Urine 
x 
Collect urine 
 
Qualitative hCG ♀∞ 
 
Dipstick UA* 
 
Urine culture* 
 
Urine NAAT for GC/CT* 
Blood 
x 
Collect blood  
 
PK levels 
 
CBC with differential and platelets* 
 
Chemistries (AST, ALT, Creatinine) (Required at Visit 16)* 
 
HIV-1/2 test (Required at Visit 16)* 
 
Syphilis serology* 
 
Plasma for archive/storage (Visit 16 only) 
Pelvic 
Samples 
x 
Collect pelvic specimens 
 
Cervicovaginal fluid for PK levels●♀ 
 
Cervical tissue for PK levels●♀ 
 
CVL for PK and PD prior to biopsy collection●♀ 
Anorectal 
Samples 
x 
Collect rectal specimens 
 
Anal HSV 1/2 detection* 
 
Rectal NAAT for GC/CT* 
 
Rectal enema effluent for PK and PD prior to biopsy collection ● 
 
Rectal fluid for PK levels●   
 
Rectal tissue for PD●  
 
Rectal tissue for PK levels●  
♀Female participants *if indicated ● Participants will be assigned to provide intensive PK samples at either Visit 14, 15 or 16 
∞Visit 14 only 
 


 
 
  
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7.9 Visit 17:  Follow-Up Safety Contact and Termination Visit 
 
Approximately one week following Visit 16, study staff will contact participants (clinic 
visit or via phone) to inquire about AEs that they might have experienced as a result of 
the study product or procedures performed. This contact will also serve as the 
participant’s study termination.   
 
Table 14: Visit 17: Follow-up Safety Contact and Termination Visit 
Visit 17: Follow-up Safety Contact/Termination Visit 
Component 
Procedures 
Administrative and 
Regulatory 
x 
Review/update locator information 
x 
Provide reimbursement (if required)~ 
x 
Schedule next visit/contact* 
Clinical 
x 
Record/update AEs  
x 
Provide available test results 
x 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for other findings* 
* if indicated;  ~ Sites to reference SOPs regarding participant reimbursement 
 
7.10 Follow-up Procedures for Participants Who Permanently Discontinue Study 
Product 
 
7.10.1 
Participants Who Become Infected with HIV-1 
 
If a participant tests positive for HIV-1 after the Enrollment Visit, they will be referred to 
local care and treatment services and may return to the research clinic for additional 
counseling and other support services, as needed. Continued study participation would 
be of no added benefit, thus follow-up visits will be discontinued and the participant will 
be considered terminated from the study.  An Early Termination Visit will occur. 
Participants who seroconvert after randomization may be offered additional laboratory 
testing (such as HIV RNA and HIV drug resistance testing), as clinically indicated per 
discussions between IoR and LC.  Please reference the MTN-026 SSP Manual for 
additional details (www.mtnstopshiv.org). 
 
7.10.2 
Participants Who Become Pregnant 
 
If a participant becomes pregnant, she will be referred to local health care services and 
may return to the research clinic for additional counseling, as needed. Continued study 
participation would be of no added benefit to the participant, thus follow-up visits and 
procedures will be discontinued and the participant will be considered terminated from 
the study.  An Early Termination Visit will occur. A participant who is pregnant at study 
termination will continue to be followed until the pregnancy outcome is ascertained, see 
Section 9.5 for additional details. 
 
Participants who become pregnant while on study product may be offered enrollment in 
MTN-016 (www.mtnstopshiv.org), provided their study site is taking part in MTN-016. 
 
For additional details regarding obtaining pregnancy outcome, please reference the 
MTN-026 SSP Manual (www.mtnstopshiv.org).   
 


 
 
  
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7.10.3 
Participants Who Permanently Discontinue Study Product for Other 
Reasons 
 
Participants who permanently discontinue study product use for any reason (clinician-
initiated or self-initiated) will be considered terminated from the study.  Continued study 
participation would be of no added benefit. An Early Termination Visit will occur. 
Participants who permanently discontinue study product use due to an AE must 
continue to be followed off-study until resolution or stabilization of the AE is 
documented.   
 
7.11 Interim Visits 
 
Interim visits may be performed at any time during the study and any procedures may 
be conducted. All interim contacts and visits will be documented in participants' study 
records and on applicable CRFs.  
 
7.12 Study Product Use / Adherence Counseling 
 
Study staff will document administration of study product.  Product adherence 
counseling will be provided to study participants upon enrollment into the study.  
Counseling will be provided in accordance with standard study methods.  Participants 
will be counseled to return to the clinic daily during the product use periods for directly 
observed gel administration.   Strategies to ensure the availability and use of the study 
product when participants are not able to present to the clinic for direct observation will 
be provided.  Counseling also will include reminders to contact study staff with 
questions about study product use. 
   
 
For participants who have adherence problems and/or issues presenting to the clinic for 
the administration of study product, every effort will be made to identify adherence 
strategies to increase their rates of study product use and attendance to daily clinic 
visits throughout the course of the study. 
 
7.13 Clinical Evaluations and Procedures 
 
Physical Examination 
The physical examination will include the following assessments:  
 
x General appearance 
x Weight*  
x Vital signs 
 Temperature 
 Pulse  
 Blood pressure 
 Respirations 
x Height* 
x Abdomen*  


 
 
  
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x Head, Eye, Ear, Nose and Throat (HEENT) Examination* 
x Oral mucosa* 
x Lymph nodes*  
x Neck*  
x Heart* 
x Lungs*  
x Extremities* 
x Skin*  
x Neurological* 
x Other components as indicated by participant symptoms 
 
*may be omitted after the Screening Visit 
 
Pelvic Examination 
The pelvic examination may include the following:  
x Visual exam 
x Speculum exam 
x Bimanual exam 
 
Anorectal Examination 
The anorectal examination may include the following:  
x Visual exam 
x Digital exam 
x Anoscopy  
x Flexible sigmoidoscopy  
 
Detailed information regarding the pelvic and rectal examinations, as well as the 
associated procedures required for collecting cervical/vaginal/rectal specimens at each 
visit can be found in the MTN-026 SSP Manual.  
 
Mucosal Safety 
Mucosal safety will be assessed by visual appearances of the rectal mucosa at the time 
of both anoscopy and flexible sigmoidoscopy, and quantified with reference to the 
DAIDS toxicity tables. Safety assessment procedures are consistent with RMP02/MTN-
006, MTN-007 and MTN-017. 
 
Additional clinical assessments may be performed at the discretion of the examining 
clinician in response to symptoms or illnesses present at the time of the exam.  
 
7.14 Behavioral Assessments 
 
Participants will respond to brief computer administered self-interviews (CASI) at the 
Enrollment visit (Visit 2), after the single dose (Visit 3) and a follow-up assessment will 
occur after the 7 daily doses are applied (Visit 14). The baseline assessment, done at 
enrollment, will include, among other topics, questions on participants’ prior experience 
and comfort using rectal products as well as douching or other rectal hygiene practices. 


 
 
  
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The follow-up assessments will explore reactions to product, applicator, and 
administration method. These assessments will allow us to identify product attributes 
likely to challenge and facilitate future sustained use of dapivirine gel when applied 
rectally by participants (secondary objective: acceptability).  Suggestions for product 
improvement will also be collected. Survey assessments have been used in prior rectal 
microbicide trials (e.g., MTN-006, MTN-007, MTN-017, Project Gel).30-32 Using validated 
measures allows us to compare and contrast findings across these trials.  
  
An in-depth interview is planned after the application of a single dose (Visit 3) and 
following the application of 7 daily doses (Visit 14). The in-depth interviews will include, 
among other topics, questions on user acceptability of the product, user-centered 
suggestions for product design and delivery, and experiences with the direct 
observation administration method.33  These interviews will be triangulated with the 
behavioral data to understand participants’ experiences in greater depth. 
 
7.15 Pharmacokinetics, Pharmacodynamics and Mucosal Safety  
 
Table 15: PK, PD, and Mucosal Safety Sampling Table 
Visit 
Specimens Collected to Assess 
Drug Concentrations (PK) 
Specimens Collected for  
Anti-HIV Activity (PD) 
Specimens Collected for 
Mucosal Safety 
Visit 2:   
Enrollment 
(Baseline Samples)  
 
x 
CVL 
x 
Rectal tissue 
x 
Rectal enema effluent prior to 
biopsy collection 
x Rectal fluid  
x Rectal tissue 
 
Visit 3:  
SINGLE Dosing Visit 
x Blood (Hours: 0 min., 30-60 or 120 
minutes matched to fluid/tissue 
sample collection)  
x Rectal fluid (30-60 or 120 minutes) 
x Rectal tissue (30-60 or 120 
minutes) 
x 
Rectal tissue (30-60 or 120 
minutes) 
x Rectal fluid (30-60 or 120 
minutes) 
x Rectal tissue (30-60 or 120 
minutes) 
Visits 4, 5 and 6 
x Blood collected at each visit 
x Cervicovaginal fluid♀* 
x CVL prior to biopsy collection♀* 
x Cervical tissue♀*  
x Rectal fluid* 
x Rectal enema effluent prior to 
biopsy collection* 
x Rectal tissue*  
x 
CVL prior to biopsy 
collection♀* 
x 
Rectal tissue* 
x 
Rectal enema effluent prior to 
biopsy collection* 
 
Visit 7 
Initial Dosing Visit 
x Blood (0 hour) 
x Rectal fluid (0 hour)  
 
 
Visit 8 (~24 hours 
after the initial 
application of product) 
x Blood (24 hour) 
x Rectal fluid (24 hour) 
 
 
Visit 13 (Final Dose) 
x Blood (Hours: 0 minutes and 30-60 
or 120 minutes, matched to 
fluid/tissue sample collection)  
x Rectal fluid (30-60 or 120 minutes) 
x Rectal tissue (30-60 or 120 
minutes) 
x Rectal enema effluent prior to 
biopsy collection 
x Cervicovaginal fluid ♀  
x CVL prior to biopsy collection♀ 
x Cervical tissue♀  
x 
Rectal tissue (30-60 or 120 
minutes) 
x 
CVL prior to biopsy 
collection♀ 
x 
Rectal enema effluent prior to 
biopsy collection 
x Rectal fluid (30-60 or 120 
minutes) 
x Rectal tissue (30-60 or 120 
minutes) 


 
 
  
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Visit 
Specimens Collected to Assess 
Drug Concentrations (PK) 
Specimens Collected for  
Anti-HIV Activity (PD) 
Specimens Collected for 
Mucosal Safety 
Visits 14, 15, 16 
x Blood collected at each visit 
x Cervicovaginal fluid♀* 
x CVL prior to biopsy collection♀* 
x Cervical tissue♀*  
x Rectal fluid* 
x Rectal enema effluent prior to 
biopsy collection 
x Rectal tissue*  
x 
CVL prior to biopsy 
collection♀* 
x 
Rectal tissue* 
x 
Rectal enema effluent prior to 
biopsy collection  
 
♀Females only *Participants will be assigned to provide intensive PK samples at either 24, 48, or 72 hrs after the final administered 
dose 
 
7.16 Laboratory Evaluations 
 
Local Laboratory 
The local laboratory will run the following, as indicated: 
 
x Urine specimens 
 Urine GC/CT by NAAT 
 Qualitative hCG 
 Urine dipstick/culture 
 
x Anorectal specimens 
o Rectal fluids for:  
 Rectal GC/CT by NAAT 
 HSV 1/2 detection  
o Rectal tissue for: 
 PD  
 
x Pelvic specimens 
 HSV 1/2 detection 
 
x Blood specimens 
 HIV-1/2 serology, with confirmatory testing as needed 
 CBC with differential and platelets  
 Syphilis serology 
 Creatinine, AST, ALT 
 Hepatitis B surface antigen 
 HCV serology 
 HSV 1/2 serology  
 Coagulation (PT/INR) 
 
x Cervicovaginal specimens 
 Vaginal GC/CT by NAAT  
 


 
 
  
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Laboratory Center (LC) 
x Blood specimens 
 PK (Pharmacology Core) 
 Plasma archive/storage 
 
x Rectal specimens  
o Rectal fluids and/or lavage for:  
 PK (Pharmacology Core) 
 PD (Protocol Support Core) 
 Mucosal safety  
o Rectal tissue for: 
 PK (Pharmacology Core) 
 Mucosal safety 
 
x Cervicovaginal specimens  
o Cervicovaginal fluid and/or lavage for:  
 PK (Pharmacology Core) 
o Cervical tissue for: 
 PK (Pharmacology Core) 
o Cervicovaginal lavage for: 
 PD (Protocol Support Core) 
 
7.17 Specimen Collection and Processing 
 
The study site will adhere to the standards of good clinical laboratory practice 
(https://www.niaid.nih.gov/sites/default/files/gclp.pdf) in accordance with current DAIDS 
Laboratory Requirements and the MTN-026 SSP Manual (www.mtnstopshiv.org) for 
proper collection, processing, labeling, transport, and storage of specimens at the local 
laboratory. Specimen collection, testing, and storage at the site laboratories will be 
documented when applicable using the Laboratory Data Management System (LDMS). 
In cases where laboratory results are not available due to administrative or laboratory 
error, the site is permitted to re-draw specimens. Further, as part of quality control, 
researchers may need to look at short pieces of non-coding repetitive DNA sequence 
(3-7 base pairs) from blood in the event of sample mix-up.  This test will only let 
researchers know the number of times this short segment is repeated and not specific 
genes or specific sequences of base pairs.  This sequence element does not contain 
any information about genes, therefore researchers will not be able to identify if 
participants are predisposed to specific diseases or any other genetic information based 
on this information.  This test will be an important tool for distinguishing whether two 
samples collected at the same or different time points are likely from the same 
person.  The test will only be used as part of a sample investigation with the knowledge 
of the site in situations where a known or suspected sample mix-up has occurred.  No 
genetic testing (limited or genome-wide) is planned on leftover samples that are stored 
for the purposes of future research. 
 


 
 
  
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7.18 Specimen Handling 
 
Specimens will be handled in accordance with current requirements for DAIDS 
Sponsored and/or Funded Laboratories in Clinical Trials.  
(https://www.niaid.nih.gov/research/daids-clinical-research-policies-us-labs) 
 
7.19 Biohazard Containment 
 
As the acquisition 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 recommended by the CDC and National 
Institutes of Health (NIH). All biological specimens will be transported using packaging 
mandated by Code of Federal Regulations (CFR) 42 Part 72. All dangerous goods 
materials, including diagnostic specimens and infectious substances, must be 
transported according to instructions detailed in the International Air Transport 
Association (IATA) Dangerous Goods Regulations. Biohazardous waste will be 
contained according to institutional, transportation/carrier, and all other applicable 
regulations. 
 
 
8 
ASSESSMENT OF SAFETY 
 
8.1 Safety Monitoring 
 
The site IoR is responsible for continuous close safety monitoring of all study 
participants and for alerting the Protocol Team if unexpected concerns arise. A sub-
group of the Protocol Team, including the Protocol Chair, DAIDS Medical Officer, and 
Protocol Safety Physicians will serve as the PSRT. The MTN Statistical Data 
Management Center (SDMC) prepares routine AE and clinical data reports (blinded to 
treatment assignment) for review by the PSRT, which meets via conference call 
approximately once per month or as needed throughout the period of study 
implementation to review safety data, discuss product use management, and address 
any potential safety concerns.  
 
8.2 Clinical Data and Safety Review 
 
A multi-tiered safety review process will be followed for the duration of this study. The 
study site investigators are responsible for the initial evaluation and reporting of safety 
information at the participant level and for alerting the PSRT if unexpected concerns 
arise. Participant safety is also monitored at the Network level through a series of 
routine reviews conducted by the SDMC, the PSRT and study sponsors. Additional 
reviews may be conducted at each of these levels as dictated by the occurrence of 
certain events.  
 


 
 
  
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MTN SDMC staff will review incoming safety data on an ongoing basis. Events identified 
as questionable, inconsistent, or unexplained will be queried for verification. Adverse 
event reports submitted in an expedited manner to the DAIDS Safety Office will be 
forwarded to the DAIDS Medical Officer and SDMC staff for review. 
 
The PSRT will meet approximately every month via conference call to review clinical 
data reports generated by the MTN SDMC. The content, format and frequency of the 
clinical data reports will be agreed upon by the PSRT and the SDMC in advance of 
study implementation. In addition to the routine safety data reviews, the PSRT will 
convene on an ad hoc basis to make decisions regarding the handling of any significant 
safety concerns. If necessary, experts external to the MTN representing expertise in the 
fields of microbicides, biostatistics, HIV acquisition and medical ethics may be invited to 
join the PSRT safety review. A recommendation to pause or stop the trial may be made 
by the PSRT at this time or at any such time that the team agrees that an unacceptable 
type and/or frequency of AEs has been observed. 
 
The Study Monitoring Committee (SMC) will review participant safety data as part of 
their regular reviews (see Section 10.8.1), since no Data and Safety Monitoring Board 
oversight is planned for MTN-026. The SMC may recommend that the study proceed as 
designed, proceed with design modifications, or be discontinued. Members of the SMC 
will be independent investigators with no interest (financial or otherwise) in the 
outcomes of this study. If at any time a decision is made to discontinue enrollment 
and/or study product use in all participants, DAIDS will notify the FDA and the Site IoR 
will notify the responsible IRB/EC expeditiously. 
 
In addition to the safety monitoring, the MTN SMC will conduct interim reviews of study 
progress, including rates of participant accrual, retention, completion of primary and 
main secondary endpoint assessments, and study or lab issues.  The SMC will meet 
approximately once during study implementation, but not less than once a year.    
These reviews will take place as needed. At the time of these reviews, or at any other 
time, the SMC may recommend that the study proceed as designed, proceed with 
design modifications, or be discontinued. 
 
8.3 Adverse Events Definitions and Reporting Requirements 
 
8.3.1 
Adverse Events 
 
An AE is defined as any untoward medical occurrence in a clinical research participant 
administered an investigational product and which does not necessarily have a causal 
relationship with the investigational product. As such, an AE can be an unfavorable or 
unintended sign (including an abnormal laboratory finding, for example), symptom or 
disease temporally associated with the use of an investigational product, whether or not 
considered related to the product. This definition is applied to all study groups, and is 
applied to all groups beginning at the time of enrollment (i.e., once a participant is 
randomized). The term “investigational product” for this study refers to all study 
products. 
 


 
 
  
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Study participants will be provided instructions for contacting the study site to report any 
untoward medical occurrences they may experience. In cases of potentially life-
threatening events, participants will be instructed to seek immediate emergency care. 
Where feasible and medically appropriate, participants will be encouraged to seek 
evaluation where a study clinician is based, and to request that the clinician be 
contacted upon their arrival. With appropriate permission of the participant, whenever 
possible, records from all non-study medical providers related to untoward medical 
occurrences will be obtained and required data elements will be recorded on study 
CRFs. Given the differences in appearance and viscosity between the two study 
products, study staff who apply a participant’s gel are not to be the same clinic staff who 
assess his/her safety.  All participants reporting an untoward medical occurrence will be 
followed clinically until the occurrence resolves (returns to baseline) or stabilizes. 
 
Study site staff will document in source documents and the appropriate AE Log CRF all 
AEs reported by or observed in enrolled study participants regardless of severity and 
presumed relationship to study product. AE severity will be graded per the DAIDS Table 
for Grading Adult and Pediatric Adverse Events, Version 2. 1, July 2017 and/or 
Addenda 1, 2 and 3 (Female Genital [Dated November 2007], Male Genital [Dated 
November 2007] and Rectal [Clarification dated May 2012] Grading Tables for Use in 
Microbicide Studies). Please note that asymptomatic BV and asymptomatic candidiasis 
will not be reportable AEs. In addition, fetal losses (e.g., spontaneous abortions, 
spontaneous fetal deaths, stillbirths) will not be reported as AEs. However, untoward 
maternal conditions that either result in or result from fetal losses are reported as 
reproductive system AEs.  Further, changes in genital bleeding judged to be related to a 
woman's contraceptive use or return of menstruation postpartum will not be considered 
an AE, nor will a pelvic exam be required for follow-up.  
 
Bleeding 
at 
the 
time 
of 
speculum, 
anoscope, 
or 
flexible 
sigmoidoscope 
insertion/removal and/or biopsy collection that is judged by the clinician to be within the 
range of normally anticipated will not be reportable as an AE. Bleeding of greater 
quantity or longer duration than typical will still be reported. Fecal urgency, bloating and 
flatulence associated with rectal procedures deemed to be within the range of normally 
expected will also not be reportable as AEs. 
 
In cases where a genital or anorectal AE is covered in multiple tables, the Rectal 
Grading Table for Use in Microbicide Studies (Addendum 3 clarification dated May 
2012) will take first priority followed by the Female or Male Genital Grading Tables 
(Addendum 1 [dated November 2007] and Addendum 2 [dated November 2007], 
respectively).   
 


 
 
  
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8.3.2 
Serious Adverse Events 
 
An SAE will be defined by the Manual for Expedited Reporting of Adverse Events to 
DAIDS (Version 2.0, January 2010), as an AE that:  
 
x Results in death 
x Is life-threatening  
x Results in persistent or significant disability/incapacity  
x Is a congenital anomaly/birth defect 
x Requires inpatient hospitalization or prolongation of existing hospitalization 
Note: Per ICH SAE definition, hospitalization itself is not an AE, but is an 
outcome of the event. Thus, hospitalization in the absence of an AE is not 
regarded as an AE, and is not subject to expedited reporting. The following are 
examples of hospitalization that are not considered to be AEs: 
o Protocol-specified admission (e.g., for procedure required by study 
protocol) 
o Admission for treatment of target disease of the study, or for pre-existing 
condition (unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator) 
o Diagnostic admission (e.g., for a work-up of an existing condition such as 
persistent pretreatment lab abnormality) 
o Administrative admission (e.g., for annual physical) 
o Social admission (e.g., placement for lack of place to sleep) 
o Elective admission (e.g., for elective surgery) 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed above.  
 
8.3.3 
Adverse Event Relationship to Study Product 
 
Relatedness is an assessment made by a study clinician of whether or not the event is 
related to the study agent. Degrees of relatedness will be categorized according to 
current DAIDS-approved guidelines. Per the Manual for Expedited Reporting of Adverse 
Events to DAIDS (Version 2.0, January 2010), the relationship categories that will be 
used for this study are: 
 
x Related: There is a reasonable possibility that the AE may be related to the study 
agent(s) 
x Not Related: There is not a reasonable possibility that the AE is related to the 
study agent(s) 
 


 
 
  
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8.4 Adverse Event Reporting Requirements 
 
8.4.1 
Expedited Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse Events (AEs) 
are outlined in Version 2.0 of the DAIDS Expedited Adverse Event (EAE) Manual, which 
is available on the Regulatory Support Center (RSC) website at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/manual.  
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for expedited AE reporting to DAIDS. In the event of 
system outages or technical difficulties, expedited AEs may be submitted via the DAIDS 
EAE 
Form. 
For 
questions 
about 
DAERS, please 
contact 
DAIDS-ES 
at 
CRMSSupport@niaid.nih.gov. Site queries may also be sent from within the DAERS 
application 
itself. 
 
Where DAERS has not been implemented, sites will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form. This form is available on 
the 
RSC 
website, 
http://rsc.tech-res.com/clinical-research-sites/safety-
reporting/daids/paper-eae-reporting. For questions about EAE reporting, please contact 
the RSC (DAIDSRSCSafetyOffice@tech-res.com) or call 1-800-537-9979 or 301-897-
1709; or fax 1-800-275-7619 or 301-897-1710. 
 
8.4.2 
    Reporting Requirements for this Study        
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will 
be used for this study.  The study agents for which expedited reporting are required are: 
0.05% 
dapivirine 
gel, 
Universal 
Placebo 
gel 
and 
the 
applicator.           
                     
8.4.3 
Grading Severity of Events 
 
The grading of severity of events and the reporting period will be the same as for all 
AEs, as described in Section 8.3.1. The most current Division of AIDS Table for Grading 
Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017and Addenda 1, 2 
and 3 (Female Genital [Dated November 2007], Male Genital [Dated November 2007] 
and Rectal [Clarification dated May 2012] Grading Tables for Use in Microbicide 
Studies), will be used and are available on the RSC website at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables.  
 
8.4.4 
  Expedited AE Reporting Period 
 
The expedited AE reporting period for this study begins at enrollment (i.e., 
randomization) and continues through the participant’s termination from the study. 
 
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 


 
 
  
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Manual will be reported to DAIDS if the study staff become aware of the events on a 
passive basis (from publicly available information). 
 
8.5 
Pregnancy and Pregnancy Outcomes 
 
Pregnant women are excluded from this study. 
 
A participant who is pregnant at study termination will continue to be followed until the 
pregnancy outcome is ascertained, see Section 9.5 for additional details. Pregnancy 
outcomes will not be expeditiously reported to the DAIDS Medical Officer (MO) unless 
there is an associated AE in the pregnant participant that meets expedited reporting 
criteria or the pregnancy results in a congenital anomaly meeting the Manual for 
Expedited Reporting of EAEs to DAIDS (Version 2.0, January 2010) guidelines for 
expedited reporting.  
 
8.6 Regulatory Requirements 
 
Information on all reported AEs will be included in reports to the FDA and other 
applicable government and regulatory authorities. Site IoRs/designees will submit AE 
and any relevant safety information in accordance with local regulatory requirements. 
 
8.7 Social Harms Reporting 
 
Although study sites make every effort to protect participant privacy and confidentiality, 
it is possible that participants’ involvement in the study could become known to others 
and that social harms may result. Social harms that are judged by the IoR/designee to 
be serious or unexpected will be reported to the PSRT and responsible site IRBs/ECs 
according to their individual requirements. 
 
 
9 
CLINICAL MANAGEMENT 
 
Guidelines for clinical management and permanent discontinuation of study product are 
outlined in this section. In general, the IoR/designee has the discretion to permanently 
discontinue study product use at any time if s/he feels that continued product use would 
be harmful to the participant or interfere with treatment deemed clinically necessary. 
The IoR/designee will document all permanent discontinuations on applicable CRFs. 
 
9.1 Grading System 
 
AE severity grading is described in Section 8.4.3. 
 


 
 
  
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9.2 Dose Modification Instructions 
 
No dose modifications will be undertaken in this study. 
 
9.3 General Criteria for Permanent Discontinuation of Study Product 
 
Permanent Discontinuation 
A participant will be permanently discontinued from product use by the IoR/designee for 
any of the following reasons: 
x Reported use of the following prohibited medications:  
o Heparin 
o Lovenox® 
o Warfarin 
o Plavix® (clopidogrel bisulfate) 
o Hormone-replacement therapy in tablet, injectable or gel form  
x Acquisition of HIV infection; for those who acquire HIV study product should be 
held beginning immediately upon recognition of the first reactive rapid HIV test  
x Pregnancy  
x Breastfeeding  
x Anorectal STIs 
x Participant is unable or unwilling to comply with required study procedures, or 
otherwise might be put at undue risk to their safety and well-being by continuing 
product use, according to the judgment of the IoR/designee. 
 
9.4 Follow-up in Response to Observed Adverse Events 
 
Grade 1 or 2  
In general, a participant who develops a Grade 1 or 2 AE as defined by the Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected 
Version 2.1, July 2017 or Addenda 1, 2 and 3 (Female Genital [Dated November 2007], 
Male Genital [Dated November 2007] and Rectal [Clarification Dated May 2012] 
Grading Tables for Use in Microbicide Studies), regardless of relationship to study 
product may continue product use. If the IoR/designee opts to discontinue study 
product, the PSRT must be notified. 
 
 
Grade 3 Unrelated 
For participants who develop a Grade 3 AE as defined by the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 
2017 or Addenda 1, 2 and 3 (Female Genital [Dated November 2007], Male Genital 
[Dated November 2007] and Rectal [Clarification Dated May 2012] Grading Tables for 
Use in Microbicide Studies), determined to be unrelated to study product, the IoR must 
consult with PSRT regarding continued study product use.   Pending a response from 
the PSRT, study product use may continue.  
 


 
 
  
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Grade 3 Related or Grade 4 
For participants who develop a Grade 3 related or any Grade 4 AE as defined by the 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected Version 2.1, July 2017 or Addenda 1, 2 and 3 (Female Genital [Dated 
November 2007], Male Genital [Dated November 2007] and Rectal [Clarification Dated 
May 2012] Grading Tables for Use in Microbicide Studies), regardless of relationship to 
study product, study product must be permanently discontinued. 
 
9.5 Pregnancy 
 
For female participants, pregnancy testing will be performed at scheduled study visits 
and participants will be encouraged to report all signs or symptoms of pregnancy to 
study staff. The IoR/designee will counsel any participant who becomes pregnant 
regarding possible risks to the fetus according to site SOPs. The IoR/designee also will 
refer the participant to all applicable services; however, sites will not be responsible for 
paying for pregnancy-related care.  
 
A documented negative pregnancy test performed by study staff is required for 
inclusion; however, a self-reported pregnancy is adequate for exclusion from 
screening/enrollment into the study. A participant who is pregnant at study termination 
will continue to be followed until the pregnancy outcome is ascertained (or, in 
consultation with the PSRT, it is determined that the pregnancy outcome cannot be 
ascertained). Pregnancy outcomes will be reported on relevant CRFs; outcomes 
meeting criteria for EAE reporting also will be reported on EAE forms. Participants who 
become pregnant may take part in observational studies, including pregnancy registries. 
 
A participant who becomes pregnant during the course of the study will have study 
product discontinued and will be terminated from the study, as per Section 7.10.2, and 
may be offered enrollment in MTN-016 (www.mtnstopshiv.org), provided their study site 
is taking part in MTN-016.  
 
9.6 Criteria for Early Termination of Study Participation 
 
Participants may voluntarily withdraw from the study for any reason at any time. The 
IoR/designee also may withdraw participants from the study to protect their safety 
and/or if they are unwilling or unable to comply with required study procedures, after 
consultation with the PSRT. Participants also may be withdrawn if NIAID, MTN, 
government or regulatory authorities, including the FDA and Office for Human Research 
Protections (OHRP), or site IRBs/ECs terminate the study prior to its planned end date. 
Every reasonable effort is made to complete a final evaluation of participants who 
withdraw or are withdrawn from the study prior to completing follow-up (see Section 
7.10.3 for details regarding the Early Termination Visit). Study staff members will record 
the reason(s) for all withdrawals in participants’ study records.  
 
 


 
 
  
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10 
STATISTICAL CONSIDERATIONS 
 
10.1 Overview and Summary of Design 
 
MTN-026 is a Phase I, multi-site, double-blind, two arm, randomized trial (2:1) that 
assesses the PK of 0.05% dapivirine gel exposure when applied once and then used 
daily for 7 days by healthy, HIV-uninfected, men and women under direct observation in 
the clinic. Approximately 27 individuals will be randomized. 
 
10.2 Study Endpoints 
 
Primary Endpoints 
Consistent with the primary study objectives to (1) evaluate the safety of dapivirine gel 
formulation when applied rectally and (2) characterize the systemic and compartmental 
pharmacokinetics of dapivirine gel following rectal application, the following endpoints 
will be assessed: 
 
x Safety 
Grade 2 or higher AEs as defined by the Division of AIDS Table for Grading 
the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, 
July 2017 and/or Addenda 1, 2 and 3 (Female Genital [Dated November 
2007], Male Genital [Dated November 2007] and Rectal [Clarification Dated 
May 2012] Grading Tables for Use in Microbicide Studies) 
 
x Pharmacokinetics 
Dapivirine concentrations 
o Plasma  
o Rectal fluid 
o Rectal mucosal tissue homogenates 
 
10.3 Primary Study Hypotheses 
 
MTN-026 hypothesizes that the gel containing dapivirine will be as safe and as well-
tolerated as the gel containing placebo. 
 
10.4 Sample Size and Power Calculations 
 
10.4.1 Safety Endpoints 
 
The proposed total sample size for assessing safety in the randomized portion of the 
study is approximately N=27 participants randomized into 2 arms in a 2:1 
(active:control) ratio, giving 18 participants in the active arm and 9 participants in the 
control arm.  This sample size is based upon the size of similar Phase 1 studies of 
microbicides for HIV prevention. 
 


 
 
  
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As a means to characterize the statistical properties of this study, the table below 
presents the probability of observing zero, at least one, and two or more safety 
endpoints among the 18 participants in the active arm for various “true” event rates: 
 
Table 16: Analysis of Safety Event Frequency 
An alternative way of describing the statistical properties of the study design is in terms 
of the 95% confidence interval for the true rate based on the observed data.  The table 
below shows the exact 2-sided 95% confidence intervals for the probability of an event 
based on a particular observed rate.  If none of the 27 participants receiving a treatment 
regimen experience a safety event, the 95% exact 2-sided upper confidence bound for 
the true rate of such events in a particular arm of the study is 18.5%.  
 
Table 17: Exact 2-sided 95% Confidence Intervals Based on Observing a Particular Rate of Safety 
Endpoints for Arms of Size 18 
Observed event rate 
Confidence interval (%) 
0/18 
0.0, 18.5 
1/18 
0.1, 27.3 
2/18 
1.4, 34.7 
3/18 
3.6, 41.4 
 
An additional aim of the study is to compare the safety between the active and placebo 
products.  Assuming a two-sided test with α=0.05 or α=0.10 and 80% power, the table 
below provides the difference in the rates of safety events (proportion of participants 
experiencing the safety event of interest) between the active and placebo arms that is 
detectable with 80% power for a given rate in the placebo arm.  For example, if the true 
rate of a given toxicity endpoint in the placebo gel arm is 11.1% (1 of 9 participants 
experiencing a safety event), the proposed sample size provides 85% power to exclude 
safety endpoint rates greater than 67% (61% with α=0.10) which translates to at least 
12 of 18 participants in the active arm.  Hence, while comparisons will be made 
between the drug containing VR arm of the study and the placebo VR arm, the study 
will only have power to detect very large differences in safety event rates. 
 
Table 18: Difference in the Rates of Safety Events 
 
 
 
 
Event Rate 
P (0 events | n=18) 
P (>1 event | n=18) 
P (>2 events | n=18) 
1% 
83.5 
16.5 
1.4 
5% 
39.7 
60.3 
22.6 
10% 
15.0 
85.0 
55.0 
15% 
5.4 
94.6 
77.6 
25% 
0.6 
99.4 
96.1 
35% 
0.0 
100.0 
100.0 
Rate in Placebo Gel Arm 
Rate in a Drug Containing Gel Arm Detectable with at least 80% 
Power 
 
α=0.05 
α=0.10 
11.1% (1 of 9) 
67% (12 of 18) 
61% (11 of 18) 
22.2% (2 of 9) 
78% (14 of 18) 
72% (13 of 18) 


 
 
  
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10.5 Participant Accrual, Follow-up and Retention 
 
Based on previous studies of rectal products with similar eligibility requirements, the 
accrual of approximately 27 eligible participants will take approximately 6-8 months. 
Individuals lost to follow-up or to permanent product discontinuation may be replaced 
after statistical and team input have been received. However, every effort will be made 
to complete their regularly scheduled safety evaluations. The site will target retention of 
95% of enrolled participants over the follow-up period.  
 
10.6 Randomization 
 
Participants will be randomized in a 2:1 ratio to the two arms of the study stratified by 
study site.  The randomization scheme will be generated and maintained by the MTN 
SDMC. 
 
10.7 Blinding 
 
Study staff and participants will be blinded to the random treatment assignment of all 
study participants. The study products will be packaged in individual identical wrappers.  
Blinding will be maintained until all data are entered into the study database, all study 
endpoint data and other data included in the final analysis have been cleaned and 
verified, and the data are ready for final analysis.  This will be explained to participants 
as part of the study.  See Section 8.3.1 for additional information. 
 
There are no circumstances under which it is expected that unblinding will be necessary 
for the provision of medical treatment or to otherwise protect the safety of study 
participants. As described in Section 7.10.3, study product use may be discontinued for 
any reason by the Investigator or the participant. Knowledge of the specific product to 
which the participant was assigned should not be necessary to guide further follow-up 
and/or treatment. If an Investigator feels that specific product knowledge is necessary to 
protect participant safety, the Investigator will notify the PSRT to review and approve 
the request.  
 
10.8 Data and Safety Monitoring and Analysis 
 
10.8.1 Study Monitoring Committee  
 
No Data and Safety Monitoring Board oversight is planned for this study. The MTN SMC 
will conduct interim reviews of study progress, including rates of participant accrual, 
retention, completion of primary and main secondary endpoint assessments, study or 
lab issues, and, in a closed report, safety data by arm of the study. These reviews will 
take place approximately once during study implementation, but not less than once a 
year.  Reviews may also be conducted on an as needed basis. At the time of this 
review, or at any other time, the SMC may recommend that the study proceed as 
designed, proceed with design modifications, or be discontinued. 


 
 
  
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10.8.2 Primary Analysis 
When the use of descriptive statistics to assess group characteristics or differences is 
required, the following methods will be used: for categorical variables, the number and 
percent in each category; for continuous variables, the mean, median, standard 
deviation, quartiles and range (minimum, maximum). Within-treatment group 
assessment of the change from the baseline measurement to a follow-up measurement 
will be analyzed using McNemar’s test (for categorical response variables) or the paired 
t-test or Wilcoxon signed-ranks test (for continuous variables). When use of formal 
testing to assess differences between users of the placebo gel and users of the gel 
containing dapivirine is required, the following methods will be used: for binomial 
response variables, chi-square tests and logistic regression (or exact testing methods); 
for continuous variables, t-tests and linear regression or nonparametric methods if data 
are non-Normal.  
To assess the adequacy of the randomization, participants in each of the two arms will 
be compared for baseline characteristics including demographics and laboratory 
measurements using descriptive statistics. Due to the small sample size, formal 
comparisons will not be done.  
 
Safety Endpoints 
 
All visits in which a participant has been exposed to the study product will be included in 
the primary analyses of safety. Secondary intent to treat analyses may also be 
performed. The number and the percentages of participants experiencing each safety 
endpoint (see Section 10.2) will be tabulated by study arm. Each participant will 
contribute once in each category (i.e., only for highest severity AE for each participant) 
for the calculation of event rates. Exact binomial confidence intervals will be calculated 
for each safety endpoint for each arm and Fisher’s Exact test used to test for 
differences in event rates between the arms.  
 
Pharmacokinetic Analysis 
 
We will use descriptive statistics such as the mean and median and corresponding 95% 
confidence intervals to describe the dapivirine concentrations in all biological matrices 
assessed at all visits. Pre-dose concentrations during visits 4-7 will be used to assess 
approach to steady-state. The 30-60 minute sample will be used to describe the 
concentrations soon after a gel dose, and the 2 hour sample roughly approximates the 
time to peak concentrations among different matrices. Composite concentrations from 
the 2 hour sample (Visit 3 single dose, Visit 13 multiple dose) and concentrations from 
Visit 4-6 and Visits 14-16, respectively, for the single and multiple dose periods will be 
used to estimate terminal elimination half-life from each matrix sampled. The single 
dose Visit 3 and multiple dose Visit 7 will be compared to provide an estimate of 
concentration accumulation with multiple dosing.  
 


 
 
  
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10.8.3   Missing Data 
 
A retention rate of 95% is targeted.  Based on previous MTN trials, minimal missing 
data is expected.  If missing data rates are higher than anticipated (over 10%), robust 
methods such as nonparametric tests and generalized estimating equations (GEE) 
using all available baseline predictors of the missing outcomes as covariates will be 
used to obtain less biased estimates of the treatment effect. 
 
 
11 
DATA HANDLING AND RECORDKEEPING 
 
11.1 Data Management Responsibilities 
 
Study CRFs will be developed by the MTN SDMC in conjunction with the protocol team. 
Quality control reports and queries routinely will be generated and distributed by the 
SDMC to the study sites for verification and resolution. As part of the study activation 
process, the study sites must identify all CRFs to be used as source documents. Study 
CRF data will be entered and cleaned using the Medidata Rave EDC tool, a data 
management system compliant with the International Council on Harmonization (ICH) 
Good Clinical Practices (GCP) and US CFR guidelines for electronic data capture. 
 
11.2 Source Documents and Access to Source Data/Documents 
 
All study sites will maintain source data/documents in accordance with current DAIDS 
policies. (https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf)  
 
Each IoR/designee will maintain, and store securely, complete, accurate and current 
study records throughout the study. In accordance with U.S. regulations regarding 
testing investigational products, the IoR/designee will maintain all study documentation 
for at least two years following the date of marketing approval for the study products 
being tested for the indication in which they were studied. If no marketing application is 
filed, or if the application is not approved, the records will be retained for two years after 
the investigation is discontinued and the US FDA is notified.  
 
Study records must be maintained on site for the entire period of study implementation. 
Thereafter, instructions for record storage will be provided by DAIDS. No study records 
may be moved to an off-site location or destroyed prior to receiving approval from 
DAIDS. 
 
11.3 Quality Control and Quality Assurance 
 
All study sites will conduct quality control and quality assurance procedures in 
accordance 
with 
current 
DAIDS 
policies. 
(https://www.niaid.nih.gov/sites/default/files/qmppolicy.pdf) 
 


 
 
  
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12 
 CLINICAL SITE MONITORING 
 
Study monitoring will be carried out by Pharmaceutical Product Development, Inc. 
(PPD) (Wilmington, NC) in accordance with current DAIDS policies. Study monitors will 
visit the site to do the following: 
 
x Review informed consent forms, procedures, and documentation 
x Assess compliance with the study protocol, Good Clinical Practices (GCP) 
guidelines, and applicable regulatory requirements (US and non-US), including 
CFR Title 45 Part 46 and Title 21 Parts 50, 56, and 312  
x Perform source document verification to ensure the accuracy and completeness 
of study data 
x Verify proper collection and storage of biological specimens 
x Verify proper storage, dispensing, and accountability of investigational study 
products 
x Assess implementation and documentation of internal site quality management 
procedures 
 
The IoR/designee will allow study monitors to inspect study facilities and documentation 
(e.g., informed consent forms, clinic and laboratory records, other source documents, 
CRFs), as well as observe the performance of study procedures. The IoR/designee also 
will allow inspection of all study-related documentation by authorized representatives of 
the MTN LOC, SDMC, LC, NIAID, FDA, OHRP, IRBs/ECs and other local and US 
regulatory authorities. A site visit log will be maintained at the study site to document all 
visits. 
 
 
13 
 HUMAN SUBJECTS PROTECTIONS 
Site investigators will make efforts to minimize risks to participants. Participants and 
study staff members will take part in a thorough informed consent process. Before 
beginning the study, the IoR/designee will have obtained IRB/EC approval and the 
protocol will have been submitted to the FDA. The IoR/designee will permit audits by the 
NIH, the FDA, OHRP, MTN LOC, IRBs/ECs, SDMC, and other local and US regulatory 
authorities or any of their appointed agents. 
 
13.1 Institutional Review Boards/Ethics Committees 
 
Each participating institution is responsible for assuring that this protocol, the associated 
site-specific informed consent forms, and study-related documents (such as participant 
education and recruitment materials) are reviewed by an IRB/EC responsible for 
oversight of research conducted at the study sites. Any amendments to the protocol 
must be approved by the responsible IRBs/ECs prior to implementation. 


 
 
  
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Subsequent to the initial review and approval, the responsible IRBs/ECs must review 
the study at least annually. Each IoR/designee will make safety and progress reports to 
the IRBs/ECs at least annually and within three months after study termination or 
completion. These reports will include the total number of participants enrolled in the 
study, the number of participants who completed the study, all changes in the research 
activity, and all unanticipated problems involving risks to human subjects or others. In 
addition, the results of all SMC reviews of the study will be provided to the IRBs/ECs. 
The study site will submit documentation of continuing review to the DAIDS Protocol 
Registration Office in accordance with the DAIDS Protocol Registration Policy and 
Procedures Manual. 
 
13.2 Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, 
each site must have the protocol and the protocol consent forms approved, as 
appropriate, by their local IRB/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 (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 when the DAIDS 
PRO receives a complete registration packet. Receipt of an Initial Registration 
Notification indicates successful completion of the protocol registration process. A copy 
of the Initial Registration Notification should be retained in the site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an 
amendment, sites should implement the amendment immediately. Sites are required to 
submit an amendment registration packet to the DAIDS PRO at the RSC. The DAIDS 
PRO will review the submitted protocol registration packet to ensure that all 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. 
 
13.3 Study Coordination 
 
DAIDS holds the Investigational New Drug (IND) application for this study. 
 
Study implementation will be directed by this protocol, which may not be amended 
without prior written approval from the Protocol Chair and DAIDS Medical Officer. Study 


 
 
  
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implementation will also be guided by a common study-specific procedures manual that 
provides further instructions and operational guidance on conducting study visits; data 
and forms processing; specimen collection, processing, and shipping; AE assessment, 
management and reporting; dispensing study products and documenting product 
accountability; and other study operations. Standardized study-specific training will be 
provided to all sites by the MTN LOC, SDMC, LC and other designated members of the 
Protocol Team.  
 
Close coordination between protocol team members is necessary to track study 
progress, respond to queries about proper study implementation, and address other 
issues in a timely manner. The PSRT will address issues related to study eligibility and 
AE management and reporting as needed to assure consistent case management, 
documentation, and information-sharing across sites. Rates of accrual, adherence, 
follow-up, and AE incidence will be monitored closely by the team as well as the SMC. 
 
13.4 Risk Benefit Statement 
 
13.4.1 
Risks 
 
It is not expected that this trial will expose human subjects to unreasonable risk. 
 
Phlebotomy 
Phlebotomy may lead to excessive bleeding, discomfort, feelings of dizziness or 
faintness, bruising, swelling, venous thrombosis, and/or infection.  
 
Pelvic Exam & Cervical Biopsy Collection 
Pelvic examination and vaginal fluid collection may cause mild discomfort and/or vaginal 
bleeding or spotting. Cervical biopsies carry the risk of discomfort or pain during the 
procedure and for a few hours afterwards. Participants may have mild vaginal spotting 
(bleeding) for one or two days, and will be instructed to avoid sexual intercourse for 7 
days following biopsy collection.  
 
Participants will be instructed not to use NSAIDs, aspirin (over 81 mg per day) and/or 
other drugs that are associated with the increased likelihood of bleeding for 3 days 
before and after the collection of the rectal biopsies.  Female participants are to refrain 
from penile-vaginal intercourse for 3 days before and for 7 days following cervical 
biopsy collection.  If participants engage in sexual intercourse before the biopsy has 
healed they may experience some temporary discomfort.  If participants are sexually 
active they may also be at increased risk for STIs and HIV acquisition, if exposed. There 
is a small risk of infection and heavier bleeding. Participants will be instructed to contact 
the clinic if symptoms are bothersome, if heavy bleeding is noted (soaking through a 
pad in an hour or less) or if the participant develops any abnormal odor or discharge 
from the vagina. 
 
Rectal Enema 
An enema will be standard procedure that may be used prior to insertion of a flexible 
sigmoidoscope since fecal matter can obscure the test. The main risk from having an 


 
 
  
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enema is temporary discomfort.  A hollow tube about the thickness of a pencil will be 
used to put approximately 120 mL of normal saline 0.9% into the rectum and flush it out 
again (a larger volume may be required if the initial volume does not produce results), 
along with any stool that is there. There is a risk of a bloated/cramping feeling. The tube 
is small, but it might cause some anal or rectal discomfort if the subject has any 
hemorrhoids or other painful conditions.    
 
Anoscopy 
Insertion of a lubricated anoscope will likely cause some discomfort. 
 
Flexible Sigmoidoscopy and Rectal Biopsy Collection 
Flexible sigmoidoscopy is a commonly practiced endoscopic medical procedure and will 
not involve any increased risk over usual sigmoidoscopy performed for clinical 
indications.  There is a low risk of infection, mild rectal irritation, low blood pressure, and 
feeling a sudden urge to defecate during or after the flexible sigmoidoscopy procedure. 
There is a very low risk of intestinal tear during the flexible sigmoidoscopy procedure. 
 
There is a risk of limited rectal bleeding 1-2 days after flexible sigmoidoscopy, 
associated with collection of biopsy samples. The rate of perforation of a hollow viscus 
following endoscopic biopsy occurs less than 88 out of every 100,000 times.34  A recent 
retrospective analysis of approximately 1,000 research flexible sigmoidoscopies 
(including collection of rectal biopsies) conducted at the University of Pittsburgh 
demonstrated an overall adverse event rate of 1.6%. The majority of AEs were 
gastrointestinal in nature and of mild/moderate severity.35 
 
Participants will be instructed to refrain from sexual intercourse and counseled not to 
use NSAIDs, aspirin (over 81 mg per day) and/or other drugs that are associated with 
the increased likelihood of bleeding for 3 days before and after the flexible 
sigmoidoscopy.  If participants engage in sexual intercourse before the biopsy has 
healed they may experience some temporary discomfort. 
 
Rectal Fluid Collection 
There is the risk of mild discomfort in addition to a slight risk of bleeding with the 
insertion of rectal swabs and sponges for collection of rectal fluid.  
 
Rectal Applicator (for Administration of Study Product) 
Use of an applicator to deliver a microbicide into the rectal compartment may be 
associated with minor anorectal trauma including lacerations and bruising in the 
anorectal area. Side effects observed with rectal application of microbicides in previous 
research studies include: Mild rectal fullness; incontinence or diarrhea; flatulence; mild 
abdominal pain; and proctalgia. 
 
Other Risks 
Disclosure of HIV and STI status may cause worry, sadness or depression. Disclosure 
of HIV-positive status has been associated with depression, suicidal ideation, and denial 
as well as social isolation. Trained counselors will be available to help participants deal 
with these feelings.  


 
 
  
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Participation in clinical research includes the risks of loss of confidentiality and 
discomfort with the personal nature of questions when discussing sexual behaviors. 
 
Participants at sites requiring partner notification in response to diagnosed STI or HIV 
infection could have problems in their relationships with their sexual partners. 
Participants also could have problems in their partner relationships associated with 
maintenance of study-required abstinence.  
 
Site staff will make every effort to protect participant privacy while in the study.  
Although study sites make every effort to protect participant privacy and confidentiality, 
it is possible that participants' involvement in the study could become known to others, 
and that social harms may result (i.e., because participants could become known as 
HIV-positive or at "high risk" for HIV infection).  For example, participants could be 
treated unfairly or discriminated against, or could have problems being accepted by 
their families and/or communities.   
 
Adverse events among participants who dosed vaginally with the gel included:  
x Metrorrhagia 
x Headache 
x Vaginitis bacterial 
x Vaginal candidiasis 
x Vulvovaginal pruritus 
x Upper respiratory tract infection 
 
These side effects may or may not be associated with rectal use of dapivirine gel. 
 
In previously completed studies involving rectally-applied products, the following 
gastrointestinal AEs were common and/or occurred at a Grade 3 or higher: 
x Abdominal distension  
x Abdominal bloating 
x Abdominal pain/cramps 
x Defecation urgency  
x Diarrhea  
x Flatulence  
x Tenesmus 
 
These side effects may or may not be associated with the use of dapivirine gel. 
 
13.4.2 
Benefits 
 
Participants in this study may experience no direct benefit. Participants and others may 
benefit in the future from information learned from this study. Specifically, information 
learned in this study may lead to the development of safe and effective interventions to 
prevent HIV acquisition and transmission. Participants also may appreciate the 
opportunity to contribute to the field of HIV prevention research.  


 
 
  
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Participants will receive HIV/STI risk reduction counseling, HIV and STI testing, physical 
examination, pelvic examination, and routine laboratory testing related to blood, liver, 
and kidney function. Participants may be provided or referred for STI treatment free of 
charge, and STI testing and treatment may be offered and/or referrals may be provided 
(for their partners). For other medical conditions identified as part of the study screening 
and/or follow-up procedures, participants will be referred to other sources of care 
available in their community. Some volunteers may have the opportunity to access 
expedient treatment and decreased morbidity due to early diagnosis and treatment of 
abnormalities identified during tests, examinations and referrals. 
 
13.5 Informed Consent Process 
 
Written informed consent will be obtained from each study participant prior to screening. 
Written informed consent also will be obtained for long-term specimen storage and 
possible future testing, although consent for long-term specimen storage is not required 
for study participation. In obtaining and documenting informed consent, the IoR and 
their designees will comply with applicable local and US regulatory requirements and 
will adhere to GCP and to the ethical principles that have their origin in the Declaration 
of Helsinki. Study staff must document the informed consent process in accordance with 
the Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials (https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf). 
Participants will be provided with copies of the informed consent form if they are willing 
to receive them.  
 
In addition to informed consent form, the Protocol Team will work with study staff and 
community representatives to develop appropriate materials about the study and a 
standardized approach to the informed consent process to be implemented at the study 
site, which will be detailed in the MTN-026 SSP Manual.  
 
The informed consent process will cover all elements of informed consent required by 
research regulations. In addition, the process specifically will address the following 
topics of importance to this study: 
 
x The unknown safety and unproven efficacy of the study products 
x The need to abstain from sexual intercourse for protocol defined periods, 
regardless of study treatment group 
x The importance of participants in both study groups to the success of the study 
x The importance of adherence to the study visit and procedures schedule  
x The potential medical risks of study participation (and what to do if such risks are 
experienced) 
x The potential social harms associated with study participation (and what to do if 
such harms are experienced) 
x The real yet limited benefits of study participation  
x The distinction between research and clinical care 


 
 
  
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x The right to withdraw from the study at any time 
 
13.6 Participant Confidentiality 
 
All study procedures will be conducted in private, and every effort will be made to 
protect participant privacy and confidentiality to the extent possible. The study site will 
implement confidentiality protections that reflect the local study implementation plan and 
the input of study staff and community representatives to identify potential confidentiality 
issues and strategies to address them. In addition to local considerations, the 
protections described below will be implemented at the study site. 
 
All study-related information will be stored securely. All participant information will be 
stored in locked areas with access limited to study staff. All laboratory specimens, study 
data collection, and administrative forms will be identified by coded number only to 
maintain participant confidentiality. All records that contain names or other personal 
identifiers, such as locator forms and informed consent forms, will be stored securely. 
All local databases will be secured with password protected access systems. Forms, 
lists, logbooks, appointment books, and any other listings that link participants’ ID 
numbers to identifying information will be stored in a locked file in an area with limited 
access. Participants’ study information will not be released without their written 
permission, except as necessary for review, monitoring, and/or auditing by the following: 
 
x Representatives of the US Federal Government, including the US FDA, the US 
OHRP, NIH, and/or contractors of the NIH, and other local and US regulatory 
authorities 
x PPD 
x Representatives of the MTN LOC, SDMC, and/or LC 
x Study staff  
x Site IRBs/ECs 
 
The MTN has a Certificate of Confidentiality from the US Department of Health and 
Human Services that is applicable to the US sites participating in this study. This 
Certificate protects study staff from being compelled to disclose study-related 
information by any US Federal, State or local civil, criminal, administrative, legislative or 
other proceedings. It thus serves to protect the identity and privacy of study participants.  
Thus it serves to protect the identity and privacy of study participants. 
 
13.7 Special Populations 
 
13.7.1 
Pregnant Women 
 
Women who test positive for pregnancy at Screening or Enrollment Visits will not be 
eligible to participate in this study. Should a woman test positive for pregnancy after 
Enrollment, study product will be permanently discontinued and participants will be 
withdrawn from the study, per Section 7.10.2. During the informed consent process, 


 
 
  
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women will be informed that the study product is not a method of contraception and the 
effects of the study product on a developing human fetus are unknown. 
 
All potential participants are required by the eligibility criteria for Screening and 
Enrollment to be sexually abstinent for the protocol defined periods and using effective 
contraception as defined by the protocol. 
 
13.7.2 
Children 
 
The NIH has mandated that children be included in research trials when appropriate. 
This study meets “Justifications for Exclusion” criteria for younger children as set forth 
by the NIH. Specifically, “insufficient data are available in adults to judge potential risk in 
children” and “children should not be the initial group to be involved in research studies.” 
This 
study 
does 
not 
plan 
to 
enroll 
children 
under 
18 
years 
old. 
 
13.8 Compensation 
 
Pending IRB/EC approval, participants will be compensated for time and effort in this 
study, and/or be reimbursed for travel to study visits and time away from work. Site 
specific reimbursement amounts will be specified in the site specific informed consent 
forms. 
 
13.9 Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases 
including HIV-1 identified among study participants to health authorities. Participants will 
be made aware of reporting requirements during the informed consent process. 
 
13.10 Access to HIV-related Care 
 
13.10.1 
HIV Counseling and Testing 
 
HIV test-related counseling will be provided to all potential study participants who 
consent to undergo HIV-1 screening to determine their eligibility for this study, and to all 
enrolled participants at each follow-up HIV-1/2 testing time point. Testing will be 
performed in accordance with the algorithm in Appendix II. Counseling will be provided 
in accordance with standard HIV counseling policies and methods at each site and 
additionally will emphasize the unknown efficacy of the study products in preventing 
HIV-1 infection. In accordance with the policies of the NIH, participants must receive 
their HIV-1/2 test results to take part in this study.  
 
13.11 Study Discontinuation 
 
This study may be discontinued at any time by NIAID, the MTN, the US FDA, the 
OHRP, other government or regulatory authorities, or site IRBs/ECs. 
 
 


 
 
  
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14 
 PUBLICATION POLICY 
 
DAIDS/NIAID and MTN policies will govern publication of the results of this study. Any 
presentation, abstract, or manuscript will be submitted by the investigator to the MTN 
Manuscript Review Committee, DAIDS, NIAID, NIMH, and IPM for review prior to 
submission. 
 
 
 


 
 
  
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15 
APPENDICES 
 


 
 
  
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APPENDIX I:  SCHEDULE OF STUDY VISITS AND EVALUATIONS 
 
Visit 1 
SCR 
Visit 2 
ENR 
Visit 3 
Dosing 
Visit 
Visit 4, 5, 6 
(Sampling 
Assigned 4, 5, 
or 6) 
Visit 7, 8, 
9, 10, 11, 
12: Dosing 
Visits* 
Visit 13 
(Final 
Dose)/ 
Early 
Term 
Visit 14, 15, 
16,  
(Sampling 
Assigned 14, 
15 or 16) 
Visit 17 
F/U 
Contact 
ADMINISTRATIVE AND REGULATORY 
  
  
  
  
Informed consent 
(SCR/ENR) 
X 
  
  
  
  
  
  
  
Assess consent form 
comprehension 
X 
 
 
 
 
 
 
 
Review informed 
consent/Confirm participant 
willingness to participate in 
study 
  
X 
  
  
  
  
  
  
Assign PTID  
X 
  
  
  
  
  
  
  
Collect demographic data 
X 
  
  
  
  
  
  
  
Locator information 
X 
X 
X 
X 
X 
X 
X 
X 
Assess eligibility 
X 
  
  
  
  
  
  
  
Confirm participant eligibility 
  
X 
  
  
  
  
  
  
Provide reimbursement 
X 
X 
X 
X 
X 
X 
X 
~ 
Schedule next study 
visit/contact 
▲ 
▲ 
X 
X 
X 
X 
X 
▲ 
Randomization 
  
X 
  
  
  
  
  
  
BEHAVIORAL/COUNSELING 
  
  
  
  
  
HIV pre-/post-test and 
HIV/STI risk reduction 
counseling 
X 
X 
  
  
▲  
(Required 
at Visit 7) 
  
▲  
(Required at 
Visit 16) 
  
Protocol counseling 
(Adherence counseling and 
product use instructions) 
X 
X 
X 
X 
X 
X 
X 
  
Behavioral assessment 
 
X 
X 
 
 
□ 
X 
(Visit 14 only) 
 
In-depth interview 
 
 
X 
 
 
□ 
X 
(Visit 14 only) 
 
CLINICAL 
  
  
  
  
  
  
  
  
Medical history 
X 
X 
X 
X 
X 
X 
X 
Menstrual history 
♀ 
♀ 
♀ 
♀ 
♀ 
♀ 
♀ 
 
General/Targeted physical 
exam 
X 
X 
▲  
▲  
▲ 
▲  
▲ 
  
Perform pelvic examination 
♀ 
♀ 
♀▲ 
♀ Φ 
(Visit 4, 5 or 6) 
♀▲ 
♀ 
♀ Φ 
(Visit 14, 15 or 
16) 
  
Perform rectal examination 
X 
X 
X 
Φ 
(Visit 4, 5 or 6) 
▲ 
(Visits 7 & 
8 only) 
X 
Φ 
(Visit 14,15 or 
15) 
  
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Treat for UTI/RTI/STI or refer 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
Provide available test results 
X 
X 
X 
X 
X 
X 
X 
X 
Record/update AEs 
 
 
X 
X 
X 
X 
X 
X 
LABORATORY  
  
  
  
  
URINE 
  
  
  
  
Qualitative hCG 
♀ 
♀ 
  
  
▲♀  
(Required 
at Visit 7) 
  
♀  
(Visit 14 only) 
  
Dipstick UA 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
 
Urine Culture 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
 
NAAT for GC/CT 
X 
▲  
▲ 
▲ 
▲ 
▲ 
▲ 
  
BLOOD 
  
  
  
  
CBC with differential and 
platelets 
X 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
 
Chemistries 
(AST/ALT/Creatinine)  
X 
▲ 
▲ 
▲ 
▲ 
▲ 
▲  
(Required at 
Visit 16) 
 
Plasma for archive/storage 
  
X 
  
  
X 
(Visit 7 only) 
  
X 
(Visit 16 only) 
  
Plasma PK (Visits 3 and 13 at 
hour 0 and either 30-60 or 120 
minutes; single time point at all 
  
 
Φ 
X 
X  
(Visits 7 & 8 
only) 
Φ 
X 
  


 
 
  
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Visit 1 
SCR 
Visit 2 
ENR 
Visit 3 
Dosing 
Visit 
Visit 4, 5, 6 
(Sampling 
Assigned 4, 5, 
or 6) 
Visit 7, 8, 
9, 10, 11, 
12: Dosing 
Visits* 
Visit 13 
(Final 
Dose)/ 
Early 
Term 
Visit 14, 15, 
16,  
(Sampling 
Assigned 14, 
15 or 16) 
Visit 17 
F/U 
Contact 
other visits) 
Syphilis Serology 
X 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
 
HIV-1/2 test 
X 
X 
  
  
 ▲ 
(Required at 
Visit 7) 
  
▲  
(Required at 
Visit 16) 
 
HSV 1/2 serology  
X 
  
  
  
  
  
  
 
HBsAg 
X 
  
  
  
  
  
  
  
HCV serology 
X 
  
  
  
  
  
  
  
Coagulation (PT/INR)  
X 
  
  
  
  
  
  
  
PELVIC SAMPLES 
  
  
  
  
Vaginal NAAT for GC/CT 
♀ 
  
  
  
  
  
  
  
Cervicovaginal lavage for PK 
and PD (prior to biopsy 
collection) 
  
♀ 
  
♀ Φ (Visit 4, 5 
or 6) 
  
♀ 
♀ Φ (Visit 14, 
15 or 16) 
  
Cervicovaginal fluid for PK 
  
  
  
♀ Φ (Visit 4, 5 
or 6) 
  
♀ 
♀ Φ (Visit 14, 
15 or 16) 
  
Cervical tissue for PK 
  
  
  
♀ Φ (Visit 4, 5 
or 6) 
  
♀ 
♀ Φ (Visit 14, 
15 or 16) 
  
Pap test 
♀▲ 
 
 
 
 
 
 
 
ANORECTAL SAMPLES 
  
  
  
  
HSV 1/2 detection 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
  
Rectal fluid for adherence PK 
(Visits 3 and 13 at either 30-
60 or 120 minutes) 
  
  
Φ 
Φ (Visit 4, 5 or 
6) 
X (Visits 7 & 
8 only) 
Φ 
Φ (Visit 14, 
15 or 16) 
  
Rectal tissue for PK (Visits 3 
and 13 at either 30-60 or 120 
minutes)  
  
  
Φ 
Φ (Visit 4, 5 or 
6) 
  
Φ 
Φ (Visit 14, 
15 or 16) 
  
Rectal fluid for mucosal 
safety (Visits 3 and 13 at 
either 30-60 or 120 minutes) 
  
X 
Φ 
  
 
Φ 
  
  
Rectal tissue for mucosal 
safety (Visits 3 and 13 at 30-
60 min or 120 minutes) 
 
X 
Φ 
 
 
Φ 
 
 
Rectal tissue for PD (Visits 3 
and 13 at either 30-60 or 120 
minutes) 
  
X 
Φ 
Φ (Visit 4, 5 or 
6) 
  
Φ 
Φ (Visit 14, 
15 or 16) 
  
Rectal enema effluent for PK 
and PD prior to biopsy 
collection 
  
X 
  
Φ (Visit 4, 5 or 
6) 
  
Φ 
Φ (Visit 14, 
15 or 16) 
  
NAAT for GC/CT 
X 
▲ 
▲ 
▲ 
▲ 
▲ 
▲ 
  
STUDY PRODUCT/SUPPLIES 
  
  
  
  
Provision of study product  
  
  
X 
  
X 
X Ө 
  
  
Provision of lubricant 
 
 
X 
 
X 
X Ө 
 
 
Observe dose application(s) 
  
  
X 
  
X 
X Ө 
  
  
Collect unused study product 
 
 
 
 
 
X 
 
 
Offer condoms 
 
 
 
X 
(Visit 6 only) 
 
 
 
 
X = Required, ▲ = As Indicated, ♀ = Female participants, Φ = Participants will be assigned to provide samples at specific dates and/or times, ~ 
Sites to reference SOPs regarding participant reimbursement , □= Required if Early Termination only, Ө= Omit at Early Termination  
* The washout period should coincide with female participants’ menses. 
  
 
  
 
 


 
 
  
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APPENDIX II:  ALGORITHM FOR HIV ANTIBODY TESTING FOR SCREENING AND 
FOLLOW-UP 
 


 
 
 
 
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APPENDIX III: SAMPLE INFORMED CONSENT FORM (SCREENING, 
ENROLLMENT, LONG-TERM STORAGE AND FUTURE TESTING) 
 
DIVISION OF AIDS, NIAID, NIH 
 
MTN-026 
 
A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and Pharmacokinetic 
Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults 
 
Version 2.0 
  
July 21, 2017 
 
PRINCIPAL INVESTIGATOR: [Sites to insert] 
PHONE: [Sites to insert] 
Short Title for the Study: Dapivirine Gel Rectal Safety and PK Study 
 
INFORMED CONSENT 
 
You are being asked to take part in this research study because you are a healthy, HIV-negative 
man or woman between the ages of 18 and 45 years old and reported at least one experience 
of receptive anal sex in the last year. Approximately 27 people will participate in this study. This 
Microbicide Trials Network (MTN) study is sponsored by the US National Institutes of Health 
(NIH). The products being used in this study include dapivirine gel and placebo gel; these 
products will be explained later in this document.  The study products are supplied by the MTN.  
The study gel is inserted with an applicator into the rectum.  Participants are asked to apply one 
dose of study gel 8 times over the course of this study.  At this site, the person in charge of this 
study is [INSERT NAME OF PRINCIPAL INVESTIGATOR].  
 
Before you decide if you want to join this study, we want you to learn more about it. This 
consent form gives you information about the study. Study staff will talk with you and answer 
any questions you may have.  Once you read and understand the study and its requirements, 
you can decide if you want to join.  If you do decide to take part in the trial, you will sign your 
name on this form. A copy of this document will be offered to you. Signing this consent form 
does not mean you will be able to join the study. You must first complete the screening tests 
and exams to see if you are eligible. 
 
It is important to know that your participation in this research is your decision and taking part in 
this study is completely voluntary (see Your Rights as a Research Participant/Volunteer for 
more information).  
 


 
 
 
 
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WHAT IS THE PURPOSE OF THIS STUDY? 
The main purpose of this research study is to find out if gel containing the study drug dapivirine 
is safe when inserted into the rectum after a single dose, followed by 7 daily doses.  Another 
purpose of this study is to better understand how dapivirine is absorbed by and eliminated from 
the body.  
 
STUDY PRODUCT 
Dapivirine has been previously tested for safety, acceptability, and HIV prevention. HIV is the 
virus that causes AIDS.  Now researchers would like to know more about the safety of dapivirine 
gel applied rectally and how it is processed within the body. To do this, they first need to better 
understand what effect this drug has on the body, including in and around the rectum and anus.  
 
Dapivirine works in a specific way to potentially prevent HIV; it is thought to prevent HIV from 
making copies of itself, thereby stopping the spread of HIV in the body.  
 
This study is not testing to see if dapivirine prevents HIV infection. Researchers do not yet know 
if this drug will work in humans to protect against HIV. There are only two known effective ways 
to prevent HIV: condoms and/or the use of pre-exposure prophylaxis (PrEP).  PrEP is a new 
HIV prevention method in which people who do not have HIV take an oral tablet to reduce their 
risk of becoming infected. Study staff can provide you with additional information about PrEP if 
you are interested in learning more. 
 
While dapivirine has been tested before in humans, this is the first time it has been tested as a 
rectal gel. 
 
STUDY GROUPS  
All of the eligible participants will be randomized to one of two rectal gel study groups:  
x 
Dapivirine gel, or  
x 
Placebo gel (which has no dapivirine or any other active ingredient(s) in it).  
 
Approximately 18 people will be in the dapivirine gel study group and 9 people will be in the 
placebo gel group. You will be assigned to a group by random chance (the equivalent of 
throwing dice). It is important that you know that you will receive a gel that may or may not 
contain dapivirine. This study is double-blind, which means neither you nor the study clinician 
will know which group you are in until the study is completed.  You will be asked to apply the 
study gel in your rectum once daily 8 times over the course of the study.  
 
Both study groups are important to this study. No matter which study group you are in, you must 
remember that we do not know if the drug contained within the gel will work to protect men and 
women from getting HIV. Participants in each study group will have the same study visit 
schedule. 
 


 
 
 
 
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WHAT WILL HAPPEN DURING THE MTN-026 STUDY VISITS? 
The MTN-026 study includes a total of 16 clinic visits and one contact (via phone or in person) 
including the Screening Visit which is taking place today, if you decide to sign this informed 
consent form.  Visits will take place here, at this study clinic. 
 
[SITES TO UPDATE THE STUDY VISIT/PROCEDURE DESCRIPTIONS TO ALIGN WITH THE 
FLOW OF STUDY VISITS.] 
 
 
 
Screening Visit:  
 
The procedures done today will take about [SITES TO INSERT TIME]. 
x 
Study staff will ask you where you live and other questions about you, your medical 
health (including what medications you are taking), menstrual history (for females), your 
sexual practices and your understanding of the study requirements.   
x 
You will be asked to provide and/or update study staff with your contact information (i.e. 
about how we can contact you). 
x 
Ask you to abstain from some medications at certain timepoints during the study: 
 
Medication: 
Abstain For How Long? 
x 
NSAIDs (nonsteroidal anti-
inflammatory drugs)  
x 
Aspirin (over 81 mg per day) 
x 
Any other drug that is associated 
with an increased likelihood of 
bleeding 
x 
72 hours (3 days) prior to study visits at 
which tissue samples are scheduled to 
be collected 
x 
72 hours (3 days) after each visit at 
which tissue samples were collected 
 
x 
Study staff will: 
 
Perform a physical exam. 
 
Talk with you about sexually transmitted infections (STIs), HIV, HIV/STI testing, and 
ways to avoid HIV and other infections passed through sex.   
 
Talk with you about the requirements of the study including, but not limited to, 
restrictions on sexual practices: 
 
(I AM MALE)  For men, sex for this study is defined as anal intercourse, receptive oral 
anogenital stimulation (e.g., partner placing their mouth on your anogenital area), finger 
stimulation, and the use of sex toys.  Males will be asked to abstain from the following 
activities at these timepoints during the study: 


 
 
 
 
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Activity: 
Abstain For How Long? 
x 
Receptive anal intercourse 
x 
Receptive oral anogenital 
stimulation (e.g., partner placing 
their mouth on your anogenital 
area) 
x 
Inserting any non-study products or 
objects into your rectum, including: 
o 
Rectal medications 
o 
Enemas 
o 
Lubricants 
o 
Sex toys (dildos, anal 
plugs, etc.) 
o 
Fingers 
x 
72 hours (3 days) prior to each study 
visit 
x 
On the day(s) you dose with gel 
x 
72 hours (3 days) following biopsy 
collection 
 
(I AM FEMALE)  For women, sex for this study is defined as receptive penile-vaginal 
intercourse, anal intercourse, receptive oral intercourse, finger stimulation, and the use 
of sex toys. Females will be asked to abstain from the following activities at these 
timepoints during the study: 
Activity: 
Abstain For How Long? 
x 
Anal intercourse 
x 
Receptive penile-vaginal intercourse 
x 
Receptive oral anogenital 
stimulation (e.g., partner placing 
their mouth on your anogenital area) 
x 
Inserting any non-study products or 
objects into your vagina, including: 
o 
Vaginal medications 
o 
Douches 
o 
Lubricants 
o 
Sex toys (dildos, etc.) 
o 
Fingers 
x 
Inserting any non-study products or 
objects into your rectum, including: 
o 
Rectal medications 
o 
Enemas 
o 
Lubricants 
o 
Sex toys (dildos, anal plugs, 
etc.) 
o 
Fingers 
x 
72 hours (3 days) prior to each study 
visit 
x 
On the day(s) you dose with gel 
x 
1 week (7 days) following biopsy 
collection  
 
At your Screening Visit, study staff will also: 
 
Test your urine for sexually-transmitted diseases and other infections 
 
Take a blood sample [SITES TO INSERT AMOUNT]: 
o To test the health of your blood, liver and kidneys. 
o To test for infections that typically are passed through sex, including HIV, herpes 
simplex virus (HSV), hepatitis B, hepatitis C, and syphilis. 
 
You will be told your test results as soon as they are available.  You will 
talk with the study staff about the meaning of your results, how you feel 
about them, and learn about ways to prevent HIV and other sexually 


 
 
 
 
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transmitted infections.  Sometimes HIV tests are not clearly positive, but 
also not clearly negative.  In that case, we will do more tests until we are 
sure of your status.  To participate in the study you must receive the 
results of your HIV test.  If the test shows you have HIV, you cannot join 
the study.  We will refer you to available sources of medical care and 
other services you may need.  The study staff will tell you about other 
studies you may be eligible for, if any.  
 
Perform a rectal examination, during which rectal swabs will be taken.  These will be 
used to test for infections passed through sex. To collect these samples, study staff 
will insert a short hollow tube called an anoscope into your rectum.  The clinician will 
insert swabs and/or sponges through the hollow tube to collect the sample. 
 
 (For females):  
o Test your urine for pregnancy  
 
If you are pregnant you cannot join this study.  
 
Study staff will talk with you about ways to avoid becoming pregnant.   
 
Perform a pelvic examination: 
o The study clinician will use a speculum, a plastic or metal instrument used to 
separate the walls of the vagina, to check your vagina and cervix (the tissue that 
attaches the vagina to the uterus) for signs of infection, and other problems.  
They will also take some fluids to test for sexually transmitted infections and 
diseases (commonly known as STIs or STDs) and other problems. 
o The study staff may also collect samples from your cervix for a “Pap test” or “Pap 
smear”.  Study staff will inform you of the results of your Pap test.  It takes about 
[SITES TO INSERT AMOUNT OF TIME] before Pap test results are ready If you 
are less than 21 years of age, a Pap test is not needed to join the study. If you 
are 21 years of age or older and can provide a written report confirming either a 
normal Pap test in the past 3 years, or an abnormal Pap test for which no 
treatment was required, you will not need to have a Pap test taken at this 
screening visit.  The results of your Pap test may affect whether or not you can 
join the study. 
 
Give you treatment or refer you for treatment of sexually transmitted infections, if 
needed. 
 
Inform you about other services, if needed.  
 
Provide you with the results of your tests, when available. It is expected that all of 
your results will be available by [SITES TO SPECIFY TIMEFRAME].     
 
Reimburse you for your visit 
 
Schedule your next visit to enroll in the study, if you are willing and eligible. 
 
If you decide not to join MTN-026, blood and other samples collected at this visit will not be kept 
or used for any tests other than those listed above.  
 
Enrollment Visit: 
 
Your Enrollment Visit (the visit where you enter the study), will take about [SITES TO INSERT 
TIME.] In addition to the procedures listed below, it is possible that study clinicians may need to 
perform additional tests if medically necessary (for example, you report having symptoms of a 
urinary, genital, or other infection and/or other issues).   


 
 
 
 
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The following procedures are specific to the Enrollment Visit, which will take place up to 45 days 
after your Screening Visit: 
 
x 
Answer questions to confirm you are able and willing to join the study 
x 
Provide and/or update study staff with your contact information (i.e. about where you live 
and how we can contact you) 
x 
Be assigned to one of two study groups:  
o This may affect how long some of your study visits will last. For example: At some of 
your study visits after the Enrollment Visit, the rectal fluid and rectal tissue samples may 
be collected one time after inserting the study gel,  either between 30-60 minutes later 
or two hours later, depending on which group you have been assigned to.  You will be 
able to find out today at which visit(s) you will be asked to stay longer and for how long 
you will have to stay at the clinic for these visits.  
x 
Talk with study staff about the following: 
o The rules of the study and how to follow the rules, including the sexual abstinence 
requirement. If you do not think you can be sexually abstinent for the required 
length of time before and after study visits then you should not join this study.  
o Sexually transmitted infections (STIs), HIV, HIV/STI testing, and ways to avoid HIV and 
other infections passed through sex.   
x 
Discuss any health or medical problems you may have had in the past or since your last visit 
(including what medications you are taking) 
x 
You will be asked some questions about your experience and comfort using rectal products, 
as well as douching or other rectal hygiene practices, among other things. Some of these 
questions may be asked via computer.  
x 
Study staff will also take a blood sample [SITES TO INSERT AMOUNT] : 
o In case there’s a question about your test results at a later time.  
o To test your blood for HIV, the virus that causes AIDS: 
o At this visit and some other visits as noted below, your blood is tested for HIV.  
You will be told your test results as soon as they are available.  You will talk with 
the study staff about the meaning of your results, how you feel about them, and 
learn about ways to prevent HIV and other sexually transmitted infections.  
Sometimes HIV tests are not clearly positive, but also not clearly negative.  In 
that case, we will do more tests until we are sure of your status.  If the test shows 
you have HIV, we will refer you to available sources of medical care and other 
services you may need.  The study staff will tell you about other studies you may 
be eligible for, if any. 
x 
Have a physical exam 
x 
Have a rectal exam where: 
o Rectal fluid and tissue samples will be collected. The samples collected at your 
Enrollment Visit (before you receive any doses of study gel) and at other visits will help 
researchers better understand how the study drug enters and exits the body and what 
effect the drug has.  When these samples are collected at future visits, similar tests will 
be done.  
o To collect rectal fluid samples: Study staff will insert a short hollow tube called an 
anoscope inside your rectum. The clinician will insert swabs and/or sponges 
through the hollow tube to collect the sample. 


 
 
 
 
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o To collect rectal tissue samples: A flexible sigmoidoscopy will be performed.  A 
flexible sigmoidoscope is a flexible, hollow tube is placed inside your rectum so 
that the study clinician can take samples of tissue.  In preparation for the sample 
collection you will have an enema (rectal lavage).  During an enema, a hollow 
tube about the thickness of a pencil will be used to put some saline solution (salt 
water) through your anus and squeeze it into your rectum to flush it out and 
cleanse the bowel of fecal matter.  An enema may be standard procedure prior to 
insertion of an anoscope or flexible sigmoidoscope, since fecal matter can 
obscure the test. This may need to be repeated so that any stool that is there is 
removed.  The study clinician will then collect approximately 20 tissue samples, 
each about the size of a grain of rice. 
x 
(For females): 
o Update study staff about your menstrual history 
o Test your urine for pregnancy 
o Have a pelvic exam 
 
The study clinician will use a speculum.   
 
A vaginal wash will be performed.  The study clinician will rinse your 
vagina and cervix with about 2 teaspoons of sterile (very clean) fluid, and 
then will collect the fluid in a tube for testing.  The fluid collected will be 
used for research purposes only, to better understand how the study drug 
enters and exits the body. When these samples are collected at future 
visits, similar tests will be done.  
x 
Receive treatment or be referred for treatment issues that the study staff may find 
x 
Receive test results, if available 
x 
Be reimbursed for your visit 
x 
Schedule your next visit, if applicable.  
 
Dosing Visit (Visit 3): 
 
Your first Dosing Visit is the visit at which you will receive your first dose of the study gel. This 
visit will take between [SITES TO SPECIFY TIMEFRAME] to complete. In addition to the 
procedures listed below, it is possible that study clinicians may need to perform additional tests 
if medically necessary (for example, you report having symptoms of a urinary, genital, or other 
infection and/or other issues).   
 
You will: 
x 
Update study staff with your contact information 
x 
Review the rules of the study and how to follow the rules, including about sexual abstinence 
and insertion of non-study products or objects 
x 
Discuss any health or medical problems you may have had since your last visit (including 
what medications you are taking) 
x 
(For females) Update study staff about your menstrual history 
x 
Have a computer-administered interview. This interview may take approximately 45-60 
minutes and will occur over video chat, e.g., Google Hangout, Skype, FaceTime, etc.  This 
conversation will be recorded, but your responses will be kept private and confidential, and 
the audio-recording will be destroyed after it has been transcribed and checked. You will be 


 
 
 
 
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asked questions about your thoughts on the study product, what might make the product 
more appealing to use and your experience with administering the gel in the clinic.   
x 
Study staff will insert one dose of study gel using a lubricated applicator, perform a rectal 
examination and collect rectal fluid and tissue to help researchers better understand how the 
study drug enters and exits the body and what effect the drug has.  These samples may be 
collected one time after inserting the study gel, either between 30-60 minutes later or two 
hours later, depending on which group you have been assigned to.  
o To collect rectal fluid samples: Study staff will insert a short hollow tube called an 
anoscope inside your rectum. The clinician will insert swabs and/or sponges 
through the hollow tube to collect the sample. 
o To collect rectal tissue samples: A flexible sigmoidoscopy will be performed.  A 
flexible sigmoidoscope is a flexible, hollow tube is placed inside your rectum so 
that the study clinician can take samples of tissue.  In preparation for the sample 
collection you will have an enema (rectal lavage).  During an enema, a hollow 
tube about the thickness of a pencil will be used to put some saline solution (salt 
water) through your anus and squeeze it into your rectum to flush it out and 
cleanse the bowel of fecal matter.  An enema may be standard procedure prior to 
insertion of an anoscope or flexible sigmoidoscope, since fecal matter can 
obscure the test. This may need to be repeated so that any stool that is there is 
removed.  The study clinician will then collect approximately 20 tissue samples, 
each about the size of a grain of rice. 
x 
You will be asked some questions about your experience using the study product. Some of 
these questions may be asked via computer.  
x 
Study staff will:  
o Take blood samples [SITES TO INSERT AMOUNT] at several timepoints including 
prior to gel administration and either between 30-60 minutes later or two hours after 
gel administration, depending on which group you have been assigned to.  An 
intravenous cannula (IV tube) may be placed for 1 to 2 hours after you apply the rectal 
gel for the blood draws.  
o Give you any available test results and provide you with treatment or refer you for 
treatment if your test results indicate that you require it.  
o Reimburse you for your visit 
o Schedule your next visit or contact. 
 
Sampling Visits (Visits 4-6): 
 
Your Sampling Visits will take place approximately 24 hours (1 day), 48 hours (2 days), and 72 
hours (3 days) after you receive your first dose of the study gel. Each of these visits will take 
between [SITES TO SPECIFY TIMEFRAME] to complete. Some procedures (noted below) will 
not take place at every visit, but rather will take place at one of the three sampling visits.  In 
addition to the procedures listed below, it is possible that study clinicians may need to perform 
additional tests if medically necessary (for example, you report having symptoms of a urinary, 
genital, or other infection and/or other issues).   
 
At these visits, you will: 
x 
Update study staff with your contact information 


 
 
 
 
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x 
Review the rules of the study and how to follow the rules, including about sexual abstinence 
and insertion of non-study products or objects 
x 
Discuss any health or medical problems you may have had since your last visit (including 
what medications you are taking) 
x 
(For females) Update study staff about your menstrual history 
x 
Study staff will:  
o Perform a rectal examination 
o Rectal samples (fluid and tissue) will be collected (Visit 4, Visit 5 or Visit 6 only). These 
samples will help researchers to better understand how the study drug enters and exits 
the body and what effect the drug has.   
 
To collect rectal fluid samples: Study staff will insert a short hollow tube called an 
anoscope inside your rectum. The clinician will insert swabs and/or sponges 
through the hollow tube to collect the sample. 
 
To collect rectal tissue samples: A flexible sigmoidoscopy will be performed.  A 
flexible sigmoidoscope is a flexible, hollow tube is placed inside your rectum so 
that the study clinician can take samples of tissue.  In preparation for the sample 
collection you will have an enema (rectal lavage).  During an enema, a hollow 
tube about the thickness of a pencil will be used to put some saline solution (salt 
water) through your anus and squeeze it into your rectum to flush it out and 
cleanse the bowel of fecal matter.  An enema may be standard procedure prior to 
insertion of an anoscope or flexible sigmoidoscope, since fecal matter can 
obscure the test. This may need to be repeated so that any stool that is there is 
removed.  The study clinician will then collect approximately 20 tissue samples, 
each about the size of a grain of rice. 
o (For females) Perform a pelvic exam at Visit 4, Visit 5 or Visit 6 only. A speculum will 
be inserted and the following will be collected: 
 
Pelvic samples including vaginal fluid and cervical tissue to measure the amount 
of the study drug in your body.  A vaginal wash will be performed.  The study 
clinician will rinse your vagina and cervix with about 2 teaspoons of sterile (very 
clean) fluid, and then will collect the fluid in a tube for testing.  In addition, 
approximately 2 small tissue samples (biopsies), each about the size of a grain of 
rice, will then be taken from your cervix.  
 
Take a blood sample [SITES TO INSERT AMOUNT]: 
 
To help researchers to better understand how the study drug enters and 
exits the body  
o Give you any available test results 
o Be offered study condoms (Visit 6) 
o Reimburse you for your visit 
o Schedule your next visit or contact. 
 
Dosing Visits (Visits 7-12): 
 
Your Dosing Visits will take place starting approximately two weeks after Visit 6. They will be 
scheduled to take place approximately 24 hours (1 day) apart. These visits will take between 
[SITES TO SPECIFY TIMEFRAME] to complete. Some procedures (noted below) will not take 
place at every visit.  In addition to the procedures listed below, it is possible that study clinicians 


 
 
 
 
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may need to perform additional tests if medically necessary (for example, you report having 
symptoms of a urinary, genital, or other infection and/or other issues).   
 
At these visits, you will: 
x 
Update study staff with your contact information 
x 
Review the rules of the study and how to follow the rules, including about sexual abstinence 
and insertion of non-study products or objects 
x 
Discuss any health or medical problems you may have had since your last visit (including 
what medications you are taking) 
x 
(For females) Update study staff about your menstrual history  
x 
Study staff will:  
 
Perform a rectal examination (Visits 7 and 8), during which rectal swabs will be taken 
to help researchers to better understand how the study drug enters and exits the 
body. 
o To collect these samples, study staff will insert a short hollow tube called an 
anoscope into your rectum.  The clinician will insert swabs and/or sponges 
through the hollow tube to collect the samples. 
 
Take a blood sample [SITES TO INSERT AMOUNT]: 
o In case there’s a question about your test results at a later time. (Visit 7) 
o To test your blood for HIV, the virus that causes AIDS. (Visit 7) 
o To help researchers to better understand how the study drug enters and exits the 
body (Visit 7 and 8) 
 
(For females) Test your urine for pregnancy (Visit 7) 
 
Give you one dose of the study gel.  Study staff may help you insert the study gel if 
you cannot do it on your own.  Study lubricant and an applicator pre-filled with the 
study gel will be provided. Study staff will observe you inserting the gel to help 
ensure the gel is inserted successfully and correctly.  In addition, at Visit 7 you will 
receive an extra dose of gel and lubricant to take home with you to use in the event 
that you cannot attend your clinic visit. Study staff will tell you more about this later. 
 
Talk with you (Visit 7) about sexually transmitted infections (STIs), HIV, HIV/STI 
testing, and ways to avoid HIV and other infections passed through sex 
 
Give you any available test results 
 
Reimburse you for your visit 
 
Schedule your next visit or contact. 
 
Final Dosing Visit (Visit 13): 
 
Your Final Dosing Visit will take place approximately 24 hours (1 day) after Visit 12. This visit 
will take between [SITES TO SPECIFY TIMEFRAME] to complete. In addition to the 
procedures listed below, it is possible that study clinicians may need to perform additional tests 
if medically necessary (for example, you report having symptoms of a urinary, genital, or other 
infection and/or other issues).   
 
At this visit, you will: 
x 
Update study staff with your contact information 
x 
Review the rules of the study and how to follow the rules, including about sexual abstinence 
and insertion of non-study products or objects 


 
 
 
 
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x 
Discuss any health or medical problems you may have had since your last visit (including 
what medications you are taking) 
x 
(For females) Update study staff about your menstrual history  
x 
Study staff will:  
o Give you one dose of the study gel.  Study staff may help you insert the study gel if 
you cannot do it on your own.  Study lubricant and an applicator pre-filled with the 
study gel will be provided. Study staff will observe you inserting the gel to help ensure 
the gel is inserted successfully and correctly. 
o Perform a rectal examination and collect rectal fluid and tissue to help researchers 
better understand how the study drug enters and exits the body and what effect the 
drug has.  These samples may be collected one time after inserting the study gel, 
either between 30-60 minutes later or two hours later, depending on which group you 
have been assigned to.  
 
To collect rectal fluid samples: Study staff will insert a short hollow tube 
called an anoscope inside your rectum. The clinician will insert swabs 
and/or sponges through the hollow tube to collect the sample. 
 
To collect rectal tissue samples: A flexible sigmoidoscopy will be 
performed.  A flexible sigmoidoscope is a flexible, hollow tube is placed 
inside your rectum so that the study clinician can take samples of tissue.  In 
preparation for the sample collection you will have an enema (rectal 
lavage).  During an enema, a hollow tube about the thickness of a pencil 
will be used to put some saline solution (salt water) through your anus and 
squeeze it into your rectum to flush it out and cleanse the bowel of fecal 
matter.  An enema may be standard procedure prior to insertion of an 
anoscope or flexible sigmoidoscope, since fecal matter can obscure the 
test. This may need to be repeated so that any stool that is there is 
removed.  The study clinician will then collect approximately 20 tissue 
samples, each about the size of a grain of rice. 
o (For females) Perform a pelvic examination and collect: 
 
Pelvic samples including vaginal fluid and cervical tissue to measure the amount 
of the study drug in your body.  A vaginal wash will be performed.  The study 
clinician will rinse your vagina and cervix with about 2 teaspoons of sterile (very 
clean) fluid, and then will collect the fluid in a tube for testing.  In addition, 
approximately 2 small tissue samples (biopsies), each about the size of a grain of 
rice, will then be taken from your cervix.  
o Take a blood sample [SITE TO INSERT AMOUNT] to help researchers to better 
understand how the study drug enters and exits the body at two timepoints, prior to gel 
administration and either between 30-60 minutes later or two hours later, depending 
on which group you have been assigned to.  An intravenous cannula (IV tube) may be 
placed for 1 to 2 hours after you apply the rectal gel for the blood draws.  
o Collect any unused study gel, applicators or lubricant 
o Give you any available test results 
o Reimburse you for your visit 
o Schedule your next visit or contact. 
 
Sampling Visits (Visits 14-16): 
 


 
 
 
 
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Your Sampling Visits will take place approximately 24 hours (1 day), 48 hours (2 days), and 72 
hours (3 days) after you receive your last dose of the study gel. These visits will take between 
[SITES TO SPECIFY TIMEFRAME] to complete. Some procedures (as noted below) will not 
take place at every visit; but rather will take place at one of the 3 sampling visits.  In addition to 
the procedures listed below, it is possible that study clinicians may need to perform additional 
tests if medically necessary (for example, you report having symptoms of a urinary, genital, or 
other infection and/or other issues).   
 
At these visits, you will: 
x 
Update study staff with your contact information 
x 
Review the rules of the study and how to follow the rules, including about sexual abstinence 
and insertion of non-study products or objects 
x 
Discuss any health or medical problems you may have had since your last visit (including 
what medications you are taking) 
x 
(For females) Update study staff about your menstrual history  
x 
You will be asked some questions about your experience using the study product (Visit 14). 
Some of these questions may be asked via computer.  
x 
Have a computer-administered interview (Visit 14). This interview may take approximately 
45-60 minutes and will occur over video chat, e.g., Google Hangout, Skype, FaceTime, etc.  
This conversation will be recorded, but your responses will be kept private and confidential, 
and the audio-recording will be destroyed after it has been transcribed and checked. You 
will be asked questions about your thoughts on the study product, what might make the 
product more appealing to use and your experience with administering the gel in the clinic.   
x 
Perform a rectal exam, during which time rectal samples (fluid and tissue) will be collected 
(Visit 14, Visit 15 or Visit 16 only). These samples will help researchers to better understand 
how the study drug enters and exits the body and what effect the drug has.   
 
To collect rectal fluid samples: Study staff will insert a short hollow tube called an 
anoscope inside your rectum. The clinician will insert swabs and/or sponges 
through the hollow tube to collect the sample. 
 
To collect rectal tissue samples: A flexible sigmoidoscopy will be performed.  A 
flexible sigmoidoscope is a flexible, hollow tube is placed inside your rectum so 
that the study clinician can take samples of tissue.  In preparation for the sample 
collection you will have an enema (rectal lavage).  During an enema, a hollow 
tube about the thickness of a pencil will be used to put some saline solution (salt 
water) through your anus and squeeze it into your rectum to flush it out and 
cleanse the bowel of fecal matter.  An enema may be standard procedure prior to 
insertion of an anoscope or flexible sigmoidoscope, since fecal matter can 
obscure the test. This may need to be repeated so that any stool that is there is 
removed.  The study clinician will then collect approximately 20 tissue samples, 
each about the size of a grain of rice.  
x 
(For females) Perform a pelvic examination and collect (Visit 14, Visit 15 or Visit 16 only): 
 
Pelvic samples including vaginal fluid and cervical tissue to measure the amount 
of the study drug in your body.  A vaginal wash will be performed.  The study 
clinician will rinse your vagina and cervix with about 2 teaspoons of sterile (very 
clean) fluid, and then will collect the fluid in a tube for testing.  In addition, 
approximately 2 small tissue samples (biopsies), each about the size of a grain of 
rice, will then be taken from your cervix.  


 
 
 
 
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x 
Provide a blood sample [SITE TO INSERT AMOUNT]: 
o In case there’s a question about your test results at a later time. (Visit 16) 
o To measure the amount of study drug in your blood (Visits 14, 15, 16) 
o To check the health of your blood, liver and kidneys (Visit 16) 
o To test your blood for HIV (Visit 16) 
x 
(For females) Test your urine for pregnancy (Visit 14) 
x 
Talk with you (Visit 16) about sexually transmitted infections (STIs), HIV, HIV/STI testing, 
and ways to avoid HIV and other infections passed through sex 
x 
Give you any available test results 
x 
Reimburse you for your visit 
x 
Schedule your next visit or contact. 
 
Last Study Visit or Contact (Visit 17) 
 
Your Last Study Visit or Contact will take place approximately one week after Visit 16.  An in-
clinic visit will take place, if needed; if not, your last study contact may take place by phone. This 
visit/contact will take approximately [SITES TO SPECIFY TIMEFRAME] to complete. 
 
At this visit, you will: 
x 
Update study staff with your contact information 
x 
Be reimbursed for your visit  
x 
Schedule your next visit or contact (if necessary) 
x 
Be given any available test results 
x 
Discuss any health or medical problems you may have had since your last visit 
(including what medications you are taking) 
 
It is important that you remember that at any time during the study, study staff can answer any 
questions you may have about the procedures mentioned above or any other aspect of this 
study. 
 
Additional Visits and Procedures 
In addition to the procedures listed above, it is possible that study clinicians may need to 
perform additional tests, if necessary (e.g., if you report having symptoms of a urinary, genital, 
or other infection and/or other issues).  These tests might include the following: 
o Physical exam 
o Pelvic exam  
o Rectal exam 
o Test anal/rectal samples for sexually-transmitted diseases 
o Test cervix/vaginal samples for  sexually-transmitted diseases 
o Test your urine for sexually-transmitted diseases or other infections 
o Test your blood for sexually-transmitted diseases  
o Test your blood to check the health of your blood, liver and kidneys 
o Give you treatment or refer you for treatment of sexually transmitted infections or 
other issues, if needed. 
 


 
 
 
 
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Further you may need to provide additional samples if any of the above procedures need to be 
repeated due to issues with sample processing, and/or testing or shipping.  Additional testing 
may be performed as part of quality control. 
 
If you become infected with HIV 
Your participation in this study will not cause HIV infection. However, there is always a chance 
that through sexual activity or other activities you may become infected with HIV. In the unlikely 
event that you become infected with HIV, study staff will give you counseling and refer you to 
available medical care and other services you may need. The study does not pay for this care. 
Tests will be performed to see if you have HIV drug resistance.  This will allow your doctor to 
know what HIV drugs would be best for the treatment of your type of HIV. If the HIV test shows 
that you have been infected with HIV, you will stop using the study gel. You may be referred to 
other research studies. Continued study participation would be of no added benefit to you, so 
your participation in the study will be discontinued. 
 
RISKS AND/OR DISCOMFORTS  
Whenever your blood is drawn, you may have: 
x 
Excessive bleeding  
x 
Discomfort 
x 
Feelings of dizziness or faintness 
x 
Bruising, swelling and/or infection 
x 
Development of a blood clot within a vein 
 
Use of an applicator to deliver the study gel into the rectum may be associated with minor 
trauma in and around the rectum and anus, including lacerations (minor cuts) and bruising. 
 
During rectal exams and collection of rectal fluid and tissue samples, insertion of a lubricated 
anoscope will likely cause mild discomfort. Insertion of rectal swabs and sponges may also 
cause mild discomfort, in addition to a slight risk of bleeding. A flexible sigmoidoscopy is a 
commonly practiced medical procedure where a flexible tube with a light source is used to look 
inside the rectum and lower colon. The procedures done in this study will not involve any 
increased risk over usual flexible sigmoidoscopy performed for clinical indications. The risks 
associated with these procedures include mild discomfort, a sudden urge to relieve the bowels, 
the feeling of having a “bloated stomach”, low blood pressure, light bleeding following a bowel 
movement, as well as flatulence following the procedure. Endoscopic biopsies to collect rectal 
tissue samples are painless and heal quickly within 3 days. On extremely rare occasions, the 
endoscopic procedure or biopsies may lead to pain, infection (sepsis), bleeding or perforation 
(small hole or tear) of the gastrointestinal tract. Perforation occurs approximately once out of 
every 1,000 procedures. If this extremely rare complication occurs, antibiotics and surgery to 
repair the tear may be necessary. 
 
(For females) During pelvic exams and vaginal fluid collection you may feel discomfort or 
pressure in your vagina and/or pelvis. Due to the pelvic exam you may also have vaginal 
bleeding or spotting, which will stop shortly after the examination. Cervical biopsies carry the 
risk of discomfort or pain during the procedure and for a few hours afterwards. Participants may 
have spotting (bleeding) for one or two days. With cervical biopsies there is also a small risk of 
infection and heavier bleeding. You may also be at increased risk for STIs and HIV acquisition, 


 
 
 
 
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if exposed. You will be encouraged to call the clinic to report any problems after the collection, 
especially if heavy bleeding is noted (soaking through a pad or tampon in an hour or less) or if 
you develop any abnormal vaginal odor or discharge. 
 
Study Gels 
The study rectal gel can cause some side effects for both males and females. We do not yet 
know all the side effects of the gels. Some, but not all, participants who used gels in other 
studies have had: 
x 
Discharge from the rectum 
x 
Irritation and discomfort 
x 
Abdominal bloating, feeling full, or a sense of abdominal pressure 
x 
A sudden, almost uncontrollable need to relieve the bowels 
x 
Diarrhea (loose, frequent stools) 
x 
Passing gas from the intestinal tract 
x 
Feeling a constant need to pass stools, despite an empty bowel 
 
These side effects may or may not be associated with rectal use of dapivirine gel. 
 
Study Drug 
The following side effects have been associated with the use of dapivirine in male and female 
participants in other studies. These side effects may or may not be associated with the use of 
dapivirine when the drug is placed into a rectal gel: 
x 
Headache 
x 
Abdominal pain 
x 
Hypophosphataemia (Abnormally low level of phosphates in the blood) 
x 
Neutropenia (Abnormally low level of white blood cells in the blood) 
 
(For females)  
x 
Vaginal bleeding at irregular intervals, particularly between your expected menstrual 
periods 
x 
Vaginal discharge 
x 
Vaginal candidiasis, i.e. yeast infection 
x 
Urinary tract infection 
x 
Gynecological chlamydia infection 
x 
Bacterial Vaginosis 
x 
Upper respiratory tract infection, such as the common cold  
 
For females, the most common side effects associated with dapivirine in previous studies (in 
which dapivirine was placed into a vaginally-applied gel or a vaginal ring): 
x 
Vaginal discharge 
x 
Irregular vaginal bleeding 
x 
Bacterial vaginosis 
 


 
 
 
 
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(For both males and females) 
It is also possible that you may have an allergic reaction to the study product. Signs of allergic 
reaction may include: rash, dizziness, itching, muscle aches, nausea, fainting, facial flushing, 
chest tightness, cough, hives, fever, and shortness of breath. 
 
Other Possible Risks 
You may become embarrassed and/or worried when discussing your sexual practices, ways to 
protect against HIV and other infections passed through sex, and your test results. You may feel 
anxious while waiting for your test results, and after receiving them. Trained study counselors 
will help you deal with any feelings or questions you have.  
 
We will make every effort to protect your privacy and confidentiality during the study visits. Your 
visits will take place in private. However, it is possible that others may learn of your participation 
here and, because of this, may treat you unfairly or discriminate against you. For example, you 
could have problems getting or keeping a job, or being accepted by your family or community. 
Finding out your HIV status could cause depression and/or suicidal thoughts.  Finding out your 
HIV status could also cause problems between you and your partner(s). If you have any 
problems, study counselors will talk with you and/or your partner to try to help resolve them.  
 
It is possible that you and/or your partner(s) may experience problems in your relationship(s) 
associated with maintenance of the study-required abstinence.   
 
The interviews that take place at some of your clinic visits will be computer-administered and 
questions of a personal nature may be asked. Responding to these questions may make you 
uncomfortable.  You should NOT identify anyone in the interviews and any names that might be 
mentioned during the interview will NOT be retained.  Instead a generic description will be used 
in the records (i.e., if you refer to a friend’s name, “FRIEND1” will be noted).   
 
(For Females) Pregnancy and Breastfeeding  
The study gel does not prevent pregnancy. You must agree to use an effective method of birth 
control such as birth control pills or another hormonal-based method (except for vaginal rings), 
or an intrauterine device (IUD), unless you or your partner have been sterilized (i.e., no longer 
able to become pregnant), and/or you have been sexually abstinent for more than 90 days and 
plan to continue for the duration of the study.   
 
We do not know what effect dapivirine has on pregnancy, including the effect of dapivirine on 
the fetuses of women who use the rectal gel when pregnant, or the babies of women who use 
the gel when breastfeeding. Because of this, pregnant women and women who are 
breastfeeding may not join this study. Women who join this study will have pregnancy tests 
while in the study.  
 
If you become pregnant during the study, study staff will refer you to available medical care and 
other services you or your baby may need. The study does not pay for this care. You will stop 
using the gel and you will exit the study. We will contact you to find out about your pregnancy 
and the outcome of your pregnancy. The outcome of your pregnancy is important to study staff; 
therefore your pregnancy will be followed until the results of your pregnancy are known. [SITES 


 
 
 
 
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TO INCLUDE/AMMEND THE FOLLOWING: We may also contact you about a study that 
collects information about pregnancy and children up to one year old.] 
 
BENEFITS 
You will receive no direct benefit from receiving study gel during your participation in this study. 
Information learned from this study may help in the development of ways to prevent the spread 
of HIV in the future. You will receive pelvic (females) and rectal exams and counseling and 
testing for HIV and STIs. You will also have tests to check the overall health of your liver, 
kidneys, and blood cells. 
 
This study cannot provide you with general medical care, but study staff will refer you to other 
available sources of care.  
 
You will receive free male condoms, if you need them. If you are infected with HIV, you will be 
referred for medical care, counseling, and other services available to you. Medical care for HIV 
infection will not be part of this study. You will need to receive care for HIV infection from your 
own health care provider or we will provide you with a referral. If you have an STI diagnosed, 
you will receive medicine or a referral, if needed, and study staff will discuss options available 
for counseling and treatment of your partner.  
 
NEW INFORMATION 
You will be told of any new information learned during this study that might affect your 
willingness to stay in the study. For example, if information becomes available that shows that 
the gel may be causing bad effects, you will be told about this. You will also be told when study 
results may be available, and how to learn about them. 
 
WHY YOU MAY STOP TAKING THE STUDY DRUG EARLY OR BE WITHDRAWN FROM 
THE STUDY WITHOUT YOUR CONSENT 
A study clinician may need to remove you from the study early without your permission if: 
x 
The study is cancelled by the US FDA, US NIH, the US Office for Human Research 
Protections (OHRP), MTN, the local government or regulatory agency, or the Institutional 
Review Board (IRB)/ the Ethics Committee (EC). An IRB or EC is a committee that watches 
over the safety and rights of research participants 
x 
The Study Monitoring Committee (SMC) recommends that the study be stopped early (A 
SMC reviews the progress of the study and the kinds of effects that people report while they 
are participating in the study) 
x 
You are found to be infected with HIV 
x 
(Females) You become pregnant or begin breastfeeding 
x 
You are not able to keep appointments or follow study requirements 
x 
Other reasons that may prevent you from completing the study successfully 
 
In the event that you are removed from or choose to leave this study, you will be asked to 
complete some of the procedures described for Visit 13, if you are willing to do so.  
 
The study clinician will ask you to stop using the study rectal gel but continue to come in for 
follow-up visits and procedures if you have a bad reaction to the study gel. 
 


 
 
 
 
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ALTERNATIVE OPTIONS  
We do not know if the drug contained within the gel works to protect men and women from 
getting HIV.  Currently there are two known methods to reduce your risk of contracting HIV, the 
use of condoms and/or the use of oral pre-exposure prophylaxis (PrEP) medication, Truvada®.  
If you are interested in these alternative options you may want to discuss them with your doctor. 
 
COSTS TO YOU 
[Site to complete according to site capacity] There is no cost to you for study related visits, the 
rectal gel, physical/pelvic/rectal examinations, laboratory tests or other procedures. Treatments 
available to you from the study site for infections passed through sex will be given to you free of 
charge or you will be referred for available treatment for the duration of the study. 
 
REIMBURSEMENT 
[SITES TO INSERT INFORMATION ABOUT LOCAL REIMBURSEMENT:] You will receive 
[SITES TO INSERT AMOUNT $xx] for your time, effort, and travel to and from the clinic at each 
scheduled visit. You may receive [SITES TO INSERT AMOUNT $xx] for any visits which occur 
in between your normally scheduled visits.  
  
CONFIDENTIALITY 
Efforts will be made to keep your information confidential. However, it is not possible to 
guarantee confidentiality. Your personal information may be disclosed if required by law. The 
study staff may use your personal information to verify that you are not in any other research 
studies. This includes studies conducted by other researchers that study staff know about. Any 
publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by: 
x 
Representatives of the US Federal Government, including the US Food and Drug 
Administration (FDA), US Office for Human Research Protections (OHRP), NIH, and/or 
contractors of NIH 
x 
Other local and US regulatory authorities 
x 
Study monitors 
x 
Site IRB/EC 
x 
Study staff 
 
[Sites to include/amend the following:] [LOCAL/STATE/NATIONAL] regulations require 
study staff to report the names of people who test positive for HIV and other infections passed 
during sex to the [LOCAL HEALTH AUTHORITY]. Outreach workers from the [LOCAL 
HEALTH AUTHORITY] may then contact you about informing your partners, since they also 
should be tested. If you do not want to inform your partners yourself, the outreach workers will 
contact them, according to the confidentiality guidelines of the [HEALTH AUTHORITY]. 
 
[US sites to include/amend the following:] 
The researchers will do everything they can to protect your privacy. In addition to the efforts of 
the study staff to help keep your personal information private, we have obtained a Certificate of 
Confidentiality from the US Federal Government. This Certificate protects study staff from being 
forced to tell people who are not connected with this study, such as the court system, about 
your participation or information you give for study purposes. However, if the study staff learns 


 
 
 
 
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of possible child abuse and/or neglect or a risk of harm to you or others, they will be required to 
tell the proper authorities. This Certificate does not prevent you from releasing information about 
yourself and your participation in the study.  
 
RESEARCH-RELATED INJURY 
[SITES TO SPECIFY INSTITUTIONAL POLICY:] It is unlikely that you will be injured as a result 
of study participation. If you are injured, the [institution] will give you immediate necessary 
treatment for your injuries. You [will/will not] have to pay for this treatment. You will be told 
where you can receive additional treatment for your injuries. The U.S. National Institutes of 
Health (NIH) does not have a mechanism to pay money or give other forms of compensation for 
research related injuries. You do not give up any legal rights by signing this consent form. 
 
YOUR RIGHTS AS A RESEARCH PARTICIPANT/VOLUNTEER 
[SITES TO SPECIFY INSTITUTIONAL POLICY:] 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. If you 
choose not to participate or to leave the study, you will not lose the benefit of services to which 
you would otherwise be entitled at this clinic. If you want the results of the study after the study 
is over, let the study staff members know. 
 
PROBLEMS OR QUESTIONS 
If you ever have any questions about the study, or if you have a research-related injury, you 
should contact [insert name of the investigator or other study staff] at [insert telephone 
number and/or physical address]. 
 
If you have questions about your rights as a research participant, you should contact [insert 
name or title of person on the IRB/EC or other organization appropriate for the site] at 
[insert physical address and telephone number]. 
 


 
 
 
 
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CONSENT FOR LONG-TERM STORAGE AND FUTURE TESTING OF SPECIMENS  
There might be a small amount of blood, vaginal fluid, cervical tissue, cervical fluid, rectal 
tissue and rectal fluid left over after we have done all of the study related testing.  We 
would like to ask your permission to store these leftover samples and related health 
information for use in future studies.  This health information may include personal facts 
about you such as your race, ethnicity, sex, medical conditions and your age range.  If 
you agree, your samples and related health data will be stored safely and securely at 
facilities that are designed so that only approved researchers will have access to the 
samples. Some employees of the facilities will need to have access to your samples to 
store them and keep track of where they are, but these people will not have information 
that directly identifies you.  You can still enroll in this study if you decide not to have 
leftover samples stored for future studies.  If you do not want the leftover samples stored, 
we will destroy these specimens.  The specific type of testing planned for your leftover 
specimens is not yet known, however samples may be used by the MTN Laboratory 
Center to complete additional quality assurance and control testing, ensuring that tests 
function correctly and supply accurate data.  No genetic testing (limited or genome-wide) 
is planned on leftover samples that are stored for the purposes of future research. It is 
important that you know that any future testing/studies planned for these specimens must 
be approved by an Ethics Committee/Institutional Review Board before they can be done.  
You can withdraw your consent for the storage and future testing of specimens at any 
time by providing a request to the person in charge of this study. However, researchers 
will not be able to destroy samples or information from research that is already underway. 
 
_______________ 
 
 
Initials and Date 
I DO agree to allow my biological specimens and health data to 
be stored and used in future research studies. 
 
_______________ 
 
 
Initials and Date 
I DO NOT agree to allow my biological specimens and health 
data to be stored and used in future research studies. 
 


 
 
 
 
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SIGNATURES- VOLUNTARY CONSENT 
 
[INSERT SIGNATURE BLOCKS AS REQUIRED BY THE LOCAL IRB/EC] If you have 
read this consent form, or had it read and explained to you, and you understand the 
information, and you voluntarily agree to take part in the study, please sign your name 
or make your mark below. 
 
____________________ ________________________ ______________ 
Participant Name   
Participant Signature/Mark Date 
(print) 
 
____________________ ________________________ ______________ 
Study Staff Conducting  
Study Staff Signature 
 
Date 
Consent Discussion (print) 
 
 
____________________ ________________________ ______________ 
Witness Name (print) 
Witness Signature  
 
Date 
 
 
 
 
 
 


 
 
 
 
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Reference List 
 
 1.  International Partnership for Microbicides (IPM). Investigator's Brochure: Dapivirine 
Vaginal Gel. Version 7.0. 8-28-2013.  
 
 2.  Clark MR, Friend DR. Pharmacokinetics and topical vaginal effects of two tenofovir 
gels in rabbits. AIDS Res Hum Retroviruses 2012;28(11):1458-1466. 
 3.  Fletcher P, Harman S, Azijn H et al. Inhibition of human immunodeficiency virus 
type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse 
transcriptase inhibitor. Antimicrob Agents Chemother 2009;53(2):487-495. 
 4.  Di FS, Van RJ, Giannini G et al. Inhibition of vaginal transmission of HIV-1 in hu-
SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel 
formulation. AIDS 2003;17(11):1597-1604. 
 5.  CONRAD. Investigator's Brochure: Universal Placebo Gel.  2005.  
 
 6.  Tien D, Schnaare RL, Kang F et al. In vitro and in vivo characterization of a 
potential universal placebo designed for use in vaginal microbicide clinical trials. 
AIDS Res Hum Retroviruses 2005;21(10):845-853. 
 7.  Gilead Sciences. Investigator's Brochure: Tenofovir Gel (GS-1278). Second 
Edition. 3-31-2005.  
 
 8.  Patton DL, Sweeney YT, Balkus JE et al. Preclinical safety assessments of UC781 
anti-human immunodeficiency virus topical microbicide formulations. Antimicrob 
Agents Chemother 2007;51(5):1608-1615. 
 9.  Guttner J, Klaus S, Heinecke H. [Embryotoxicity of intraperitoneally administered 
hydroxyethylcellulose in mice (author's transl)]. Anat Anz 1981;149(3):282-285. 
 10.  International Partnership for Microbicides. Investigator's Brochure: Dapivirine 
Vaginal Gel, Including Rectal Gel (Version 8.0 Final).  1-178. 9-4-2015.  
 
 11.  International Partnership for Microbicides (IPM). Investigator's Brochure: Dapivirine 
Vaginal Gel (Version 7.0 Final). Version 7.0. 8-28-2013.  
 
 12.  Bunge KE, Dezzutti CS, Rohan LC et al. A Phase 1 trial to assess the safety, 
acceptability, pharmacokinetics, and pharmacodynamics of a novel dapivirine 
vaginal film. JAIDS 2016;71(5):498-505. 
 13.  Robinson JA. FAME 02B Study: TEAEs (Personal Communication). Conser E, 
editor.  10-4-2016. 10-10-2016.  


 
 
 
 
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 14.  International Partnership for Microbicides. PK/PD of Single Dose Dapivirine 
Vaginal Film (FAME-02B).  8-29-2016.  ClinicalTrials.gov. 10-7-2016.  
 
 15.  Baeten JM, Palanee-Phillips T, Brown ER et al. Use of a vaginal ring containing 
dapivirine for HIV-1 prevention in women. N Engl J Med 2016;375(22):2121-2132. 
 16.  International Partnership for Microbicides (IPM). Investigator's Brochure: Dapivirine 
Vaginal Ring (Version 10.0 Final).  3-9-2016.  
 
 17.   Safety and efficacy of dapivirine vaginal ring for HIV-1 prevention in African 
women. 2016 Conference on Retroviruses and Opportunistic Infections (CROI); 16 
Feb 22; 2016. 
 18.   Safety, Pharmacokinetics and Pharmacodynamics of Two Daily Dapivirine Vaginal 
Microbicide Gels for HIV Prevention.  International Microbicides Conference 
M2012, Sydney, 2012.; 2012. 
 19.  CSR Reference. Final Clinical Study Report for IPM 014A - A double-blind, 
randomized, placebo-controlled Phase I/II trial to evaluate the safety and 
acceptability of dapivirine Gel 4759, 0.05% 2.5g, a vaginal microbicide, conducted 
using daily monitored adherence in healthy HIV-negative women.  4-18-2013.  
 
 20.  Cranston RD, Hoesley C, Carballo-Dieguez A et al. A randomized male tolerance 
study of dapivirine gel following multiple topical penile exposures (MTN 012/IPM 
010). AIDS Res Hum Retroviruses 2014;30(2):184-189. 
 21.  Robinson JA, Marzinke MA, Bakshi RP et al. Comparison of dapivirine vaginal gel 
and film formulation pharmacokinetics and pharmacodynamics (FAME 02B) (Epub 
ahead of print). AIDS Research and Human Retroviruses 2016. 
 22.  Nel AM, Smythe SC, Habibi S, Kaptur PE, Romano JW. Pharmacokinetics of 2 
dapivirine vaginal microbicide gels and their safety vs. Hydroxyethyl cellulose-
based universal placebo gel. J Acquir Immune Defic Syndr 2010;55(2):161-169. 
 23.  Nel A SSHSRJ. Comparison of Safety and PK of Two Formulations of Dapivirine 
Vaginal Gel in Healthy, HIV-Negative Women [abstract]. 16th Conference on 
Retroviruses and Opportunistic Infections . 2-8-2009.  
 
 24.  Dreisbach R. Handbook of Poisoning: diagnosis & treatment. 9th ed. ed. Los Altos, 
Calif.: Lange Medical Publications; 1977. 
 25.  Schwartz JL, Ballagh SA, Kwok C et al. Fourteen-day safety and acceptability 
study of the universal placebo gel. Contraception 2007;75(2):136-141. 


 
 
 
 
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 26.  Anton PA, Saunders T, Elliott J et al. First phase 1 double-blind, placebo-
controlled, randomized rectal microbicide trial using UC781 gel with a novel index 
of ex vivo efficacy. PLoS One 2011;6(9):e23243. 
 27.  Anton PA, Cranston RD, Kashuba A et al. RMP-02/MTN-006: A phase 1 rectal 
safety, acceptability, pharmacokinetic, and pharmacodynamic study of tenofovir 
1% gel compared with oral tenofovir disoproxil fumarate. AIDS Res Hum 
Retroviruses 2012;28(11):1412-1421. 
 28.  McGowan I, Hoesley C, Cranston RD et al. A phase 1 randomized, double blind, 
placebo controlled rectal safety and acceptability study of tenofovir 1% gel (MTN-
007). PLoS One 2013;8(4):e60147. 
 29.   Safety and pharmacokinetics/pharmacodynamics of dapivirine and maraviroc 
vaginal rings. 21st Conference on Retroviruses and Opportunistic Infections; 14 
Mar 3; 2014. 
 30.  Carballo-Dieguez A, Dolezal C, Bauermeister JA, O'Brien W, Ventuneac A, Mayer 
K. Preference for gel over suppository as delivery vehicle for a rectal microbicide: 
results of a randomised, crossover acceptability trial among men who have sex 
with men. Sex Transm Infect 2008;84(6):483-487. 
 31.  Carballo-Dieguez A, Giguere R, Dolezal C et al. Rectal-specific microbicide 
applicator: evaluation and comparison with a vaginal applicator used rectally. AIDS 
Behav 2014;18(9):1734-1745. 
 32.  Ventuneac A, Carballo-Dieguez A, McGowan I et al. Acceptability of UC781 gel as 
a rectal microbicide among HIV-uninfected women and men. AIDS Behav 
2010;14(3):618-628. 
 33.  Morrow KM, Rosen RK, Salomon L et al. Using integrated mixed methods to 
develop behavioral measures of factors associated with microbicide acceptability. 
Qual Health Res 2011;21(7):987-999. 
 34.  Gatto NM, Frucht H, Sundararajan V, Jacobson JS, Grann VR, Neugut AI. Risk of 
perforation after colonoscopy and sigmoidoscopy: a population-based study. J Natl 
Cancer Inst 2003;95(3):230-236. 
 35.  The safety of multiple flexible sigmoidoscopies in clinical trial participants (Poster). 
HIV Research for Prevention (HIV R4P) 2016; 16 Oct 11; 2016. 
 
 

SAP_001.pdf: 
 
 
 
 
 
Page 1 of 14 
 
NCT03239483 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
MTN-026 
A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and 
Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 
Seronegative Adults  
 
 
 
 
 
 
 
Statistical Center for HIV/AIDS Research and Prevention 
 
 
Elizabeth Brown, ScD 
Clara Domínguez Islas, PhD 
Holly Gundacker, MS 
 
 
 
SAP Version 1.0 
03 January 2019 
 


 
 
 
 
 
 
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MTN-026 Statistical Analysis Plan 
All proprietary rights reserved 
Page 2 of 14 
Approval Signature Page 
 
MTN-026 
 
Statistical Analysis Plan 
 
A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and 
Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 
Seronegative Adults 
 
I have read this Statistical Analysis Plan and approve its contents. 
 
 
 
______________________________ 
 
 
 
_____________________ 
Elizabeth Brown, SD 
 
 
 
 
 
Date 
PI, Lead Statistician 
Fred Hutchinson Cancer Research Center, VIDD 
 
 
______________________________ 
 
 
 
_____________________ 
Clara Domínguez Islas, PhD 
 
 
 
 
Date 
Staff Scientist, Lead Statistician 
Fred Hutchinson Cancer Research Center, VIDD 
 
 
______________________________ 
 
 
 
_____________________ 
Holly Gundacker, MS 
 
 
 
 
 
Date 
Statistical Research Associate 
SCHARP 
 
 
 


 
 
 
 
 
 
Confidential 
MTN-026 Statistical Analysis Plan 
All proprietary rights reserved 
Page 3 of 14 
TABLE OF CONTENTS 
1. LIST OF ABBREVIATIONS AND ACRONYMS ......................................................................... 4 
2. INTRODUCTION ................................................................................................................. 4 
2.1 GENERAL DESIGN CONSIDERATIONS ................................................................................................ 4 
2.2 STUDY OBJECTIVES AND ENDPOINTS ............................................................................................... 5 
2.3.1 Randomization ................................................................................................................ 6 
2.3.2 Blinding ............................................................................................................................ 7 
2.3.3 Sample Size and Power.................................................................................................... 7 
3. GENERAL DATA ANALYSIS CONSIDERATIONS ...................................................................... 7 
3.1 ANALYSIS SET(S) ......................................................................................................................... 7 
3.2 STATISTICAL ANALYSIS ISSUES ........................................................................................................ 7 
4. INTERIM ANALYSIS AND DATA MONITORING COMMITTEE ................................................. 7 
5. GENERAL ANALYSIS METHODS ........................................................................................... 8 
6. TRIAL PARTICIPANT DISPOSITION ....................................................................................... 8 
6.1 DISPOSITION OF PARTICIPANTS ...................................................................................................... 8 
6.2 TREATMENT EXPOSURE ................................................................................................................ 9 
6.3 PROTOCOL DEVIATIONS ................................................................................................................ 9 
7. BASELINE DATA ................................................................................................................. 9 
7.1 DEMOGRAPHICS.......................................................................................................................... 9 
7.2 BASELINE MEDICAL HISTORY ......................................................................................................... 9 
7.3 VITAL SIGNS ............................................................................................................................. 10 
7.4 PHYSICAL EXAM ........................................................................................................................ 10 
7.5 ANORECTAL AND PELVIC EXAMS................................................................................................... 10 
7.6 HEMATOLOGY .......................................................................................................................... 10 
8. PRIMARY ENDPOINT ANALYSES ....................................................................................... 10 
8.1 ADVERSE EVENTS ...................................................................................................................... 10 
8.2 PHARMACOKINETICS EVALUATIONS ............................................................................................... 11 
8.2.1 DAPIVIRINE CONCENTRATIONS IN BLOOD, RECTAL FLUID AND RECTAL TISSUE....................................... 11 
9. SECONDARY ENDPOINTS .................................................................................................. 13 
9.1 ACCEPTABILITY ......................................................................................................................... 13 
9.2 MUCOSAL SAFETY ..................................................................................................................... 13 
10. SAFETY ANALYSES .......................................................................................................... 13 
10.1 ADVERSE EVENTS AND DEATHS .................................................................................................. 13 
10.2 LABORATORY EVALUATIONS RESULTS .......................................................................................... 13 
10.3 OTHER SAFETY MEASURES ........................................................................................................ 14 


 
 
 
 
 
 
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Page 4 of 14 
1. LIST OF ABBREVIATIONS AND ACRONYMS  
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CV 
coefficient of variation 
DPV 
dapivirine 
eCRF electronic case report form 
HIV 
Human Immunodeficiency Virus 
HIV-1 Human Immunodeficiency Virus type 1 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
SAP 
statistical analysis plan 
SGOT serum glutamic-oxaloacetic transaminase 
SGPT serum glutamic pyruvic transaminase 
SMC 
study monitoring committee 
STI 
sexually transmitted infection 
t1/2 
terminal elimination half-life 
2. INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical analyses 
that will be conducted to assess the safety, pharmacokinetics and acceptability of the dapivirine gel 
administered into the rectum, when compared to a placebo gel, among HIV-uninfected men and women.  
2.1 General Design Considerations 
 
The following is a protocol summary of the study. 
 
Protocol title:  
A Randomized, Double Blind, Placebo-Controlled Phase 1 Safety and 
Pharmacokinetic Study of the Dapivirine Gel (0.05%) Administered Rectally to 
HIV-1 Seronegative Adults  
Short Title:  
Dapivirine Gel Rectal Safety and PK Study 
Clinical Phase: 
Phase 1 
IND Sponsor: 
DAIDS 
Protocol Chair: 
Ross D. Cranston, MD, FRCP  
Sample Size: 
approximately 27 participants 
Study Population:  
HIV-uninfected men and women between the ages of 18 and 45 years (inclusive)  
Study Sites: 
Sites selected by the MTN leadership 
Study Design: 
Phase 1, two-arm, placebo-controlled, double-blinded, multi-site, randomized trial 
(2:1)  
Study Duration: 
Approximately 40 days of follow-up per participant is planned with a projected 
accrual period of 6-8 months 
Study Products: 
Dapivirine gel (0.05%) 


 
 
 
 
 
 
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MTN-026 Statistical Analysis Plan 
All proprietary rights reserved 
Page 5 of 14 
 
 
Universal HEC placebo gel  
Study Regimen: 
Participants will be randomized in a 2:1 ratio to receive a single dose of either 
dapivirine gel or universal HEC placebo gel rectally, followed by 7 daily doses of 
the same product to be administered under direct observation in the clinic.  
 
2.2 Study Objectives and Endpoints 
Primary Objectives: 
 
 
Safety 
 
• 
To assess the safety of dapivirine gel formulation when applied rectally. 
 
 
Pharmacokinetics 
• 
To characterize the systemic and compartmental pharmacokinetics of dapivirine gel following 
rectal application. 
 
Secondary Objectives: 
 
 
Acceptability 
 
• 
To identify product attributes considered likely to challenge and facilitate future sustained use of 
rectally applied dapivirine gel. 
 
Mucosal Safety 
 
• 
To evaluate the mucosal safety of dapivirine gel when applied rectally. 
 
Exploratory Objectives: 
 
 
Ex Vivo Efficacy 
 
• 
To assess the preliminary (ex vivo) efficacy of dapivirine gel formulation after product is applied 
rectally. 
 
Pharmacokinetics 
 
• 
To characterize the vaginal pharmacokinetics of dapivirine gel following rectal application in 
women.  
  
Primary Endpoints: 
 
Safety 
 
• 
The proportion of participants with: 
o 
Grade 2 or higher AEs as defined by the Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 and/or Addenda 
1, 2 and 3 (Female Genital [Dated November 2007], Male Genital [Dated November 
2007] and Rectal [Clarification Dated May 2012] Grading Tables for Use in Microbicide 
Studies). 


 
 
 
 
 
 
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Page 6 of 14 
Pharmacokinetics 
 
• 
Dapivirine concentrations  
o 
Blood 
o 
Rectal fluid 
o 
Rectal mucosal tissue homogenates.  
 
Secondary Endpoints: 
 
 
Acceptability 
 
• 
Product attributes considered likely challenge future sustained use 
Mucosal Safety 
 
• 
Rectal Proteomics  
• 
Rectal transcriptome 
• 
Rectal microflora 
• 
Rectal histology 
• 
Rectal tissue flow cytometry 
Exploratory Endpoints: 
 
 
Ex Vivo Efficacy 
 
• 
Changes in HIV-1 p24 levels in colorectal explant culture supernatant  
• 
Anti-HIV activity in rectal fluid 
• 
Anti-HIV activity in cervicovaginal fluid (in women) 
Pharmacokinetics 
 
• 
Dapivirine concentrations  
o 
Cervicovaginal fluid (in women) 
o 
Cervical tissue (in women) 
2.3.1 Randomization 
Participants were randomized in a 2:1 ratio to the dapivirine and placebo arms, stratified by study site.  
 
Participants were also sequentially assigned in a 1:1 ratio to provide intensive PK samples at either 30-60 
or 120 minutes after administration of the gel on Visits 3 and 13. Participants were also sequentially 
assigned in a 1:1:1 ratio to provide intensive PK samples at either Visits 4 and 14, Visits 5 and 15 or 
Visits 6 and 16.  
 
The randomization scheme has been generated and maintained by the MTN SDMC. 
 


 
 
 
 
 
 
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2.3.2 Blinding 
Study staff and participants are blinded to the random treatment assignment of all study participants.  
 
2.3.3 Sample Size and Power 
The proposed sample size for this study was 27 participants, with 18 in the active arm and 9 in the control 
arm. The study has power to detect only very large differences in safety event rates between active and 
control arms. With 5% significance level, the study has 85% power to detect a rate in safety endpoint 
greater than 67% in the active arm when assuming an 11.2% rate in the control arm. On the other hand, 
the proposed sample size ensures a reasonable frequency of safety events that are not too rare. For 
example, if the true event rate of an adverse event is 10%, then the probability of observing at least one 
adverse event in the study is 85%.  
3. GENERAL DATA ANALYSIS CONSIDERATIONS 
3.1 Analysis Set(s) 
The analysis set for the primary safety endpoint will include all enrolled participants who received at least 
one dose of the study product (either the dapivirine or the placebo gel). The analysis set for the primary 
PK endpoint will include enrolled participants who were assigned to receive the active treatment and who 
received at least one dose of the study product (dapivirine gel).  
 
Participants enrolled but lost to follow-up between enrollment visit (Visit 2) and the first dosing visit (Visit 
3) or who were never administered the gel will not be included in the analysis sets. Enrolled participants 
who received the study product but were found to be ineligible (enrollment violations) will preferably be 
included in the analysis sets, in order to capture all adverse events potentially related to the study 
product. Sensitivity analysis of the primary safety endpoint excluding these participants will be conducted. 
 
All the participants to be excluded from the analysis sets will be identified prior to data lock and to the 
unblinding of the data and the reasons for exclusion will be properly documented.  
3.2 Statistical Analysis Issues 
Based on previous MTN trials, minimal missing data is expected. Any missing data will be tabulated as a 
separate category when reporting data summaries.  
 
If missing data rates are higher than anticipated (over 10%), sensitivity analyses for the primary safety 
endpoint will be conducted. For these sensitivity analyses, we will impute extreme values to the missing 
data and report the resulting analyses.  
4. INTERIM ANALYSIS AND DATA MONITORING COMMITTEE 
No interim statistical analysis was planned or performed for the MTN-026 study.  
 
One safety monitoring committee (SMC) review was conducted for MTN-026, on May 14, 2018, for which 
a closed report was produced. Evaluation of safety was based on descriptive tables of adverse events, 
with no formal statistical testing.  


 
 
 
 
 
 
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5. GENERAL ANALYSIS METHODS 
Descriptive statistics will be used to summarize continuous (mean and standard deviation, median and 
interquartile range, quartiles, range, and number of missing data values) and categorical (frequencies, 
relative frequencies, percentages, and number of missing data values) outcomes. Line, scatter, and box 
plots will be used, as appropriate, to visualize trends in longitudinally repeated measures.  
 
Confidence intervals will be obtained using the Clopper-Pearson method for binary outcomes, while for 
continuous outcomes these will be based on the Student’s-t statistic. Unless otherwise specified, 95% 
confidence intervals will be provided.  
 
When use of formal testing to assess differences between participants in active and placebo arms are 
required, the following methods will be used: for binomial response variables, a Fisher’s exact test; for 
continuous variables, t-tests or nonparametric methods. Unless otherwise specified, results from two-
sided hypothesis tests will be reported.  
6. TRIAL PARTICIPANT DISPOSITION 
6.1 Disposition of Participants 
Enrollment of participants took place at three study sites: Birmingham, AL, and Pittsburgh, PA, in the US 
and Bangkok in Thailand.  
 
6.1.1 Study Screening and Enrollment 
 
The number of participants screened, the number of participants who were enrolled and not enrolled, the 
number of participants with each reason for not enrolling, and the number of participants considered 
evaluable for each primary and secondary endpoint will be displayed in tables overall and by site. These 
summaries will also be displayed by arm in a CONSORT diagram. 
 
Dates of site activation, first enrollment and last enrollment, as well as the number of participants enrolled 
the screening-to-enrollment ratio will be displayed in tables overall and by site and by arm. 
 
6.1.2 Retention 
 
For each visit, a participant is expected to have returned to the site clinic within a specified visit window, 
based on the participant’s date of enrollment visit or, for sampling visits, based on the previous dosing 
visit. The proportion of participants retained at a scheduled visit is obtained by dividing the number of 
participants who have completed the visit by the number of participants expected for that visit. Tables will 
be presented that show by visit the number and percentage of expected, retained, missed visits, and lost-
to-follow-up or terminated participants, overall and by arm and by site. No formal statistical testing will be 
conducted. 
 
6.1.3 Treatment Discontinuation 
 
The number and percentage of participants who ended product use early (prior to visit 13), as well as the 
reasons for terminating product use early, as collected on the Treatment Discontinuation electronic Case 
Report Form (eCRF), will be presented in tables by arm and by site. Reasons for ending study product 
use early include the following: acquisition of HIV infection, Adverse Event, reported use of prohibited 
medications, pregnancy, breastfeeding, anorectal STIs, participant unable/unwilling to comply with 
required study procedures or otherwise might be put at undue risk to their safety and well-being by 


 
 
 
 
 
 
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continuing product use according to judgment of IOR/designee, other. No formal statistical testing will be 
conducted. 
 
6.1.4 Study Discontinuation 
 
The number and percentage of the participants who completed the study, as well as the reasons for non-
completion, as collected on the Study Discontinuation electronic Case Report Form (eCRF), will be 
presented in tables by arm and by site. Reasons for non-completion include the following: death, 
withdrawal of consent by participant, lost to follow-up, investigator decision, study terminated by sponsor, 
pregnancy, HIV infection, permanent study product discontinuation, other. No formal statistical testing will 
be conducted. 
 
6.1.5 Visit Adherence: Completion of Procedures 
 
Visit adherence will be summarized by completion of required and expected procedures overall and 
by site. This will be done for the following procedures (we mark with asterisk (*) those procedures that are 
expected only for female participants): 1) Physical exam; 2) vital signs; 3) sexual lubricant form; 4) 
pregnancy tests *; 5) chemistries; 6) pelvic exam *; 7) rectal exam; 8) plasma archive; 9) 
plasma for PK; 10) HIV Test; 11) CVL for PD*; 12) cervicovaginal fluid for PK *; 13) cervical tissue for PK 
*; 14) rectal fluid for PK; 15) rectal tissue for PK; 16) rectal fluid for mucosal safety; 17) rectal tissue for 
mucosal safety; 18) rectal tissue for PD; 19) rectal enema effluent for PK/PD; 20) behavioral assessment; 
21) In-depth interview. Tables displaying the number and percentages of participant-visits for each of 
these categories by arm and site will be presented. No formal statistical testing will be conducted. 
6.2 Treatment Exposure  
Exposure to treatment, as collected on the Directly Observed Dosing Log eCRF at visit 3 and visits 7 to 
13 will be described. The number and percentage of participants for whom the gel application was (i) 
observed in clinic, (ii) done in home, not observed or (iii) not done, will be displayed in tables by visit and 
site and by visit and study arm.  
6.3 Protocol Deviations 
A table with the number and type of protocol deviations will be presented, by site and by arm. A listing of 
all the protocol deviations will be presented, including the description of the deviations.  
7. BASELINE DATA  
7.1 Demographics 
Demographics and baseline characteristics of participants as collected on the Demographics eCRF will 
be presented by arm and by site. These characteristics include age (continuous in years, and in 
categories of five years), sex at birth, gender identity, marital and cohabitation status, highest level of 
education, race, ethnicity, and income source. No formal statistical testing will be performed. 
 7.2 Baseline Medical History 
A listing of all baseline medical history events as collected on the Baseline Medical History Log eCRF will 
be presented, including grade, severity/intensity, whether the condition is ongoing, and the beginning and 
end dates of the event. No formal statistical testing will be performed. 


 
 
 
 
 
 
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7.3 Vital Signs 
Baseline vital signs as collected on the Vital Signs eCRF at Screening and Enrollment will be presented 
by arm and visit and by site and visit. Summary statistics appropriate for the measurement scale will be 
used to describe distribution of height (at Screening only), weight, body temperature, systolic blood 
pressure, diastolic blood pressure, pulse, and rate of respiration. No formal statistical testing will be 
performed. 
7.4 Physical Exam 
Baseline physical exam results as collected on the Physical Exam eCRF at Screening and Enrollment will 
be presented in tables by arm and visit and by site and visit. Number and percentage of participants 
experiencing any abnormal physical findings at each visit will be presented as well as the number and 
proportions of participants with findings for the following organ systems and body parts: general 
appearance; head, eye, ear, nose, and throat; oral mucosa; neck; lymph nodes; heart/cardiovascular; 
lung/respiratory; abdomen; extremities; neurological; skin; and other system. No formal statistical testing 
will be performed. 
7.5 Anorectal and Pelvic Exams 
Baseline results from the anorectal exam (all participants) and the pelvic exam (female participants only), 
as collected on the Anorectal Exam and Pelvic Exam eCRFs at Screening and Enrollment will be 
presented in tables by arm and visit and by site and visit. Number and percentage of participants 
experiencing any abnormal findings at each visit will be presented as well as the number and proportions 
of participants with specific types of anorectal or pelvic exam findings. No formal statistical testing will be 
performed. 
7.6 Hematology 
Baseline hemogram and differential results as collected on the Hematology eCRF at Screening will be 
presented in tables by arm and by site. Summary statistics appropriate for continuous variables will be 
used to describe each of the following: hemoglobin, hematocrit, MCV, platelets, WBC, neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils. No formal statistical testing will be performed. 
 
7.7 Laboratory Evaluations 
 
Baseline laboratory results as collected on the Local Laboratory eCRF at Screening and Enrollment will 
be presented in tables by arm and visit and by site and visit. Summary statistics appropriate for 
continuous variables will be used to describe each of the following: AST (SGOT), ALT (SGPT), and 
creatinine values. No formal statistical testing will be performed. 
8. PRIMARY ENDPOINT ANALYSES  
8.1 Adverse Events  
For the analysis of the primary safety endpoint, we will present the number and the proportion of 
participants experiencing at least one Grade 2 or higher adverse event, overall and by study arm. Each 
participant will contribute once in each category (i.e., only the highest severity AE of each participant) for 
the calculation of event risks. Exact binomial confidence intervals, using the Pearson-Clopper method, will 
be provided and Fisher’s Exact test will be used to test for differences in risks between the arms.  
 


 
 
 
 
 
 
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Additionally, we will also present the following listings and tables of Adverse Events. No formal statistical 
testing will be conducted.  
 
- 
The total number (and percentage) of adverse experiences by severity and relationship to study 
product, overall and for each study arm and for each site.   
 
- 
Number and percentages of adverse experiences by body system/MedDRA preferred term and 
severity, by study arm and by site.  
 
- 
Number and percentages of adverse experiences by body system/MedDRA preferred term and 
relationship to study product, by study arm and by site. 
 
- 
Cumulative listing of Adverse Events, with arm, site and participant ID, MedDRA preferred term 
and AE verbatim, severity, relationship to study product, date reported to site, onset date, 
outcome date, duration in days, treatment, and outcome.  
 
8.2 Pharmacokinetics Evaluations  
8.2.1 Dapivirine concentrations in blood, rectal fluid and rectal tissue 
For participants in the active arm only, we will report the dapivirine concentration in blood at all time 
points where a sample was obtained. At each sampling time point, the concentration of dapivirine will be 
summarized using descriptive statistics (mean, standard deviation, median, interquartile range and range, 
along with number of participants). Also, 95% confidence intervals for the mean concentration will be 
obtained, using a Student’s-t distribution approximation. Given the small number of samples that are 
expected for some sampling points, a log transformation of the concentrations will be considered if the 
data suggest strong skewness. No formal statistical testing will be performed. 
 
For concentrations of dapivirine that fall below the corresponding assay’s lower limit of quantification 
(LLOQ), we will use a value equivalent to half the LLOQ of the assay. The number and percentage of 
samples that fall below the LLOQ for any given sampling time point will be reported.  
 
The time-points in the proposed sampling schedule were selected to roughly provide a description of 
some important PK characteristics. The sample taken 30-60 min after dosing time will be used to describe 
the concentrations soon after a gel dose. The sample taken 2 h after dosing will be used to roughly 
approximate peak concentrations. Concentrations from 2 h, 24h, 48 h and 72 h after dosing will be used 
to estimate terminal elimination half-life. The sample taken at dosing time after multiple doses will be used 
to estimate the concentration accumulation with multiple dosing (approach to steady state).  
 
The following figures and tables are planned to describe the concentration of dapivirine in blood, rectal 
fluid and rectal tissue:  
 
Dapivirine concentrations in blood 
 
- 
Table summarizing the concentration of dapivirine after single dose: at time of dosing (visit 3), 30-
60 min (visit 3), 120 min (visit 3), 24 h (visit 4), 48 h (visit 5) and 72 h (visit 6) after the time of 
dosing.  
- 
Table summarizing the concentration of dapivirine after the first of multiple doses: at time of 
dosing (visit 7) and 24 h after time of dosing (visit 8). 
- 
Table summarizing the concentration of dapivirine after multiple doses: at time of dosing (visit 
13), 30 – 60 min (visit 13), 120 min (visit 13), 24 h (visit 14), 48 h (visit 15) and 72 h (visit 16) after 
time of dosing.  


 
 
 
 
 
 
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- 
Individual concentration profiles for each participant (dapivirine concentration in blood over time), 
after single dosing (Visits 3 to 6) and multiple dosing (Visits 13 to 16) overlaid in one plot per 
participant.  
- 
Individual concentration profiles after single dosing (Visits 3 to 6) for all participants, overlaid on a 
single plot. 
- 
Individual concentration profiles after multiple dosing (Visits 13 to 16) for all participants, overlaid 
on a single plot. 
- 
Plot of the median of dapivirine concentration in blood over time, with vertical bars indicating 95% 
confidence interval. Separate plots for concentrations after single and after multiple dosing, as 
well as overlaid on a single plot.  
 
 
Dapivirine concentrations in rectal fluid and rectal tissue 
 
- 
Table summarizing the concentration of dapivirine after single dose: at 30-60 min (visit 3), 120 
min (visit 3), 24 h (visit 4), 48 h (visit 5) and 72 h (visit 6) after the time of dosing.  
- 
Table summarizing the concentration of dapivirine (in rectal fluid only) after the first of multiple 
doses: at time of dosing (visit 7) and 24 h after time of dosing (visit 8). 
- 
Table summarizing the concentration of dapivirine after multiple doses: at 30-60 min (visit 13), 
120 min (visit 13), 24 h (visit 14), 48 h (visit 15) and 72 h (visit 16) after time of dosing.  
- 
Individual concentration profiles, before and after dosing, overlaid on a single plot for each 
different sampling schedule.  
- 
Plot of the median of dapivirine concentration in rectal fluid and rectal tissue over time, with 
vertical bars indicating 95% confidence interval. Separate plots for concentrations after single and 
after multiple dosing as well as overlaid on a single plot.  
 
 
8.2.2 Elimination constant rate and terminal elimination half-life 
 
To determine the terminal elimination half-life of dapivirine from blood, we will use the dapivirine 
concentrations from samples at 24 h, 48 h and 72 h after the time of dosing. To determine the terminal 
elimination half-life of dapivirine from rectal fluid and rectal tissue, for each participant we will use their 
concentration at 120 min after dosing and their concentration at either 24 h, 48 h or 72 h after dosing. 
Given the sampling schedule, only about half of the participants will have concentrations of rectal fluid 
and rectal tissue at two of these sampling time points available. 
 
For the calculation of the terminal elimination half-life, for each participant, we will assume a mono-
compartmental model, with the concentration at time t given by:  
 
𝐶(𝑡) = 𝑎 𝑒− 𝛽𝑡  
 
To estimate each participant’s elimination rate constant (), we will use linear regression on the log-
transformed concentrations of dapivirine, with time (of sampling) as predictor, along with an indicator for 
samples obtained after multiple dosing. The resulting absolute value of the slope will correspond to the 
elimination rate constant  The terminal elimination half-life for each participant will be calculated from 
the elimination rate constant as 
𝑡1/2 = log(2)
𝛽
 
 
We will summarize terminal elimination half-life (t½) for blood, rectal fluid and rectal tissue, using 
descriptive statistics and will provide a 95% confidence interval, using a Student’s-t distribution 
approximation.  


 
 
 
 
 
 
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9. SECONDARY ENDPOINTS 
9.1 Acceptability 
To assess acceptability of the study gel, we will focus on the ease of use and comfortability of the study 
product, as reported by participants, using information from the Exit Behavioral Survey. We will present 
results from the section B of the survey on Gel Acceptability, specifically the following two questions:  
 
B1. Overall how easy or difficult was it to use the gel? 
1. Very difficult 
2. Difficult 
3. Easy 
4. Very easy 
 
B2. Overall, how did it feel to have the gel inside you? 
1. Very comfortable 
2. Comfortable 
3. Uncomfortable 
4. Very uncomfortable 
 
Results will be presented overall and by arm, with the number and percentage of participants in each 
category. To conduct formal statistical testing, collapsed categories will be created. For question B1, we 
will calculate the proportion of participants that responded “Easy” or “Very easy”. For question B2, we will 
calculate the proportion of participants that responded “Liked” or “Liked very much”. We will present the 
binomial proportions with exact 95% confidence intervals, overall and for each arm. Fisher’s Exact test 
will be used to test for differences between arms 
 
Results will also be presented overall and by site, with no formal statistical testing.  
9.2 Mucosal safety 
Because the evaluations for safety focused on the rectal mucosal (proteomics, transcriptome, microflora, 
histology, tissue flow cytometry) include very specialized analyses, these will be described in a separate 
statistical analysis plan and performed separately.  
10. SAFETY ANALYSES  
All participants enrolled and administered the study product will be assessed for safety and tolerability. 
10.1 Adverse Events and Deaths 
See Section 8 for the description of the analyses on Adverse Events as the primary study endpoint 
related to Safety.  
10.2 Laboratory Evaluations Results 
10.2.1 Laboratory Evaluations 
Laboratory results as collected on the Local Laboratory eCRF will be presented in tables by arm and visit 
and by site and visit. Summary statistics appropriate for the measurement scale will be used to describe 
AST (SGOT), ALT (SGPT), and creatinine values and severity grades. No formal statistical testing will be 
performed. 


 
 
 
 
 
 
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10.2.1 HIV Testing  
 
Number and percentage of participants with a positive HIV test result as collected on the HIV Test 
Results eCRF will be presented in tables by arm. No formal statistical testing will be performed. 
10.3 Other Safety Measures 
10.3.1 Anorectal Exam 
 
Anorectal exam results as collected on the Anorectal Exam eCRF will be presented in tables by arm and 
visit and by site and visit. Number and percentage of participants with any abnormal perianal 
examination, digital rectal examination, rectal mucosa from anoscopy, and sigmoidoscopy findings at 
each visit will be presented as well as the number and proportions of participants with specific findings. 
No formal statistical testing will be performed. 
 
10.3.2 Concomitant Medications 
A listing of all concomitant medications as collected on the Concomitant Medications Log eCRF will be 
presented, including, indication, date started and stopped, whether the medication is ongoing, frequency, 
route, dose, dose units, whether the medication was taken for an AE, and if so what AE(s). No formal 
statistical testing will be performed.