Conditions: HIV Infections
Keywords: Microbicides
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the safety and pharmacokinetics of PC-1005 gel when used as a rectal microbicide in HIV-uninfected men and women (cis or transgender) with a history of consensual receptive anal intercourse.

Detailed description:
PC-1005 is a multipurpose prevention technology (MPT) microbicide in development that is active against HIV, HPV, and HSV-2. This study will evaluate the safety and pharmacokinetics of PC-1005 gel when administered rectally.

The study will enroll HIV-uninfected men and women (cis or transgender) with a history of consensual receptive anal intercourse. All participants will receive 3 single escalating doses of rectally administered PC-1005: 4 mL, 16 mL and 32 mL.

The study includes a total of 9 clinic visits and 1 follow-up contact by phone or in person. Participants will receive doses of PC-1005 at Visits 3, 5, and 7. A 2-to-6 week washout period will follow each dosing visit. If no adverse events that preclude continuation to the next dose are identified during this period, participants will receive the next scheduled dose of PC-1005. Participation in this study will last approximately 3 to 5 months.

Study visits will include physical examinations, throat swabs, behavioral assessments and interviews, and collection of blood, urine, rectal tissue, and cervical, vaginal, and rectal fluid.

Arms:
arm 1: All participants will receive 3 single escalating doses of PC-1005 gel during Visits 3, 5, and 7, with a 2-to-6-week washout period between dosing visits. Each participant will be on study for approximately 3 to 5 months.

Interventions: intervention 1: PC-1005 gel
Intervention descriptions: intervention 1: PC-1005 (0.002% MIV-150/0.3% zinc acetate in 3.0% carrageenan gel) in 4 mL, 16 mL, and 32 mL doses administered rectally.

Protocol document:
Prot_000.pdf: 
MTN-037 
 
 
 
A Phase 1 Safety and Pharmacokinetic Study of PC-1005 (MIV-150/Zinc 
Acetate/Carrageenan Gel) 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: 35122 
 
 
IND Sponsor: 
DAIDS 
 
 
IND #TBD 
 
 
Protocol Chair: Craig Hendrix, MD 
 
 
 
 
Version 1.0 
 
November 9, 2017 


 
 
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MTN-037 
 
A Phase 1 Safety and Pharmacokinetic Study of PC-1005 (MIV-150/Zinc 
Acetate/Carrageenan Gel) Administered Rectally to HIV-1 Seronegative Adults  
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND ACRONYMS ..................................................................... 6 
PROTOCOL TEAM ROSTER ............................................................................................. 11 
PROTOCOL SUMMARY ..................................................................................................... 20 
1  KEY ROLES .................................................................................................................. 23 
1.1 
Protocol Identification ............................................................................................ 23 
1.2 
Funding Agencies, Sponsor and Monitor Identification ......................................... 23 
1.3 
Medical Officer ...................................................................................................... 24 
1.4 
Laboratory Centers ............................................................................................... 24 
1.5 
Data Center ........................................................................................................... 24 
1.6 
Study Implementation ........................................................................................... 24 
2  INTRODUCTION ........................................................................................................... 25 
2.1 
Background of Rectal Microbicide Research and Study Rationale ....................... 25 
2.2 
PC-1005 Gel ......................................................................................................... 26 
2.3 
Non-Clinical Studies of PC-1005 Gel .................................................................... 28 
2.4 
Animal Studies ...................................................................................................... 32 
2.5 
Clinical Studies ..................................................................................................... 37 
2.6 
Study Hypotheses and Rationale for Study Design .............................................. 41 
3  OBJECTIVES ................................................................................................................ 43 
3.1 
Primary Objectives ................................................................................................ 43 
3.2 
Secondary Objectives ........................................................................................... 43 
3.3 
Exploratory Objectives .......................................................................................... 43 
4  STUDY DESIGN ............................................................................................................ 44 
4.1 
Identification of Study Design ................................................................................ 44 
4.2 
Summary of Major Endpoints ................................................................................ 44 
4.3 
Description of Study Population ............................................................................ 45 
4.4 
Time to Complete Accrual ..................................................................................... 45 
4.5 
Study Groups ........................................................................................................ 45 
4.6 
Expected Duration of Participation ........................................................................ 45 
4.7 
Sites ...................................................................................................................... 45 
5  STUDY POPULATION ................................................................................................... 45 
5.1 
Selection of the Study Population ......................................................................... 45 
5.2 
Inclusion Criteria ................................................................................................... 46 
5.3 
Exclusion Criteria .................................................................................................. 46 
5.4 
Co-enrollment Guidelines...................................................................................... 48 
6  STUDY PRODUCT ........................................................................................................ 49 
6.1 
Regimen................................................................................................................ 49 
6.2 
Administration ....................................................................................................... 49 
6.3 
Study Product Formulation.................................................................................... 49 
6.4 
Study Applicator .................................................................................................... 49 


 
 
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6.5 
Study Product Supply and Accountability ............................................................. 49 
6.6 
Study Product Dispensing ..................................................................................... 50 
6.7 
Ancillary Study Supplies ....................................................................................... 50 
6.8 
Concomitant Medications and Practices ............................................................... 50 
7  STUDY PROCEDURES ................................................................................................ 52 
7.1 
Pre-screening ........................................................................................................ 52 
7.2 
Screening .............................................................................................................. 53 
7.3 
Enrollment (Day 0) ................................................................................................ 54 
7.4 
Follow-up Visits ..................................................................................................... 55 
7.5 
Follow-up Procedures for Participants Who Permanently Discontinue Study 
Product ................................................................................................................. 61 
7.6 
Interim Visits ......................................................................................................... 62 
7.7 
Protocol Counseling:  Adherence and Contraception Counseling ......................... 62 
7.8 
Clinical Evaluations and Procedures ..................................................................... 62 
7.9 
Behavioral Assessments ....................................................................................... 64 
7.10 
Pharmacokinetics, Pharmacodynamics and Biomarkers of Mucosal Safety ......... 64 
7.11 
Laboratory Evaluations ......................................................................................... 65 
7.12 
Specimen Management ........................................................................................ 66 
7.13 
DAIDS Laboratory Oversight ................................................................................. 67 
7.14 
Biohazard Containment ........................................................................................ 67 
8  ASSESSMENT OF SAFETY ......................................................................................... 67 
8.1 
Safety Monitoring .................................................................................................. 67 
8.2 
Clinical Data and Safety Review ........................................................................... 68 
8.3 
Adverse Events Definitions and Reporting Requirements .................................... 69 
8.4 
Adverse Event Reporting Requirements ............................................................... 71 
8.5 
Pregnancy and Infant Outcomes ........................................................................... 72 
8.6 
Regulatory Requirements ..................................................................................... 72 
8.7 
Social Harms Reporting ........................................................................................ 72 
9  CLINICAL MANAGEMENT ............................................................................................ 72 
9.1 
Grading System .................................................................................................... 73 
9.2 
Dose Modification Instructions .............................................................................. 73 
9.3 
General Criteria for Permanent Discontinuation of Study Product ........................ 73 
9.4 
Follow-up in Response to Observed Adverse Events ........................................... 73 
9.5 
HIV-1 Infection ...................................................................................................... 74 
9.6 
Pregnancy ............................................................................................................. 74 
9.7 
Criteria for Early Termination of Study Participation ............................................. 75 
10  STATISTICAL CONSIDERATIONS ............................................................................... 75 
10.1 
Overview and General Design .............................................................................. 75 
10.2 
Study Endpoints .................................................................................................... 75 
10.3 
Primary Study Hypotheses .................................................................................... 76 
10.4 
Sample Size and Power Calculations ................................................................... 76 
10.5 
Randomization Procedures ................................................................................... 77 
10.6 
Participant Accrual, Follow-up and Retention ....................................................... 77 
10.7 
Data and Safety Monitoring and Analysis ............................................................. 78 
11  DATA HANDLING AND RECORDKEEPING ................................................................. 79 
11.1 
Data Management Responsibilities ....................................................................... 79 


 
 
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11.2 
Source Documents and Access to Source Data/Documents ................................ 79 
11.3 
Quality Control and Quality Assurance ................................................................. 80 
12  CLINICAL SITE MONITORING...................................................................................... 80 
13  HUMAN SUBJECTS PROTECTIONS ........................................................................... 81 
13.1 
Institutional Review Boards/Ethics Committees .................................................... 81 
13.2 
Protocol Registration ............................................................................................. 81 
13.3 
Study Coordination ............................................................................................... 82 
13.4 
Risk Benefit Statement ......................................................................................... 82 
13.5 
Informed Consent Process .................................................................................... 85 
13.6 
Participant Confidentiality...................................................................................... 86 
13.7 
Special Populations .............................................................................................. 87 
13.8 
Compensation ....................................................................................................... 87 
13.9 
Communicable Disease Reporting ........................................................................ 87 
13.10  Access to HIV-related Care ................................................................................... 87 
13.11  Study Discontinuation ........................................................................................... 87 
14  PUBLICATION POLICY ................................................................................................. 88 
15  APPENDICES ................................................................................................................ 89 
APPENDIX I:  SCHEDULE OF STUDY VISITS AND EVALUATIONS ................................ 89 
APPENDIX II:  ALGORITHM FOR HIV TESTING FOR ...................................................... 91 
SCREENING AND FOLLOW-UP ........................................................................................ 91 
APPENDIX III: SAMPLE INFORMED CONSENT FORM (SCREENING, ENROLLMENT, 
LONG-TERM STORAGE AND FUTURE TESTING) ........................................................... 92 
 
TABLES AND FIGURES 
 
Table 1: Composition of PC-1005 ....................................................................................... 26 
Table 2: PC-1005 Formulations Tested During Preclinical Evaluation ................................ 28 
Table 3: Summary of Nonclinical Resistance Development – In vitro Studies .................... 29 
Table 4: Summary of a Nonclinical Resistance Development In vivo Study (SHIV-RT) ...... 29 
Table 5: Mutations Selected by MIV-150 ............................................................................. 30 
Table 6: Summary of PC-1005 Condom Compatibility Study .............................................. 31 
Table 7: Animal Assignment and Dose Concentrations in Rabbit Rectal Irritation Study 
for PC-1005_D and PC-707_D ............................................................................................ 35 
Table 8: Summary of Completed Clinical Studies with MIV-150 ......................................... 38 
Table 9: Lubricant Practices ................................................................................................ 42 
Table 10: Study Product Regimen ...................................................................................... 49 
Table 11: Screening Visit .................................................................................................... 53 
Table 12: Enrollment Visit ................................................................................................... 54 
Table 13: Dosing Procedures .............................................................................................. 57 
Table 14: 24-Hour Post-Dosing Visits ................................................................................. 58 
Table 15: 48-Hour Post-Dosing Visits ................................................................................. 59 
Table 16: Final Contact ....................................................................................................... 60 
Table 17: Specimens to be Collected to Assess PK, Ex Vivo Antiviral Activity, 
Histology ............................................................................................................................. 65 
Table 18: Analysis of Safety Event Frequency .................................................................... 76 
Table 19: Exact 2-sided 95% Confidence Intervals Based on Observing a Particular 
Rate of Safety Endpoints for Arms of Size 12 ..................................................................... 76 


 
 
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Figure 1: MTN-037 Study Visit Schedule ............................................................................ 21 
Figure 2: MTN-037 Study Visit Schedule ............................................................................ 52 
 
 


 
 
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MTN-037 
 
A Phase 1 Safety and Pharmacokinetic Study of PC-1005 (MIV-150/Zinc 
Acetate/Carrageenan Gel) 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 
ARV 
antiretroviral 
AST 
aspartate aminotransferase 
ASTM 
American Society for Testing and Materials 
AUC 
area under the curve 
AUCinf 
area under the curve extrapolated to infinity 
AUClast 
area under the curve up to the last measurable concentration 
BAT or BAT24 
Dosing Before and After Sex </= Two doses in 24h 
BID 
bis in die (twice a day) 
BRWG 
Behavioral Research Working Group 
BSWG 
Biomedical Science Working Group 
BV 
bacterial vaginosis 
CAPRISA 
Centre for the AIDS Programme of Research in South Africa 
CASI 
computer assisted self-interview 
CBC 
complete blood count 
CD4 
cluster of differentiation 4 
CDC 
Centers for Disease Control and Prevention 
cDNA 
complementary DNA 
CFR 
Code of Federal Regulations 
CG 
carrageenan 
CI 
Confidence Interval 
Cmax 
maximum concentration 
CMRB 
Clinical Microbicide Research Branch 
CNS 
central nervous system 
CRF 
case report form 
CRMS 
Clinical Research Management System 
CRS 
Clinical Research Site 
CT 
Chlamydia trachomatis, Chlamydia 
CTA 
Clinical Trial Agreement 
CV 
coefficient of variation 
CVL 
cervicovaginal lavage 
CWG 
Community Working Group 
CYP1A2 
cytochrome P450 family 1, subfamily A2 genetic locus  
CYP2C8 
cytochrome P450 family 2, subfamily C8 genetic locus  
CYP2C9 
cytochrome P450 family 2, subfamily C9 genetic locus  
CYP2C19 
cytochrome P450 family 2, subfamily C19 genetic locus  
CYP2D6 
cytochrome P450 family 2, subfamily D6 genetic locus  
CYP2E1 
cytochrome P450 family 2, subfamily E1 genetic locus  


 
 
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CYP3A 
cytochrome P450, family 3, subfamily A genetic locus 
CYP3A4 
cytochrome P450 family 3, subfamily A4 genetic locus  
CYP450 
cytochrome P450 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS 
DAIDS PRO 
DAIDS Protocol Registration Office 
DAPY 
di-amino-pyrimidine 
DLV 
delavirdine 
DNA 
deoxyribonucleic acid 
EAE 
expedited adverse event 
EC 
ethics committees 
EC50 
50% effective concentration 
EFV 
efavirenz 
EMBRACE 
Evaluation of Maternal and Baby Outcome Registry After 
Chemoprophylactic Exposure 
ENR 
enrollment 
FDA 
(US) Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
FMO 
flavin-containing monooxygenase 
g 
grams 
GC 
Neisseria gonorrhoeae, gonorrhea 
GCP 
Good Clinical Practices 
GEE 
generalized estimating equations 
GGT 
gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practices 
GRAS 
Generally Recognized as Safe 
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 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IL 
Interleukin 


 
 
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IND 
Investigational New Drug 
INR 
International normalized ratio 
IoR 
Investigator of Record 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IVR 
intravaginal ring 
kg 
kilogram 
LC 
Laboratory Center 
LDMS 
Laboratory Data Management System 
LLOQ 
lower limit of quantification 
LOC 
Leadership and Operations Center 
μg 
microgram 
MAGI 
multinuclear activation of a galactosidase indicator 
MDP 
Microbicides Development Programme 
mg 
milligram 
MIV-150 
Urea, N-(5-cyano-2-pyridinyl)-N'-[(1S,2S)-2-[6-fluoro-2-hydroxy-3-(1-
oxopropyl)phenyl]cyclopropyl]-; an NNRTI 
mL 
milliliter 
mM 
millimolar 
MO 
Medical Officer 
mOsm 
milliosmole 
MPA 
medroxyprogesterone acetate 
MPID 
Maternal and Pediatric Infectious Diseases 
MPT 
multipurpose prevention technology 
mRNA 
mitochondrial ribonucleic acid 
MSM 
men who have sex with men 
MT-2 
human melatonin receptor 2 
MTN 
Microbicide Trials Network 
MTT 
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole 
MZC 
MIV-150, zinc acetate (ZA), and carrageenan (CG) 
n 
number 
N-9 
nonoxynol-9 
NAAT 
nucleic acid amplification test 
NCD 
nanocrystal dispersion 
NF 
National Formulary 
ng 
nanogram 
NHANES 
National Health and Nutrition Examination Survey 
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 
NRTI 
nucleotide analogue reverse transcriptase inhibitor 
NOAEL 
no observed adverse effect level 
NOEL 
no observed effect level 
NSAIDS 
non-steroidal anti-inflammatory drugs 
NVP 
nevirapine 


 
 
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OHRP 
Office for Human Research Protections 
P24 
protein 24 
PBL 
peripheral blood lymphocytes 
PBMC 
peripheral blood mononuclear cell 
PBS 
phosphate-buffered saline 
PC-1005 
0.002% MIV-150/0.3% zinc acetate [ZA] in 3.0% carrageenan [CG] gel 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
PEP 
post-exposure prophylaxis 
PFU/pfu 
plaque-forming unit 
pH 
potential of hydrogen 
PID 
pelvic inflammatory disease 
PK 
pharmacokinetics 
PMPA 
9-[(R)-2-(phosphonomethoxy)propyl]adenine monohydrate 
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 
PsV 
pseudovirus 
PT 
prothrombin time 
PTID 
participant identification 
PVC 
polyvinyl chloride 
PVI 
penile-vaginal intercourse 
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 immunodeficiency 
SCR 
screening 
SDMC 
Statistical Data Management Center 
SHIV 
simian human immunodeficiency virus 
SMC 
Study Monitoring Committee 
SOP 
standard operating procedure 
SMS 
short message service 
SSP 
study specific procedures 
STI 
sexually transmitted infection 
SUSAR 
suspected, unexpected serious adverse reaction 
TCID 
tissue culture infective dose 


 
 
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TEAE 
treatment-emergent adverse events 
TFV 
tenofovir 
TID 
ter in die (three times a day) 
T1/2 
half-life 
Tmax 
Time at which Cmax is observed 
TPGS 
tocopheryl polyethylene glycol succinate 
UA 
urinalysis 
ULN 
upper limit of normal 
UNAIDS 
Joint United Nations Programme on HIV and AIDS 
UPMC 
University of Pittsburgh Medical Center 
USA 
United States of America 
USP 
United States Pharmacopoeia 
UTI 
urinary tract infection 
VR 
vaginal ring 
WHO 
World Health Organization 
WSI 
web-based self-interviews 
w/w 
weight/weight 
wt 
wild type 
ZA 
zinc acetate 


 
 
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MTN-037 
 
A Phase 1 Safety and Pharmacokinetic Study of PC-1005 (MIV-150/Zinc 
Acetate/Carrageenan Gel) Administered Rectally to HIV-1 Seronegative Adults  
PROTOCOL TEAM ROSTER 
 
 
 
Protocol Chair  
 
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 
 


 
 
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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 
 
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 
National Institute of Allergy and Infectious Diseases 
(NIAID), Division of AIDS (DAIDS)  
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  
National Institutes of Health (NIH) - U.S. Department 
of Health and Human Services (HHS) 
5601 Fishers Lane, Room 8B27 
Rockville, MD 20852 USA 
Phone: 240-292-4779 
Email: clelandn@niaid.nih.gov   
 
 
 
Jeanna Piper, MD 
DAIDS Senior Medical Officer 
DAIDS/NIAID/NIH/HHS 
5601 Fishers Lane 
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 
 
Jared Baeten, MD, PhD 
Co-Principal Investigator 
University of Washington 
ICRC, Dept of Global Health 
325 Ninth Avenue, Box 359927 
Seattle, WA  98104 
Phone: 206-520-3808 
Fax: 206-520-3831 
Email: jbaeten@uw.edu 
 
 
Sharon A. Riddler, MD, MPH 
Protocol Physician 
UPMC, Keystone Building, Suite 510 
3520 Fifth Avenue 
Pittsburgh, PA 15213 USA 
Phone:  412-383-1741or 412-383-1675 
Fax: 412-383-2900 
Email: riddler@dom.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 
 
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: devika@mtnstopshiv.org 
Sharon Hillier, PhD 
Principal Investigator 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-6435 
Fax: 412-641-6170 
Email: shillier@mail.magee.edu    
 
Jennifer Thomas, MSc 
Protocol Development  
and Implementation Manager  
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-5579 
Fax: 412-641-6170 
Email: thomasj15@mwri.magee.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 
 
 
 
 
 
 
 


 
 
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MTN Laboratory Center (LC) 
 
Peter Anderson, PharmD 
LC Pharmacology Core 
University of Colorado School of Pharmacy  
Mail Stop C238  
12850 E. Montview Blvd. V20-4101  
Aurora, CO  80045 USA 
Phone: 303-724-6128 
Email: Peter.Anderson@ucdenver.edu 
 
Ratiya Pamela Kunjara Na Ayudhya, MT, ASCP
Laboratory Manager 
Microbicide Trials Network 
204 Craft Avenue, Room A541 
Pittsburgh, PA  15213 USA 
Phone: 412-641-6393 
Fax: 412-641-6170 
Email: pkunjara@mwri.magee.edu 
 
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 
 
 
 
 


 
 
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MTN LOC – FHI 360 
 
Jontraye Davis, MHA 
Community Programs Associate 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 27701 USA 
Phone: 919-544-7040, Ext. 11715 
Fax: 919-544-0207 
Email: jodavis@fhi360.org 
 
Sherri Johnson, MPH 
Senior 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 
 
Tara McClure, MPH 
Clinical Research Manager 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 27701 USA 
Phone: 919-544-7040, Ext. 11012 
Fax: 919-544-0207 
Email: TMcClure@fhi360.org 
 
 
 


 
 
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MTN Statistical Data Management Center (SDMC) 
 
Elizabeth Brown, ScD 
FHCRC-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 
 
Cliff Kelly, MS 
SDMC Statistician 
FHCRC-SCHARP 
1100 Fairview Avenue North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-2502 
Fax: 206-667-4378 
Email: cwkelly@scharp.org 
 
Karen Patterson, MPH 
MTN Program and Portfolio Manager 
FHCRC-SCHARP 
1100 Fairview Ave. North, E3- 315 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-7052 
Fax: 206-667-4812 
Email: karenp@scharp.org 
 
 


 
 
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Working Group Representatives 
 
Jose A. Bauermeister, MPH, PhD  
Behavioral Research Working Group (BRWG) Representative 
University of Pennsylvania  
418 Curie Blvd., Suite 402  
Philadelphia, PA 19104  
Phone: 215-898-9993 
Email: bjose@upenn.edu 


 
 
MTN-037,  Version 1.0 
19  
 November 9, 2017 
MTN-037 
 
A Phase 1 Safety and Pharmacokinetic Study of PC-1005 (MIV-150/Zinc 
Acetate/Carrageenan Gel) Administered Rectally to HIV-1 Seronegative Adults  
 
INVESTIGATOR SIGNATURE FORM 
 
Version 1.0 
November 9, 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 (NIH) 
 
IND Sponsors: 
 DAIDS (DAIDS Protocol ID: 35122)  
 
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-037,  Version 1.0 
20  
 November 9, 2017 
MTN-037 
 
A Phase 1 Safety and Pharmacokinetic Study of PC-1005 (MIV-150/Zinc 
Acetate/Carrageenan Gel) Administered Rectally to HIV-1 Seronegative Adults  
 
PROTOCOL SUMMARY 
 
Short Title:  
Safety and PK Study of PC-1005 Applied Rectally 
 
Clinical Phase: 
Phase 1 
 
IND Sponsor: 
DAIDS 
 
Protocol Chair:  
Craig Hendrix, MD 
 
Sample Size: 
MTN-037 will enroll approximately 12 participants.   
 
Study Population:  
HIV-uninfected men and women (cis or transgender) with a history 
of consensual RAI who are 18 years or older at Screening  
 
Study Sites: 
Sites selected by MTN Executive Committee 
 
Study Design: 
Phase 1, open label, sequential dose/volume escalation study 
 
Study Duration: 
Approximately 3-5 months of follow-up per participant is planned 
with a projected accrual period of 6-8 months.  The total duration of 
the study will be approximately 11-13 months.  
 
Study Products: 
PC-1005 (0.002% MIV-150/0.3% zinc acetate [ZA] in 3.0% 
carrageenan [CG] gel) 
 
Study Regimen:  
Each participant will receive a dose of PC-1005 (4mL, 16mL or 
32mL) rectally administered by clinic staff in the clinic. Safety 
laboratory tests, PK and PD assessments will be performed within 
24 hours after each gel administration. Each participant will also be 
randomized to have a 48 hour post-dosing visit after one of the three 
doses. After a washout period of two to six weeks (to accommodate 
scheduling around the menstrual cycles of female participants) 
following each dosing visit, dosing with the next sequential 
escalating volume will be administered. A final study contact will 
occur after the third dosing visit and associated washout period.   


 
 
MTN-037,  Version 1.0 
21  
 November 9, 2017 
Figure 1: MTN-037 Study Visit Schedule 
 
 
 
Primary Objectives:  
 
Safety 
 
To evaluate the safety of PC-1005 gel formulation (0.002% MIV-150/0.3% zinc acetate 
[ZA] in 3.0% carrageenan [CG] gel) when applied rectally  
 
Pharmacokinetics 
 
To characterize the systemic and compartmental pharmacokinetics of MIV-150 following 
rectal gel application  
 
Primary Endpoints: 
 
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). 
 
Pharmacokinetics 
 
MIV-150 concentrations in: 
o Plasma  
o Rectal fluid  
o Rectal mucosal tissue homogenates 
 
Secondary Objectives:  
 
Acceptability 
 To compare the acceptability of PC-1005 gel formulation across the three doses when 
administered rectally 
 
Pharmacokinetics 
 To characterize the compartmental pharmacokinetics of MIV-150 in vaginal fluid following 
rectal gel application 
 


 
 
MTN-037,  Version 1.0 
22  
 November 9, 2017 
Secondary Endpoints:  
 
Acceptability 
 Participant self-report of comfort with gel application, liking the product across doses, and 
perceived side-effects 
 
Pharmacokinetics 
 MIV-150 concentrations in vaginal fluid 
 
Exploratory Objectives:  
 
Biomarkers of Mucosal Safety  
 
To evaluate the mucosal toxicity of PC-1005 gel formulation when applied rectally  
 
Ex Vivo Antiviral Activity 
 
To assess the preliminary (ex vivo) antiviral activity of PC-1005 gel formulation after 
product is applied rectally 
 
Exploratory Endpoints:  
 
Biomarkers of Mucosal Safety  
 
Rectal histology  
 
Tissue archive  
 
Ex Vivo Antiviral Activity 
 
Changes in HIV-1 p24 levels in colorectal explant culture supernatant  
 
Anti-HIV activity in rectal fluid 


 
 
  
MTN-037, Version 1.0 
23 
  November 9, 2017 
 
1 
KEY ROLES 
 
1.1 Protocol Identification 
 
Protocol Title:   
A Phase 1 Safety and Pharmacokinetic Study of PC-1005 
(MIV-150/Zinc 
Acetate/Carrageenan 
Gel) 
Administered 
Rectally to HIV-1 Seronegative Adults  
 
Protocol Number: 
MTN-037 
 
Short Title: 
Safety and PK Study of PC-1005 Applied Rectally 
 
Date:  
November 9, 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 
Rockville, MD  20852 USA 
 
IND Sponsors:  
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 
 


 
 
  
MTN-037, Version 1.0 
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  November 9, 2017 
 
1.3 Medical Officer 
 
Medical Officer: 
 
Jeanna Piper, MD 
DAIDS/NIAID 
5601 Fishers Lane, Room 8B68, MSC 9831 
Rockville, MD 20852 
 
1.4 Laboratory Centers 
 
 
 
 
MTN Laboratory Center (LC) 
 
 
 
204 Craft Ave. 
 
 
 
Pittsburgh, PA  15213 USA 
 
 
 
MTN LC Pharmacology Core 
 
 
University of Colorado School of Pharmacy 
 
 
12850 E. Montview Blvd. V20-4101 
 
 
Mail Stop C238 
 
 
Aurora, CO 80045 USA 
 
1.5 Data Center 
 
MTN Statistical and Data Management Center (SDMC) 
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 
 
 
 
 
MTN LOC - FHI 360 
 
 
 
359 Blackwell Street, Suite 200 
 
 
 
Durham, NC 27701 USA 
 
 


 
 
  
MTN-037, Version 1.0 
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  November 9, 2017 
 
2 
INTRODUCTION 
 
2.1 Background of Rectal Microbicide Research and Study Rationale 
 
Microbicides are products that are designed to be applied to the vaginal or rectal mucosa 
with the intent of preventing the acquisition of sexually transmitted infections (STIs) 
including the human immunodeficiency virus (HIV),1 human papillomavirus (HPV), and 
herpes simplex virus type- 2 (HSV-2). While the original impetus for vaginal microbicide 
development was to provide women with options for HIV prevention in settings where 
their partners were unwilling to use condoms for penile-vaginal intercourse, there is 
recognition that rectal microbicides are needed for men and women who practice 
receptive anal intercourse (RAI). Similar to lubricants, which are commonly used during 
anal intercourse (AI), the ideal rectal microbicide would enhance sexual pleasure and 
potentially result in higher adherence than has been found in most vaginal microbicide 
trials to date. 
 
HIV 
According to UNAIDS, there were approximately 36.7 million people worldwide living with 
HIV/AIDS at the end of 2015; that year, an estimated 2.1 million individuals worldwide 
became newly infected with HIV.2 Unprotected RAI is the sexual behavior with the highest 
per act risk of HIV acquisition, conferring approximately 10 to 20 times more risk than 
unprotected receptive vaginal intercourse .3, 4 Globally, men who have sex with men 
(MSM) are 19 times more likely to be living with HIV compared with the general 
population;5, 6 transgender women are 49 times more likely than the general population 
to be living with HIV.7 
 
HPV 
While most genital HPV infections are self-limiting and subclinical, infection is extremely 
common; estimated lifetime risk is about 75%. Some HPV types cause genital warts and 
other types are oncogenic. Condoms may not provide full protection.8 Anal HPV infection 
prevalence is high among MSM (18-89 years of age) at over 57% as detected using PCR 
testing in a large US multisite study.9  Its prevalence in studies among HIV-positive MSM 
is often double that among HIV-negative men.10 Infection with HPV increases 
susceptibility to HIV.11 HPV infection among MSM is the primary risk factor for developing 
anal cancer.10 Many HPV genotypes are associated with anal cancer and an increased 
risk among females for cervical,8 vulvar, and vaginal cancers, as well as a significant 
proportion of head and neck cancers.8  Two of the most oncogenic genotypes, HPV-16 
and 18, are associated with 75% of cervical cancers, 50% of vulvar cancers, 50–75% of 
vaginal cancers and 80% of anal cancers. While HPV vaccines are now commercially 
available for males and females, uptake has been low due to cost, dosing regimen, and 
parental objection. Other challenges are that vaccines are not fully protective against at 
least 36 other HPV strains associated with anogenital infections, and cold supply chain 
requirements limit their utility in developing countries.8, 11, 12 The vaccine is most effective 
when given prior to exposure to HPV viruses, thus prior to sexual debut.13 These 
limitations confirm the need for other preventive modalities such as microbicides with anti-
HPV activity.11 


 
 
  
MTN-037, Version 1.0 
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  November 9, 2017 
 
HSV-2 
The seroprevalence of HSV-2 among Americans ages 14-49 is 15.5%.14 A large 
population-based survey of US men (part of the NHANES study) revealed that while self-
reported same-sex sexual contact (ever) and gay sexual orientation were important 
markers for high risk of HIV infection, there were no significant differences in HSV-2 
prevalence by sexual orientation, when dichotomized as MSM-Ever and non-MSM, at 
about 18% and 12%, respectively.15Infection with HSV-2 increases susceptibility to HIV.11  
There are no FDA-approved topical antiretroviral products for HSV prevention. However, 
the CAPRISA 004 study, which evaluated the anti-HIV activity of 1% tenofovir gel using 
a BAT24 (Before and After sex, not to exceed Two doses in 24 hours) dosing strategy in 
a randomized, placebo-controlled trial among 889 HIV-uninfected South African women, 
unexpectedly showed a ‘bonus’ finding of a 51% reduction in HSV-2 incidence in the 
tenofovir arm, consistent with previous in vitro work demonstrating mucosal 
concentrations achieved with 1% tenofovir gel have direct antiherpetic activity.16  
 
2.2 PC-1005 Gel 
 
PC-1005 is a multipurpose prevention technology (MPT) microbicide in development that 
is active against HIV, HPV, and HSV-2, and has been formulated to be suitable for both 
vaginal and rectal use.17 As described below, efficacy results shown in preclinical animal 
studies suggest the potential of PC-1005 as both an on-demand (coitally dependent) 
vaginal microbicide and a method of post-exposure prophylaxis (PEP) for preventing 
HSV-2 and HPV.11 PC-1005 has been found safe for vaginal use in a Phase 1 trial in 
which women used the gel once daily for 14 days.17 MTN-037 will evaluate the safety and 
pharmacokinetics (PK) of PC-1005 gel administered rectally using an applicator. 
Demonstrating that PC-1005 is safe in the rectal compartment in men and women will be 
a critical first study for the development of PC-1005 for rectal use. If proven effective, PC-
1005 would be the first MPT of any kind to simultaneously prevent HIV, HSV-2, and HPV. 
 
PC-1005 gel is a translucent gel containing 50 µM MIV-150, a potent NNRTI not used for 
HIV treatment; 13.7 mM zinc acetate (ZA) dihydrate, a selective antiviral agent generally 
recognized as safe (GRAS) by the US FDA;17 and carrageenan (CG), a gelling agent 
derived from seaweed (also GRAS) (See Table 1 for composition of PC-1005).18 CG has 
been used as a thickener in commercially available pre-lubricated condoms and sexual 
lubricants.8 PC-1005 gel formulation is iso-osmolar. PC-1005 in its early development 
was also referred to as MZC (MIV-150, zinc acetate [ZA], and carrageenan [CG]).11, 17 
MIV-150 has been licensed to the Population Council from Medivir.19 
 
Table 1: Composition of PC-1005  
Composition of PC-1005 
% w/w 
0.002% MIV-150 and 0.3% zinc acetate [ZA] in 3.0% carrageenan [CG] gel 
Amounts/g of gel 
18.4 µg MIV-150, 0.894 mg zinc (Zn2+), and 30 mg of CG 
Concentrations 
50.0 µM MIV-150 and 13.7 mM ZA (with CG as a vehicle) 
 


 
 
  
MTN-037, Version 1.0 
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  November 9, 2017 
 
Description and Mechanism of Action 
 
PC-1005 gel’s broad spectrum activity and its excellent safety profile as shown in pre-
clinical vaginal and rectal models are due to the unique combination of active 
pharmaceutical ingredients (APIs). MIV-150 (C19H17FN4O3) is a potent, HIV-specific 
NNRTI with CYP450-mediated metabolism19 that belongs to the group of 
phenethylthiazolylthiourea derivatives.11 NNRTIs bind allosterically to the HIV reverse 
transcriptase (RT) enzyme, preventing viral replication and consequently production of 
infectious virus. While MIV-150 was originally developed as an oral antiretroviral (ARV) 
(by Medivir AB; Sweden), its characteristics of rapid systemic clearance and poor 
systemic absorption rendered it more suitable for use as a topical microbicide.20  
 
ZA is a selective antiviral agent that inhibits HIV and HSV-2, appearing to have at least 
two modes of inhibition against HIV: it inhibits HIV RT at a site not targeted by other 
RTIs,21 it has additive effects with MIV-150, and it has immunomodulatory effects that 
might impart antiviral activity.11, 21-24 Zn2+ is thought to inhibit the synthesis of HIV-RT by 
forming a highly stable RT-Zn2+ (primer-template) complex which ties up RT potentially 
for hours. Zinc-based products appear to exploit a weakness in HIV and in theory could 
slow its replication.21  
 
Carrageenan is a sulfated polysaccharide extracted from red algae and is a potent 
infection inhibitor of a variety of sexually transmitted HPVs, acting primarily by inhibiting 
HPV virion binding to heparan sulfate on the basement membrane.25 CG resembles 
heparan sulfate, an HPV attachment factor. It also acts through a post-attachment 
heparan sulfate-independent effect.  While CG demonstrates in vitro activity against HSV 
and some HIV strains, it is much more potent against genital HPV. Some CG products, 
even when diluted by a factor of 1 million, block HPV infection.8 
 
A first-generation prototype gel (MZC), used in early nonhuman primate and other animal 
studies, and a modified MZC gel are described by Kizima et al.11  Modified MZC gel 
includes a buffer as well as co-solvents and preservatives more suited to clinical testing 
in humans; its osmolality is 447mOsmol/kg and viscosity (freshly prepared) is 29,900 cP. 
It is stable for 12 months at 86°F/30°C/65% RH (relative humidity) and for 9 months at 
104°F/40°C/75% RH. After 1 month at 122°F/50°C, MZC remained stable. The gel 
exhibits shear thinning spreading behavior, an important gel property allowing gel to 
spread evenly throughout the vaginal or rectal compartment.11, 12 
 
Strength of Study Product 
 
The PC-1005 gel strength proposed for use in MTN-037 is 0.002% MIV-150/0.3% ZA in 
3.0% CG gel, called PC-1005_D by Population Council. The different formulations of PC-
1005 used in preclinical testing are shown in Table 2. 
 


 
 
  
MTN-037, Version 1.0 
28 
  November 9, 2017 
 
Table 2: PC-1005 Formulations Tested During Preclinical Evaluation 
Attribute 27 
PC- 
1005_A** 
PC- 
1005_B** 
PC- 
1005_C** 
PC-
1005_C 
Protocol: 
PC-558 
PC-
1005_D 
PC-1005_D 
Protocol: 
MTN-037 
Use 
Preclinical 
Preclinical
Preclinical
Clinical
(vaginal)
Preclinical 
(rectal) 
Clinical
(vaginal/rectal)
Carrageenan 
(λ:κ) 
 
Lot 
95:5 
 
 
PDR98-15 
60:40 
 
 
RERK-4137 
90:10
 
 
LamCarr002 
or 
LamCarr 003
90:10
 
 
LamCarr003 
82:18 
 
 
LamCarr004 
82:18
 
 
LamCarr004 
MIV-150 
assay 
In spec 
In spec 
In spec
In spec
In spec 
(In spec)*
Zinc assay 
In spec 
In spec 
In spec
In spec
In spec 
(In spec)*
Viscosity 
(cP) 
In spec 
In spec 
In spec
In spec
In spec 
(In spec)*
Osmolality 
mOsmol/kg) 
In spec 
In spec 
In spec
In spec
In spec 
(In spec)*
 
2.3 Non-Clinical Studies of PC-1005 Gel 
 
Anti-HIV-1 Activity 
PC-1005 exhibits broad, potent in vitro activity against different HIV clades, tropisms, 
phenotypes, and drug-resistant mutations (DRMs).11 MIV-150 is an allosteric inhibitor of 
HIV RT with an IC50 versus pansensitive virus in the 3 nM range in an in vitro MT-4 cell 
assay in the presence of 50% human serum. This is more potent than other licensed 
drugs in the NNRTI class tested, including efavirenz (8 nM). MIV-150 also retains activity 
against some single point mutant strains that become resistant to efavirenz. It loses 
activity in the presence of virus with 103N+100I. It does retain potency with mutant strains 
harboring 181C+138K+101E.26 MIV-150 retains this activity in the presence of semen 
using in vitro experiments against SHIV.19  MZC is active against HIVBaL infection in 
human ectocervical mucosa in a single challenge model as well as under stringent 
conditions of co-challenge with HSV-2.27  
 
While zinc does not directly prevent infection with HIV, it has been shown to enhance 
peak functioning of the immune system with resulting resistance to infection by bacteria, 
viruses, and fungi in vitro and in animal and human models.28  Zinc in the form of nontoxic, 
free Zn2+ within body cells, even in relatively low concentrations, may slow HIV viral 
replication. Zn2+ inhibits HIV-RT (reverse transcriptase) by binding RT in a relatively 
chemically inactive RT-Zn2+ (primer template) complex, potentially for hours.21  
 
The carrageenan-based vaginal microbicide gel Carraguard® exhibited some anti-
infective activity when evaluated in a Phase I safety trial. CVLs (5 mL) collected from 
participants were tested for carrageenan anti-[HIV] infective activity using an ex vivo titer 
reduction assay. Ex vivo evaluation revealed that Carraguard® gel retained some ability 
to reduce HIV infection of target cells from 15 minutes up to 8–24 hours after vaginal 
application.29 
 


 
 
  
MTN-037, Version 1.0 
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  November 9, 2017 
 
Resistance (HIV) 
MIV-150 has demonstrated a good resistance profile as displayed in Table 3 and Table 
4 below.  Additional information for individual studies may be found in the Investigator’s 
Brochure (IB).19 
 
Table 3: Summary of Nonclinical Resistance Development – In vitro Studies 
Study Type19 
Assay Type/ 
Test Model 
Outcome 
MIV-150 resistance 
development (Non-GLP) 
MT-4 cells 
Resistance development in the presence of 
MIV-150 was slower than for any other NNRTI 
studied. There is a significant delay in 
resistance mutant development after culture  
with MIV-150 compared to culture with 
marketed NNRTIs. 
MIV-150 and ZA resistance 
development and cross-
resistance with other related 
antiretrovirals (Non-GLP) 
MAGI or PBMC 
assay/MT-4 cells 
Triple mutant resistant viruses were isolated in 
the presence of increasing concentrations of 
MIV-150 in MT-4 cells resulting in IC50 > 10-
fold when compared to WT virus for MIV-150, 
MIV-160, efavirenz, and nevirapine. 
Combinations of at least 2 − 3 mutations are 
needed to decrease HIV susceptibility to MIV-
150. 
 
 
 
Table 4: Summary of a Nonclinical Resistance Development In vivo Study (SHIV-RT) 
Study Type19 
Species/ Sex 
Route/Duration 
of Dosing 
Dose 
Outcome 
In vivo selection 
of DRMs by MIV-
150 in SHIV-RT 
infected 
macaques (Non-
GLP) 
macaques/females 
(n = 4) 
Intramuscularly/ 
3 weeks daily/1 
week off/3 weeks 
daily 
0.5 mg/kg/day 
Proof-of-concept 
that MIV-150 can 
select for viruses 
expressing 
DRMs. 
macaques/females 
(n = 6) 
MIV-150 IVR/ 
8 weeks 
100 mg MIV-150 
IVR 
Sustained topical 
delivery of high 
doses of MIV-150 
select for rare 
DRMs in one-third 
of the animals. 
 
In other data from macaques, modified MZC gel applied vaginally did not select for 
NNRTI-resistant variants; DRMs were not detected in the RT gene of SHIV-RT circulating 
in 6 infected animals (Kizima et al 2014).11  
 
Cross-resistance (HIV) 
An in vitro evaluation of development of cross-resistance of HIV-1 using MIV-150 and ZA 
(separately) with other related antiretrovirals (non-GLP) suggested the absence of cross-
resistance between these APIs with a likely different mode of action.  No resistant virus 
was selected, at least during the 9-week in vitro selection, against the combination of 0.2 
nM MIV-150/180 μM ZA. MIV-150 resistant viruses were selected in the presence of MIV-


 
 
  
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  November 9, 2017 
 
150 only but not in the MIV-150/ZA combined treatment. (see Table 5).19 A ZA resistant 
mutant was found to have no cross-resistance with NNRTIs and Lamivudine.19 
 
Table 5: Mutations Selected by MIV-150 
HIV-1 
Cell system for 
resistance 
selection 
EC50  (95% confidence 
interval) 
NNRTI 
mutations 
MIV-150 (nM) 
MN WT 
N/A 
0.2 (0.18 to 0.25) 
WT 
MN MIV-150-selected 
MT-4 
>10 
L100I, K103N, Y181C 
MN MIV-150-selected 
MT-4 
>10 
E138G, Y181C, M230L 
92BR014 WT 
N/A 
0.7 (0.6 to 0.9) 
WT 
92BR014 MIV-150-selected 
PBMCs 
ND* 
K103N, E138G, Y181N, 
M230L 
92BR014 MIV-150/ZA-
selected 
PBMCs 
No resistant virus was selected 
EC50 = concentration causing half-maximal inhibition; N/A = Not applicable; ND = Not determined; * virus 
titer too low to perform the antiviral assay 
 
Mutagenicity 
Nonclinical evaluation of the mutagenic potential of MIV-150 (GLP) with Ames Test 
(bacterial reverse mutation assay, a predictive test of rodent and human carcinogenicity) 
found no evidence of mutagenic activity in any strain of Salmonella typhimurium and E. 
Coli, either with or without metabolic activation.19  
 
In vitro cytogenetics evaluation (also GLP) using Chromosome Aberration Assay found 
that frequencies of cells with structural aberrations were not significantly different from 
those seen in solvent controls. Frequencies of aberrant cells treated in cultures fell within 
the historical negative control range. MIV-150 did not induce chromosome aberrations 
when tested to the limit of solubility in cultured human peripheral blood lymphocytes in 
the absence and presence of metabolic activation.19 
 
Recent reports on the oral administration of undegraded sodium and calcium 
carrageenan of known quality to pregnant animals reveals fetotoxic effects, with or without 
frank teratogenic effects, in some species at levels that do not greatly exceed the average 
daily human rate of intake. These effects appear to be dose-dependent. While 
carrageenan exhibits no mutagenic effects as measured by the host-mediated and 
dominant lethal assay procedures, significant abnormalities appear to be induced in the 
anaphase figures of human embryonic lung cells in tissue culture at dosages that are 
slightly above average daily human intake. Parenterally administered carrageenan is 
reported to exert cytotoxic effects on macrophages, suppress delayed hypersensitivity 
reactions in some tuberculin sensitive animals, activate factors causing procoagulant 
activity in human blood platelets, increase vascular permeability, and liberate kinin in vitro, 
all of which point to the possibility of the generation of toxic effects that could cause 
adverse responses following the oral consumption of carrageenan if, during pregnancy or 
in the presence of infectious challenge or metabolic disorder, appropriate amounts of 
carrageenan should be absorbed from the gastrointestinal tract.30 (Note that MTN-037 
includes only topical application.) Additional data regarding the fetotoxicity, teratogenicity, 


 
 
  
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  November 9, 2017 
 
and mutagenicity of orally or parenterally administered CG is available in two National 
Technical Reports prepared for the FDA.31, 32  
 
Zinc is not mutagenic and has little if any clastogenic properties. Mutagenicity studies 
strongly suggest that zinc does not represent a mutagenic risk. It is not teratogenic and 
can, in fact, avert teratogenicity of other agents. Conversely, zinc deficiency may be both 
harmful to developing organisms and hazardous to human health.  In a murine 
carcinogenicity study, tumors did not develop when zinc compounds including zinc 
acetate were injected subcutaneously.33  
 
In Vitro Metabolism 
Clinical drug interaction studies have not been conducted with MIV-150. Using cDNA 
expressed isoenzymes and hepatic microsomes, CYP3A is involved in the 
biotransformation of MIV-150, although a role for CYP2C8 and FMO cannot be excluded. 
MIV-150 was not an inhibitor of CYP1A2, CYP2C9, CYP2D6, and CYP2E1 activity. 
CYP450-dependent metabolism of MIV-150 appeared to be markedly inhibited by Cmax 
or 10x Cmax concentrations of ritonavir (Cmax), indinavir (Cmax) and efavirenz (10x Cmax). 
MIV-150, even at 10x Cmax, appeared to have little or no effect on the CYP450-dependent 
metabolism of the same compounds all of which involve 3A4 metabolism. In hepatic 
microsome experiments, sulfate conjugates were a major metabolite, but glucuronide 
conjugates were not identified. 
 
In human supersome studies, MIV-150 was found to be a potent inhibitor in vitro of the 
isozymes CYP2C9, CYP2C19, and CYP3A4. In studies against specific human hepatic 
CYP450 isoenzymes in vitro, MIV-150 was a weak inhibitor of CYP2C19 and CYP3A4 
activity; IC50 values for the isozymes CYP2C9, CYP2C19, and CYP3A4 were 1.55 μg/mL 
(4.22 μM), 0.094 μg/mL (2.56 μM), and 1.12 μg/mL (3.04 μM), respectively. For reference, 
median peak plasma concentrations (Cmax) after vaginal dosing of PC-1005 range from 
75 to 114 pg/mL or greater than 1,000-fold lower concentration.  
 
Condom Compatibility 
A summary of the PC-1005 condom compatibility study is presented in Table 6. A more 
comprehensive summary follows the table. 
 
Table 6: Summary of PC-1005 Condom Compatibility Study 
Study Type 
Type of Condoms 
Outcome 
Condom compatibility 
study 
3 brands non-lubricated latex condoms, 
1 brand polyisoprene condoms, 1 brand 
polyurethane condoms, and 1 brand 
nitrile female condoms treated with: 
negative control and positive control 
treated with a degradant (mineral oil for 
latex and polyisoprene condoms, 
mineral oil or PEG 200 for polyurethane 
condoms, and toluene for nitrile 
condoms), or PC-1005 
 
PC-1005 is considered 
compatible with non-
lubricated latex and 
polyisoprene condoms. 
 
PC-1005 had a plasticizing 
effect on the polyurethane 
condoms and nitrile 
condoms, and increased 
burst volumes while 
decreasing burst pressures. 
PEG=polyethylene glycol 
 


 
 
  
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  November 9, 2017 
 
This study was conducted to assess the compatibility of PC-1005 with male and female 
condoms (FHI 360, Durham, NC). Formulation PC-1005_C was used for the study. 
Although the test method ASTM D7661 and the criteria were specifically for natural rubber 
latex male condoms, other types of condoms (synthetics) including female condoms were 
tested as recommended by the draft guidance of vaginal microbicide that FDA published 
in November 2012.  Three brands of non-lubricated latex condoms, 1 brand of 
polyisoprene condoms, 1 brand of polyurethane condoms, and 1 brand of nitrile female 
condoms were evaluated for tensile and airburst properties. The tensile and airburst 
properties of the condoms treated with PC-1005 were compared to those of negative 
control and positive control treated with a degradant (mineral oil for latex and polyisoprene 
condoms, mineral oil or PEG200 for polyurethane condoms, and toluene for nitrile 
condoms). 
 
No condoms leaked or had difficulty with their clamping mechanism. The tensile and 
airburst properties of the non-lubricated latex condoms and the polyisoprene condoms 
were within the criteria, adequate to detect less than a 10% change in airburst pressure, 
airburst volume and percent elongation, as well as a 25% change in break force. 
Therefore, PC-1005 is considered compatible with these condom types. 
 
The airburst pressure for the polyurethane condoms had a greater than 20% decrease, 
and the airburst pressure for the nitrile condoms had a greater than 10% decrease. 
However, it would be difficult to apply the same criteria of the standard ASTM D7661 to 
the other types since synthetic condoms are much more rigid than latex. The test result 
suggests that the test articles had a plasticizing effect on the polyurethane condoms and 
nitrile condoms, and increased burst volumes while decreasing burst pressures. Even 
though there was a decrease in pressure for the female condoms, the treated burst 
pressure still met the manufacturer’s requirements.19 
2.4 Animal Studies 
 
Anti-SHIV Activity 
In studies comparing the preclinical safety and efficacy of TFV 1% gel with that of MZC 
gel using in vitro, ex vivo, and in vivo assays, MZC showed greater anti-SHIV-RT activity 
than TFV 1% gel in macaque vaginal explants.34  
 
Experiments challenging macaques rectally showed blocking activity of CG gel when 
applied close to the time of challenge with SHIV-RT, likely due to both a non-specific 
barrier effect of the gel (coating of epithelium) combined with characteristic polyanion 
blockade of cell-virus interactions.11 
 
Prototype and modified ZA/CG gels were found to significantly reduce SHIV-RT infection 
in simian models. Macaques repeatedly dosed (daily for 14 days) with ZA/CG gel were 
protected against vaginal SHIV-RT infection for up to 24 hours. Dosing every other day 
also offered significant protection after challenge 8 to 24 hours after the last gel dose; a 
single dose was less effective.35  MIV-150 in CG administered vaginally in a macaque 
SHIV model protected against SHIV, with 3 doses of MIV-150 in CG being superior to 3 
doses of CG alone.36 A single dose of MIV-150 in CG administered rectally 30 minutes or 
4 hours prior to rectal exposure protected 4/4 macaques challenged with 103 TCID50 SHIV 


 
 
  
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and 2/4 challenged with 104 TCID50 SHIV applied 4 hours after the gel.20 MIV-150 in CG 
provided partial protection against vaginal SHIV-RT transmission in macaques when the 
last dose was given 8 hours before challenge.37. A single application of MIV-150 in CG 
provided full protection against vaginal SHIV-RT transmission in macaques for up to 24 
hours.38 
 
Anti-Herpes Simplex Virus (HSV-2) Activity 
MZC applied 10 minutes prior to challenge effectively blocked HSV-2 infection in 
stringent, high viral dose (106 pfu) vaginal (1000x 50% lethal dose [LD50]) and anorectal 
(10x LD50) mouse models. There was a significant decrease in infection after vaginal 
challenge (65% uninfected, p<0.0001 vs. D-PBS [Dulbecco’s phosphate-buffered saline] 
or CG alone) and anorectal challenge (55% uninfected, p = 0.0187 vs. D-PBS). At lower 
viral doses (5x103 pfu/mouse), mice dosed with MZC, CG or D-PBS were challenged with 
HSV-2 to determine the window of protection. Vaginally, a significant decrease in the 
percentage of mice infected vs. D-PBS was seen when MZC was administered between 
8 h before (p = 0.0038) and 4 h after (p = 0.0248) viral challenge; CG displayed a blocking 
effect at this lower viral dose. However, the same experiment performed via anorectal 
challenge showed no significant protection at any time point except when MZC was 
applied 10 minutes prior to challenge.11  
 
In mice, prototype and modified ZA/CG gels were found to significantly increase the 
number of animals without signs of infection when challenged rectally or vaginally with 
high-dose HSV-2.35 ZA and/or CG gels in other murine model studies protected mice (75 
to 85% survival; p < 0.001) against high-dose (106-pfu) HSV-2 rectal or vaginal challenge. 
ZA in HEC was not protective, performing similarly to aqueous ZA solution and the 
placebo controls.39    
 
Anti-Human Papillomavirus (HPV) Activity 
HPV infection may be facilitated by trauma to the cervicovaginal epithelium; CG-based 
gels may show protective potential if developed for use in clinical settings. A study with 
female macaques simulated a common gynecological procedure (cytology specimen 
collection via speculum - a Pap smear), followed by an internal digital exam using as 
lubricant either Surgilube or 1% iota-carrageenan (a known HPV inhibitor). A subgroup 
underwent speculum and digital exam alone (no cytology specimen collection). 
Subsequently each animal’s cervix was inoculated with HPV16 pseudovirus (PsV); after 
3 days cervices were removed and cryosectioned. Significant HPV infection was detected 
only in cervices of animals subject to both a speculum/digital exam and a cytology 
specimen collection.  In macaques for which the CG gel was used as lubricant, the mean 
number of infectious events decreased (CG gel vs. Surgilube, mean=3.5 events per 
section vs. mean=84 infectious events per section, difference=81 events per section, 95% 
CI=33 to 213 events per section.40 
 
The anti-HPV activity of MZC gel is solely due to its carrageenan component.12 In early 
in vitro work, carrageenans were shown to inhibit papillomavirus infection.13 MZC shows 
greater potency against some HPV strains (e.g., 18 and 45) than others (16). Mice were 
fully protected against HPV-16 when gel was vaginally applied 8 hours prior to challenge 
with HPV-16 pseudovirus (PsV).11 Infection was significantly reduced within a window of 


 
 
  
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application of 24 hours before to 2 hours after challenge. However, when mice are subject 
to anorectal challenge the protection window against HPV-16 PsV is much shorter: the 
gel was protective when applied between 2 hours before and 2 hours after challenge, 
temporally corresponding to timepoints at which rectal swabs displaying higher CG 
concentrations were collected. Significant protection continued after 8 hours; these and 
in vitro data suggest that CG blocks HPV post-challenge.11 
 
Toxicology 
Summaries of MIV-150 nonclinical toxicology in vivo studies with mice, rats, monkeys, 
and dogs can be found in the IB.19 Repeated oral dosing of MIV-150 had little to no effect 
on hepatic CYP450 activity in the mouse. Other drugs in the NNRTI class are strong 
inducers and/or inhibitors of CYP3A4 resulting in increases and/or decreases in the 
concentrations of co-administered 3A4 substrate drugs.19 In mice receiving very high 
doses of MIV-150 (>1000 mg/kg) in a behavioral study, an indication of CNS activity was 
observed.19 
 
Zinc acetate (ZA) is an FDA-approved, generally recognized as safe (GRAS) oral drug 
for Wilson's disease and zinc deficiency. No zinc toxicity was seen in rabbits after daily 
vaginal dosing with 90 mM ZA for 10 days or after a 10-day treatment with vaginally 
inserted zinc sulfate-loaded sponges.  These doses far exceed doses in the PC-1005 gel 
(13.7 mM).19 No zinc toxicity was observed in either the Population Council first-in-human 
trial (Protocol #558; described below)17 nor its run-in trial. In the run-in study, zinc blood 
levels were unchanged from baseline; median Cmax of zinc was 79 μg/mL (58-94) on Day 
3 (three days of daily dosing).17  
 
A 14-day rabbit rectal irritation study was conducted for Population Council to assess 
potential systemic toxicity and toxicokinetics of MIV-150 for varied dose concentrations 
of PC-1005_D and PC-707_D gels as compared to sham, placebo, and reference 
controls41. (See Table 7 below.) Based on the rectal irritation index, both gels were 
considered non-irritating at all examined dose concentrations. The no-observable-
adverse-effect-level (NOAEL) was considered to be the 5x dose of PC-1005 and PC-707.  
 


 
 
  
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Table 7: Animal Assignment and Dose Concentrations in Rabbit Rectal Irritation Study for PC-
1005_D and PC-707_D  
Group 
Number 
Treatment 
Dose 
Volume 
(mL/animal/day)
Dose 
Concentration 
Number of 
Animals 
Male Female
 
Main Study 
 
 
 
 
 
 
 
 
 
 
 
 
1 
Sham Control 
NA 
NA 
6 
6 
2 
PC-525a 
(Vehicle 
Control/Placebo) 
1 
0% 
6 
6 
3 
Conceptrol® 
(N-9 Reference 
Control) 
1 
4% 
6 
6 
4 
PC-1005 (1x) 
1 
0.00184% MIV-150, 
0.3% Zinc Acetate 
6 
6 
5 
PC-1005 (3x) 
1 
0.00553% MIV-150, 
0.9% Zinc Acetate 
6 
6 
6 
PC-1005 (5x) 
1 
0.00921% MIV-150, 
1.5% Zinc Acetate 
6 
6 
7 
PC-707 (1x) 
1 
0.3% Zinc Acetate 
6 
6 
8 
PC-707 (3x) 
1 
0.9% Zinc Acetate 
6 
6 
9 
PC-707 (5x) 
1 
1.5% Zinc Acetate 
6 
6 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
10 
PC-525a 
(Vehicle 
Control/Placebo) 
1 
0% 
3 
3 
11 
PC-1005 (1x) 
1 
0.00184% MIV-150, 
0.3% Zinc Acetate 
4 
4 
12 
PC-1005 (3x) 
1 
0.00553% MIV-150, 
0.9% Zinc Acetate 
4 
4 
13 
PC-1005 (5x) 
1 
0.00921% MIV-150, 
1.5% Zinc Acetate 
4 
4 
14 
PC-707 (1x) 
1 
0.3% Zinc Acetate 
4 
4 
15 
PC-707 (3x) 
1 
0.9% Zinc Acetate 
4 
4 
16 
PC-707 (5x) 
1 
1.5% Zinc Acetate 
4 
4 
 
 
 
 
 
 
 
 
 
 
 
 
a: viscous, carrageenan-based gel 
NA - Not applicable; N-9 - Nonoxynol-9 
 
 


 
 
  
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Following daily rectal administration of PC-1005 at 1x, 3x, or 5x formulations, mean AUC0-
24hr and Cmax values for MIV 150 appeared to increase from PC-1005 (1x) to PC 1005 (3x) 
with no increase from PC 1005 (3x) to PC-1005 (5x) on Days 1 and 14. On Day 1, a 1 to 
3 to 5 fold increase in dose resulted in an approximate 1 to 3.0 to 3.5 fold increase in 
AUC0-24hr values and an approximate 1 to 3.2 to 3.4 fold increase in Cmax values. On Day 
14, a 1 to 3 to 5 fold increase in dose resulted in an approximate 1 to 3.6 to 4.6 fold 
increase in AUC0-24hr values and an approximate 1 to 4.2 to 4.1 fold increase in Cmax 
values.  
 
Systemic exposure to MIV-150 appeared to increase following repeated administration of 
PC-1005. Mean AUC0-24hr accumulation ratios were 1.75, 2.03, and 2.24 at PC-1005 (1x), 
PC 1005 (3x), and PC 1005 (5x), respectively. Individual AUC0-24hr accumulation ratios 
ranged from 1.01 to 2.93 at PC-1005 (1x), from 1.11 to 2.92 at PC-1005 (3x), and from 
1.65 to 2.91 at PC 1005 (5x). 
 
The safety of PC-1005_C  and PC-525_C on vaginal and rectal mucosal epithelium at the 
site of product use was evaluated in vivo using Macaca nemestrina over 4 consecutive 
days of daily exposure. Six animals, weighing 5-10 kg and aged 4-13 years (i.e. sexually 
mature), were in each group; gel was administered at approximately the same time each 
day at a dose volume of 1.5 mL/animal (vaginal dose) or 2.5mL/animal (rectal dose). 
Colposcopy was performed to assess CV tissues, vaginal and rectal swabs were taken 
to test pH and microbiota composition, and rectal lavages were performed to evaluate 
epithelial sloughing. In the vaginal groups, neither gel caused discernable irriation to CV 
tissues and pH decreased with gel administration from 7.5 at baseline to closer to 6.5; 
animals in the rectal groups demonstrated lower pH after product exposure. No profound 
changes were seen in any of the groups with respect to microbiota. Neither gel resulted 
in increased shedding of epithelial sheets (defined as at least 3 mm) in rectal lavages 
conducted 30 minutes after each exposure. 
 
The available information on the oral administration of undegraded carrageenan at levels 
greatly exceeding the daily human intake reveals evidence of possible adverse effects on 
the gastrointestinal epithelium. Extensive investigations of carrageenan and the 
pathogenesis of gastrointestinal changes indicate the susceptibility of the guinea pig to 
ulcerative colitis when fed relatively high levels of carrageenan in the diet. The work 
suggests that the occurrence of ulcers in the large bowel of animals is a species-specific 
phenomenon where feeding of carrageenan can induce ulceration in the cecum and 
proximal colon of the guinea pig which, to date, does not appear to occur in humans, rats, 
mice, hamsters, pigs, or squirrel monkeys. Parenterally administered carrageenan has 
been reported to exert cytotoxic effects on macrophages, suppress delayed 
hypersensitivity reactions in some tuberculin sensitive animals, activate factors causing 
procoagulant activity in human blood platelets, increase vascular permeability, and 
liberate kinin in vitro.30 PC-1005 gel will be administered topically in MTN-037. 
 
In mice, CG is not damaging to either vaginal or rectal epithelial tissue. In vitro, it is not 
toxic to the ‘healthy’ Lactobacillus strains L. jensenii and L. crispatus.12 MZC and related 
gel formulations did not induce mucosal toxicity in ex vivo evaluations of safety and anti-


 
 
  
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SHIV-RT activity in macaque mucosal explants and in safety evaluations of human 
ectocervical explants.42 
 
Pregnancy, Teratogenic Effects, and Lactation 
In animals treated with MIV-150, no fetal malformations have been observed. It is not yet 
known whether any component of PC-1005 can enter breast milk of a lactating female.19 
 
Reproductive Toxicity 
The reproductive toxicity profile of PC-1005 gel administered vaginally has not been 
evaluated; animal reproduction studies have not yet been conducted.19 
 
2.5 Clinical Studies  
 
MIV-150 Oral Formulation Trials 
MIV-150 was studied in 4 Phase 1 clinical trials (see Table 8 below) in men using different 
oral formulations and dose levels by Chiron Corporation. There were no SAEs reported 
in association with MIV-150 oral administration. None of these 4 studies achieved the 
target systemic trough concentration of greater than 120 ng/mL considered necessary for 
antiviral efficacy.19 In the Chiron clinical development program, MIV-150 was given to 
over 60 volunteers in these 4 studies using micronized and nanocrystal dispersion (NCD) 
formulations. MIV-150 was well-tolerated in 2 single and 2 multiple oral dose studies with 
doses of 200 to 1600 mg per day. Relative bioavailability was greater for the NCD than 
the micronized suspension. Treatment-emergent clinical events related to study drug 
were mild and transitory, and consisted of somnolence, fatigue, and anorexia. After 
administration of NCD, the absorption of MIV-150 was rapid, with Cmax occurring within 2 
hours. After attaining Cmax, plasma concentrations declined rapidly in an apparent 
biphasic manner, and 12-hour trough levels were lower than expected. To achieve higher 
trough levels, 2 controlled-release (CR) formulations of MIV-150 with zero-order (CR01) 
and first-order (CR02) release kinetics were studied (MIV-102; Table 8). Although there 
was no significant difference between the 2 formulations, the extent of exposure was up 
to 17% greater for CR01 than CR02. CR01 was then selected for a multiple dose Phase 
1 study (MIV-103, Table 8). Mean trough levels of approximately 48.4 + 29 and 100 + 70 
ng/mL were achieved with 800 mg BID and 400 mg TID regimens, respectively. The 
AUC(0-∞) and Cmax values increased in a less than dose proportional manner over the 
ascending dose levels in all 4 trials, indicating that absorption is dissolution rate limited. 
Neither the CR01 nor CR02 formulations provided a superior profile to the parent NCD 
formulation.  
 
Additional trial details appear below in Table 8 and in the IB.19 


 
 
  
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Table 8: Summary of Completed Clinical Studies with MIV-150 
Study  
Study Name 
Population (N)
(Oral) Dose
Findings:
Adverse Events 
Findings:
PK 
MIV-101 
Bioequivalence of Micronized 
Suspension and NanoCrystal 
Dispersion Formulations and a 
Comparison of the Fed/Fasted 
Pharmacokinetics in Healthy 
Male Subjects 
MIV-150: (19) Healthy 
male volunteers aged 
18−55  
Controls: (5) Healthy 
male volunteers aged 
18-55  
400 mg micronized 
suspension single 
dose; 
200-1600 mg NCD 
single dose; 
800 mg NCD single 
dose fast/ fed (high fat 
diet) 
 
Total of 31 mild and 
transient AEs, including 9 
drug related: (nausea, 
insomnia, anorexia, 
dizziness, dry mouth, 
cough, headache, and 
taste perversion. 
Systemic exposure of 
MIV-150 was 2-fold 
greater in the fed 
compared to the fasted 
state. The drug is 
cleared by non-renal 
mechanisms 
(negligible urine drug). 
Tmax 0.5-2 hours; half-
life 10-13.5 hours; 
dose-proportionality, 
but increased 
variability at 1600 mg 
dose level. 
MIV-102 
Bioequivalence and 
Bioavailability of 2 Different 
Controlled Release 
Formulations at 3 Different 
Dose Levels in Healthy Male 
Subjects 
MIV-150: (14) Healthy 
male volunteers aged 
18−55  
Controls: (5) Healthy 
male volunteers aged 
18−55  
400-1600 mg CR01 
single dose;  
400-800 mg CR02 
single dose (high fat 
diet) 
Total of 17 mild and 
transient, 3 considered 
drug related. Drug-
related AEs included: 
fatigue, somnolence, and 
anorexia. 
Tmax 2-10 hours; half-
life 6-60 hours; sub-
proportional kinetics at 
800 and 1600 mg dose 
level. 
MIV-103 
Safety, Tolerability, and 
Pharmacokinetics of Multiple 
Oral Doses in Healthy Male 
Subjects 
MIV-150: (14) Healthy 
male volunteers aged 
18−55 
CRO1 multiple doses 
400 mg TID vs  
800 mg BID 
(regular diet) 
Total of 19 AEs of which 
13 were drug related. 
NNRTI expected CNS 
and GI related AEs 
(disturbance in attention, 
loose stools, upper 
abdominal pain). Other 
drug-related AEs 
included: fatigue, 
headache, thirst, 
weakness, and irritability. 
All drug-related AEs 
were reported in the 400 
mg TID group. 11 drug-
related AEs were mild, 2 
were moderate. 1 subject 
was discontinued for 
non-drug-related AEs 
(persistent high fasting 
blood glucose and 
glycosuria.) 
Systemic exposure to 
MIV-150 increased 
2.5- to 4-fold for the 
800 mg BID and 400 
mg TID. Tmax 3-6 
hours; half-life 10-27 
hours; steady-state 
achieved 24 hours 
after start of multiple 
dosing; sub-
proportional between 
400 and 800 mg dose 
levels. Mean plasma 
levels 71 − 217 ng/mL 
(400 mg TID) and 42 − 
163 ng/mL (800 mg 
BID). 
 


 
 
  
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Study  
Study Name 
Population (N)
(Oral) Dose
Findings:
Adverse Events 
Findings:
PK 
MIV-103b 
Ascending Multiple Oral Dose 
Study of 3 Different Doses of 
NanoCrystal Dispersion 
Formulation in Healthy Male 
Subjects 
MIV-150: (16) Healthy 
male volunteers aged 
18 − 55 years 
800 mg NCD BID; 
1200 mg NCD BID 
Total of 47 AEs of which 
29 were considered drug 
related. 4 drug-related 
AEs in the 800 mg MIV-
150 BID cohort included: 
headache, flatulence, 
rash, and papular rash. 
There was a dose-
dependent increase at 
1200 mg BID in the 
frequency of drug-related 
AEs of somnolence, 
headache, mild GI 
symptoms. Additional 
drug-related AEs at 1200 
mg BID included: 
pruritus, fatigue, 
weakness, and jaundice. 
A clinically significant AE 
of cholestatic hepatitis 
was reported. 
Systemic exposure of 
MIV-150 appeared to 
increase in a dose-
proportional manner 
between the 800 and 
1200 mg dose levels, 
although variability 
between subjects was 
greater at the higher 
dose level. Tmax 1-4 
hours; biphasic 
disposition with 3-24 
hour half-life; diurnal 
variation in clearance; 
dose-proportional but 
variable between 800 
and1200 mg dose 
levels. 
BID = twice daily; CR = controlled release; CR01=Zero-order controlled release; CR02=first-order controlled release;  NCD = NanoCrystal Dispersion;  
TID = three times daily 
 


 
 
  
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MIV 150 Gel Formulation Trial 
Prior to a Phase 1, first-in-human PC-1005 trial (the Population Council Protocol #558; 
described below),17 an open-label, safety and PK run-in trial was conducted at one US 
site with 5 healthy adult women aged 19-49. Women self-administered 4 mL PC-1005 gel 
vaginally once daily for 3 consecutive days (clinician-supervised dosing). Blood was 
collected at multiple time points from 30 minutes to 24 hours after doses 1 and 3, and 48 
and 72 hours after dose 3.  MIV-150 was detectable in all participants’ blood; 
accumulation was not noted, suggesting low systemic absorption. On Day 3, the median 
(and CV%) of MIV-150 PK parameters were: half-life (T1/2) of 4.82 (25.2) hours; Cmax of 
84.7 (48.1) pg/mL; Tmax of 3.92 hours (range 1.97–6.00 hours); and AUClast of 834 (25.0) 
pg h/mL). Blood zinc levels were unchanged from baseline.17  
 
The Population Council Protocol #558 proceeded upon satisfactory safety and PK 
assessments from the run-in trial.17 In this Phase 1, double-blind, parallel, placebo-
controlled, randomized trial with 20 HIV-seronegative women at a US site, participants 
were randomized (4:1) to apply vaginally 4 mL PC-1005_C (the same formulation, based 
on the PC-1005 specifications for Phase 1 study product, to be used in MTN-037) or 
placebo once a day for 14 days.17 Safety, PK, pharmacodynamics, and acceptability were 
evaluated. All PK sampling followed directly observed dose administration. Participants 
were randomized (1:1) to a final PK/PD assessment that included collection of CVL for 
antiviral activity, at either 4 or 24 hours after the Day 14 dose. All 7 CVLs collected 4 
hours after the Day 14 dose showed measurable anti-HPV activity in cell-based assays.17 
Participants (n=20) ranged from 19-44 years old; 52% were Black or African American. A 
total of 23 treatment emergent adverse events (TEAEs) occurred during the trial. Adverse 
events were primarily mild and/or unrelated and were comparable between groups; the 
majority of AEs were DAIDS Grade 1 (11, PC-1005; 2, placebo) or Grade 2 (4, PC-1005, 
1, placebo). There were no Grade 3 or 4 AEs and no participant discontinued product 
because of AEs. AEs designated as related by the study investigator included 
metrorrhagia, 
vaginal 
discharge, 
vulvovaginal 
pruritus, 
abdominal 
discomfort, 
constipation, and urinary tract infection in the PC-1005 group; and uterine spasm 
(cramps) in both groups. No significant histopathologic changes in cervical or vaginal 
biopsies were observed in any of the 17 women who completed the randomized period. 
Median peak (Cmax) MIV-150 concentrations ranged from 75 to 114 pg/mL and no 
accumulation of drug concentration with time was seen. Median time to peak 
concentration (Tmax) ranged from 3-5 hours at different periods of the study (overall range 
2-12 hours). Median half-life ranged from 3.9-5.5 hours.  Plasma zinc levels were 
unchanged from baseline and were within the normal range (60-130 μg/dL).17 All (7/7) 
CVLs collected 4h post-dose demonstrated antiviral (HIV, HPV) activity. High baseline 
CVL anti-HSV-2 activity precluded assessment of post-dose activity. Among those 
completing the trial (13/17, PC-1005; 3/3, placebo), 11/17 reported liking the gel overall; 
7 recommended reducing the volume.  
 
Plasma concentrations achieved through oral dosing (400 mg TID or 800 mg BID) ranged 
from 42-217 ng.mL; plasma MIV-150 concentrations in the vaginal dosing gel formulation 
study described above ranged from 75-114 pg/mL, approximately 1,000-fold lower than 
the concentrations achieved with oral dosing. There have been no rectal dosing studies 
of MIV-150. 


 
 
  
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Safety: Vaginal Administration 
Data suggest carrageenan alone is active against other infections such as HPV, show it 
to be generally recognized as safe (GRAS), safe and acceptable for topical use, and show 
it displays intrinsic antiviral activity.11 Phase 1, 2, and 3 studies have shown 3% CG gel 
to be safe and acceptable when applied vaginally.12 A large (N=6,202 South African 
women) Phase 3 clinical trial for CG-based Carraguard® gel showed that the gel was 
safe, with no side effects or increased risks. 11, 43 However, results also showed that it 
had no statistical effect on HIV infection (in the context of only 41.1% adherence, 
measured by applicator testing).  Among adherent users of the Carraguard®  gel, the 
prevalence of high-risk HPV infection was significantly lower than among adherent users 
of placebo gel.8, 11  The Carraguard® study results were the first published showing a 
protective effect against HPV infection with use of a vaginal microbicide. The CG lambda-
kappa ratios cited for the various test products referenced throughout the protocol and 
Investigator’s Brochure fall within the target specifications set for the proposed product 
by the manufacturer. Please note that Carraguard® has a carrageenan lambda-kappa 
percentage ratio of 95:5; the CG to be used in MTN-037 has a carrageenan lambda-
kappa percentage ratio of 82:18. 
 
2.6 Study Hypotheses and Rationale for Study Design 
 
Study Primary Hypotheses 
 
It is hypothesized that PC-1005 gel (0.002% MIV-150/0.3% ZA in 3.0% CG gel) will be 
safe when applied to the rectum and well-tolerated among healthy men and women (cis 
or transgender) who have a history of receptive anal intercourse (RAI). 
 
Rationale for Study Design 
 
Rectal microbicides are needed for individuals at risk of acquiring a variety of infections 
including HIV, HPV, and HSV-2 through unprotected RAI. It is important to expand the 
rectal microbicide pipeline though the addition of products such as PC-1005 (a non-
nucleoside reverse transcriptase inhibitor [NNRTI], MIV-150, combined with ZA in a CG 
gel). As most RAI is facilitated by the use of a lubricant (such as digital application to the 
perianal area, penis, and/or the rectal area prior to intercourse, or the use of pre-lubricated 
condoms), the use of a rectal gel microbicide has the potential advantage of both 
familiarity and context.  There is considerable community desire to use rectal microbicides 
as lubricants.44 
 
Rationale for the Dosing and PK Sampling Schedule 
MTN-037 is the first study to assess the safety and PK of PC-1005 gel applied rectally. A 
single dose exposure for all participants at each dose (4 mL, 16 mL, and 32 mL) will allow 
for the identification of any safety concerns. Such application may be representative of 
episodic, intermittent or coital dosing.  Intermittent dosing of rectal gel associated with 
sexual activity may be a more feasible strategy for long-term use. Experiments with 
nonhuman primates (macaques) and mice suggest a much broader time window of 


 
 
  
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protection against the three viruses when applied vaginally, as opposed to rectally.11 
However, potential use of rectal microbicide gels as coital lubricants would require gel 
application close to the time of potential viral exposure.11 This dose/volume escalation 
study design will allow for the identification of any safety concerns and provide critical PK 
and PD data. Safety assessments for each participant including a review of AEs will be 
performed prior to proceeding to the next higher dose/volume. 
 
The ideal coital-dosing regimen for PC-1005 gel applied rectally is not yet known. The 
selection of the proposed dosing range (from 4 mL up to 32 mL) is consistent with a 
growing literature regarding lubricant use practices among MSM in the US and elsewhere, 
findings that contribute toward a profile of ‘typical’ lubricant use in RAI. One study45 
conducted from 2007-2010 recruited 168 HIV seronegative, racially and ethnically 
diverse, low-income MSM (mean age 35.5 years; range not provided) residing in Los 
Angeles, California, USA who practice RAI.  At baseline and follow-up visits, participants 
who reported using lubricant were queried via computer assisted self-interview (CASI) 
about their last sexual event with up to 3 recent partners, including the amount of 
commercial lubricant used and number of re-applications. Nearly all (94.9%) reported 
using 30 mL (6 teaspoons) or less in their most recent RAI encounter (see Table 9 below). 
 
Table 9: Lubricant Practices 
Los Angeles, CA, USA 
N=289 Sexual Events
How much lubricant was used? 
          5 mL or less (1 teaspoon) 
26% 
          About 10 mL (2 tsp) 
36.8% 
          About 15 mL (3 tsp) 
21.7% 
          About 30 mL (6 tsp) 
10.4% 
          About 50 mL (10 tsp) 
5.2% 
How many times was lubricant reapplied? 
          Never 
26% 
          Once 
27.3% 
          Twice 
29.4% 
          Three or more times 
17.3% 
 
Another study46 assessed rectal lubricant use in 1995-1996 among 307 HIV seropositive 
and -negative Latino MSM residing in New York City (mean age 31; range 18-55). Of 
those reporting lubricant use (N=273) who provided responses, 94% used at least 5 mL 
(1 tsp) per encounter, about a third (35%) used ≤10mL, and nearly two thirds (60%) used 
≤15mL.   
 
Additionally, a 2008 study47 that recruited 843 HIV seropositive and –negative Peruvian 
MSM aged 18 and older (61% aged 18-29) assessed lubricant use via CASI.  While not 
queried about the amount of lubricant used, 85% of participants who reported having used 
lubricant during RAI with their most recent partner reported applying it 1-2 times (82% 
applied it prior to sexual contact). 
 
A rectal gel volume escalation study was performed with an iso-osmolar polyoxyethylene 
and carbomer gel approved for vaginal use (FemGlide; Trumbuill, CT). Participants 


 
 
  
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applied sequential single doses of 5, 20, 35, and 50 mL after which acceptability was 
assessed. Participants then were given 3 take-home doses of the highest volume they 
deemed “somewhat acceptable” or “completely acceptable” and applied the gels 2 hours 
prior to anticipated receptive anal intercourse. Up to 35 mL of the gel was acceptable to 
the majority of participants. For some participants, volumes classified as acceptable when 
applied without sex were not acceptable when used prior to and during sex. In general, 
participants stated their highly likely intentions to use microbicides when available.48 
 
 
3 
OBJECTIVES  
 
3.1 Primary Objectives 
 
Safety 
 
To evaluate the safety of PC-1005 gel formulation (0.002% MIV-150/0.3% ZA in 3.0% 
CG gel) when applied rectally 
 
Pharmacokinetics 
 
To characterize the systemic and compartmental pharmacokinetics of MIV-150 
following rectal gel application  
 
3.2 Secondary Objectives 
 
Acceptability 
 To compare the acceptability of PC-1005 gel formulation across the three doses when 
administered rectally 
 
Pharmacokinetics 
 To characterize the compartmental pharmacokinetics of MIV-150 in vaginal fluid 
following rectal gel application 
 
3.3 Exploratory Objectives 
 
Biomarkers of Mucosal Safety  
 
To evaluate the mucosal toxicity of PC-1005 gel formulation when applied rectally  
 
Ex Vivo Antiviral Activity 
 
To assess the preliminary (ex vivo) antiviral activity of PC-1005 gel formulation after 
product is applied rectally  
 
 


 
 
  
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4 
 STUDY DESIGN 
 
4.1 Identification of Study Design 
 
MTN-037 is a Phase 1, open label, sequential dose/volume escalation study 
 
4.2 Summary of Major Endpoints 
 
Primary Endpoints: 
 
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). 
 
Pharmacokinetics 
 
MIV-150 concentrations in: 
o Plasma 
o Rectal fluid 
o Rectal mucosal tissue homogenates 
 
Secondary Endpoints:  
 
Acceptability 
 
Participant self-report of comfort with gel application, liking the product across doses, 
and perceived side-effects 
 
Pharmacokinetics 
 
MIV-150 concentrations in vaginal fluid 
 
Exploratory Endpoints: 
 
Biomarkers of Mucosal Safety  
 
Rectal histology 
 
Tissue archive  
 
Ex Vivo Antiviral Activity 
 
Changes in HIV-1 p24 levels in colorectal explant culture supernatant  
 
Anti-HIV activity in rectal fluid  
 


 
 
  
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4.3 Description of Study Population 
 
The study population will consist of HIV-uninfected men and women (cis or transgender) 
with a history of consensual RAI who are aged 18 years or older and meet the criteria 
outlined in Section 5.2 and Section 5.3. 
 
4.4 Time to Complete Accrual 
 
The time to complete accrual is anticipated to be approximately 6-8 months.   
 
4.5 Study Groups  
 
MTN-037 will enroll approximately 12 evaluable participants – approximately 6 men and 
6 women.  
 
4.6 Expected Duration of Participation 
 
Each participant will be on study for approximately 3-5 months.  The total duration of the 
study will be approximately 11-13 months. 
 
4.7 Sites 
 
Sites selected by the MTN Executive Committee. 
 
 
5 
STUDY POPULATION 
 
5.1 Selection of the Study Population 
 
The inclusion and exclusion criteria in Section 5.2 and Section 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, including outpatient clinics, 
universities and community-based locations.  Recruitment materials will be approved by 
site Institutional Review Boards (IRBs) prior to use.   
 
5.1.2 
Retention 
 
Once a participant is enrolled in MTN-037, study sites will make every effort to retain the 
participant in follow-up to minimize possible bias associated with loss-to-follow-up. Sites 
will be responsible for developing and implementing local Standard Operating Procedures 
(SOPs) to target and ensure high rates of retention. 
 


 
 
  
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5.2 Inclusion Criteria 
 
Individuals who meet the following criteria are eligible for study inclusion: 
1. Men and women (cis or transgender) who are 18 years or older 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. At Screening, history of consensual RAI at least once in their lifetime per participant 
report 
 
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) 
 
9. Willing to follow abstinence requirements for the duration of study participation (See 
Section 6.8 for additional information) 
 
10. For participants of childbearing potential: a negative pregnancy test at Screening and 
Enrollment 
 
11. For participants of childbearing potential: Per participant report at Enrollment, using 
an effective method of contraception and intending to use an effective method for the 
duration of study participation; these include: 
a) Hormonal methods, excluding vaginal rings 
b) Intrauterine device (IUD) inserted at least 42 days prior to Enrollment (but not 
past the maximum length of recommended usage according to package 
instructions)  
c) Sterilization of participant or partner at least 42 days prior to Enrollment 
d) Self-identifies as having sex with women exclusively 
 
5.3 Exclusion Criteria 
 
Individuals who meet any of the following criteria will be excluded from the study:   
 
1. At Screening: 
a) Hemoglobin Grade 1 or higher* 
b) Platelet count Grade 1 or higher*  
c) White blood count Grade 2 or higher* 


 
 
  
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d) Aspartate aminotransferase (AST) or alanine transaminase (ALT) Grade 1 or 
higher* 
e) Serum creatinine >1.3× the site laboratory upper limit of normal (ULN) 
f) International normalized ratio (INR) >1.5× the site laboratory ULN 
g) History of inflammatory bowel disease by participant report 
 
*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 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. Known adverse reaction to latex or polyurethane (ever) 
 
3. Anticipated use of and/or unwillingness to abstain from the following medications 
during study participation: 
a) Anticoagulant medications 
b) Rectally-administered medications  
 
4. Known adverse reaction to any of the components of the study product   
 
5. Use of pre-exposure prophylaxis (PrEP) for HIV prevention within 1 month prior to 
Enrollment, and/or anticipated use and/or unwillingness to abstain from PrEP during 
trial participation 
 
6. Use of post-exposure prophylaxis (PEP) for potential HIV exposure within the 3 
months prior to Enrollment 
 
7. Condomless RAI and/or penile-vaginal intercourse with a partner who is known to be 
HIV-positive or whose status is unknown in the 6 months prior to Enrollment 
 
8. Non-therapeutic injection drug use in the 12 months prior to Enrollment 
 
9. Participation in research studies involving drugs, medical devices, genital or rectal 
products, or vaccines within 30 days of the Enrollment Visit 
 
10. Gynecologic, genital, or rectal procedure (e.g., tubal ligation, dilation and curettage, 
piercing, hemorrhoidal resection, polyp removal)  60 days or less prior to Enrollment, 
or rectal biopsy, 7 days or less prior to Enrollment    
Note:  Colposcopy and cervical biopsies for evaluation of an abnormal Pap test as well as 
IUD insertion/removal are not exclusionary. Anoscopy and endoscopy without rectal 
biopsies are not exclusionary 
 
11. Per participant report, medical records, clinical diagnosis and/or diagnostic testing at 
either Screening or Enrollment: 
a) Diagnosis or treatment of any anogenital STI in the past 3 months (including 
window between Screening and Enrollment) 


 
 
  
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b) Symptoms, clinical or laboratory diagnosis of active pharyngeal, anorectal 
infection 
or 
RTI 
requiring 
treatment 
per 
current 
CDC 
guidelines 
(http://www.cdc.gov/std/treatment) 
c) Current symptomatic UTI 
 
Infections requiring treatment include Neisseria gonorrhea (GC), Chlamydia 
trachomatis (CT) infection, syphilis, active herpes simplex virus (HSV) lesions, 
anogenital sores or ulcers, or symptomatic genital warts, chancroid, pelvic 
inflammatory disease (PID), symptomatic bacterial vaginosis (BV), symptomatic 
vaginal candidiasis, other vaginitis, and trichomoniasis. 
Note:  Otherwise eligible participants with an exclusionary UTI, BV and/or candida finding 
may be re-tested during the screening process. 
Note: HSV-1 or HSV-2 seropositive diagnosis with no active lesions is permitted since 
treatment is not required. 
 
12. Participants who meet any of the following additional criteria will be excluded from the 
study:  
a) Pregnant or breastfeeding at either Screening or Enrollment or planning to 
become pregnant or begin 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. 
 
b) Last pregnancy outcome 90 days or less prior to Screening 
 
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. 
 
5.4 Co-enrollment Guidelines 
 
As indicated in Section 5.2 and Section 5.3, participants must not take part in other 
research studies involving drugs, medical devices, genital products, rectal products or 
vaccines after the Screening Visit and while taking part in MTN-037 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: 
 
 Participants may take part in ancillary studies if approved by MTN-037 PSRT 
 Participants who become infected with HIV may take part in observational and/or 
interventional studies for HIV-positive persons 
 Participants who become pregnant while on study product will be offered 
enrollment in MTN-016  
 
Should any participant report concurrent participation in contraindicated studies after 
enrolling in MTN-037, the IoR/designee will consult the PSRT regarding ongoing product 
use and other potential safety considerations associated with co-enrollment. 
 


 
 
  
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6 
STUDY PRODUCT 
 
6.1 Regimen 
 
Approximately 12 participants will each receive three single escalating doses of rectally 
administered PC-1005; 4mL, 16 mL and 32 mL. After each dose is administered in the 
clinic, PK and PD sampling will be conducted. A safety evaluation will be performed 
approximately 24 hours after dosing. If there are no safety issues identified following a 
two to six week washout period, the next dose will be administered in the clinic per clinical 
management guidelines as outlined in Section 9 .  
 
Table 10: Study Product Regimen 
 
6.2 Administration 
 
Participants will be instructed to present to the clinic for each of the 3 doses of rectal gel. 
Administration of the study gel will be performed by study staff.   
 
6.3 Study Product Formulation  
 
PC-1005 is a fixed dose combination of 73.6 µg MIV-150 and 3.58 mg Zn per 4 mL of gel.  
PC-1005 gel should be stored at 25°C (77°F). Excursions are permitted between 15°C 
and 30°C (59°F and 86°F). 
 
6.4 Study Applicator  
 
The site pharmacist will prepare the dose of PC-1005 gel for each administration. The gel 
will be dispensed in a BD™ Luer-Lok™ Tip syringe with a cap and a rectal administration 
tip. The clinic staff will need to replace the cap with the rectal tip prior to administration. 
 
6.5 Study Product Supply and Accountability 
 
6.5.1 
Study Product Supply 
 
The Population Council (New York, NY) will provide single dose amber vials containing 
20 mL of PC-1005 gel. The vials are Fisher Scientific Fisherbrand™Type 1 Class A glass 
amber vials with a fitted cap. 
Visit 3 
 
 
Visit 5
 
Visit 7
4 mL PC‐1005 
 
(73.6 ug MIV‐150 and 
3.58 mg zinc) 
 
16 mL PC‐1005
 
(294.4 ug MIV‐150 
and 14.32 mg zinc) 
 
 
32 mL PC‐1005
 
(588.8 ug MIV‐150 
and 28.64 mg zinc) 


 
 
  
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The BD™ Luer-Lok™ syringes supplied by HealthCare Logistics (Circleville, OH) are 
sterile, latex-free disposable syringes.  These syringes will be provided in 5 mL, 20 mL 
and 60 mL sizes to accomodate the 4 mL, 16 Ml and 32 mL doses, repectively.  A red 
sterile Luer Lock tip cap will be placed on the tip of each syringe.   
 
The syringe tip is a Luer Lock supplied by the Professional Compounding Centers of 
America (Houston, TX). 
 
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. All unused 
study products must be returned to the MTN LOC Pharmacist after the study is complete 
unless otherwise instructed by the MTN LOC Pharmacist. 
 
6.6 Study Product Dispensing  
 
Study products will be dispensed by the pharmacist to study staff upon receipt of a written 
prescription from an authorized prescriber. 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. 
 
6.7 Ancillary Study Supplies 
 
Clinic staff will utilize study-provided lubricant to facilitate the insertion of the study product 
via the rectal administration tip. Clinic staff will also offer condoms to all participants. 
6.7.1 Retrieval of Unused Study Product 
 
Clinic staff will be instructed to return any unused doses to the site pharmacy.  
 
6.8 Concomitant Medications and Practices  
 
Enrolled study participants may use concomitant medications during study participation 
with the exception of medications and products noted as prohibited. All concomitant 
medications reported throughout the course of the study will be recorded in the study 
database. Concomitant medications include all prescription medications, over-the-
counter preparations, vitamins, nutritional supplements, and herbal preparations. 
 
Concomitant Medications 
  
The use of PEP and PrEP are prohibited during study participation. Use of rectally-
administered products, and any products containing N-9, is also prohibited. Participants 
are also prohibited from using CYP3A inhibitors and inducers.  A listing of these specific 
prohibited agents are provided in the MTN-037 SSP Manual available at 
www.mtnstopshiv.org. It is important to note that single dose oral fluconazole for the 


 
 
  
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treatment of vaginal fungal infections is permitted.   
 
Use of anticoagulants or blood-thinners (such as heparin, Lovenox®, warfarin, Plavix® 
[clopidogrel bisulfate]), is also prohibited during study participation. See Section 9.3 for 
additional information. 
 
Participants will be counseled to abstain from using aspirin (greater than 81 mg) and other 
non-steroidal anti-inflammatory drugs (NSAIDS) within 72 hours prior to and following a 
PK sample collection visit. Should a participant report taking any of the medications noted 
above, which may increase risk of bleeding, or report the use of rectal products within 72 
hours prior to biopsy collection, the visit should be rescheduled within the visit window, if 
possible. If it is determined that rescheduling the visit within the window is not possible, 
the visit may proceed at IoR discretion after proper participant counseling has occurred.  
 
Concomitant Practices  
 
All participants are to abstain from inserting any non-study products (including sex toys) 
into the rectum and receptive anal intercourse for 72 hours prior to and following clinic 
visits. Female participants should abstain from inserting anything into the vagina for 72 
hours prior to each clinic visit, including spermicides, vaginal medications (including 
hormones), vaginal douches, lubricants and moisturizers, sex toys (vibrators, dildos, etc.) 
and vaginal intercourse. 
 
All participants are to abstain from the following sexual activities for 72 hours prior to and 
after biopsy collection: receptive anal intercourse (RAI), rectal stimulation via fingers, and 
rectal insertion of sex toys. All participants are to abstain from receptive oral anogenital 
stimulation for 72 hours after biopsy collection.  
 
If desired, the IoR may request rapid PSRT consultation to assist in making the 
determination as to whether or not to proceed with the visit at that time or to reschedule 
as an interim visit. If the decision is made to reschedule as an interim visit, any missed 
procedures (including biopsy collection) should be performed during the interim visit. 
 
 
 


 
 
  
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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 as well as information 
regarding the study visit windows are provided in the MTN-037 SSP Manual available at 
http://www.mtnstopshiv.org/studies. 
 
Figure 2: MTN-037 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, 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 study sites 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 identifiers, unless a waiver is granted from the local IRB. 
Procedures and documentation will comply with local IRB requirements.  
 


 
 
  
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7.2 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 11: Screening Visit 
Visit 1-Screening Visit 
Component 
Procedures 
Administrative and 
Regulatory 
 
 
Obtain written informed consent 
 
Assess consent form comprehension 
 
Assign a unique Participant Identification (PTID) number 
 
Assess eligibility 
 
Collect demographic information 
 
Collect locator information 
 
Provide reimbursement 
 
Schedule next visit/contact* 
Behavioral/Counseling 
 
HIV pre- and post-test counseling 
 
HIV/STI risk reduction counseling 
 
Protocol counseling 
Clinical 
 
Collect medical history 
 
Perform physical examination 
 
Perform male genital examination* 
 
Perform pelvic examination* ♀ 
 
Perform rectal examination 
 
Collect concomitant medications 
 
Treat or prescribe treatment for RTI/UTI, or STIs* 
 
Disclose available test results 
Laboratory 
 
Pharyngeal 
 
NAAT for GC/CT 
Urine 
 
NAAT for GC/CT 
 
Urine dipstick/culture* 
 
Qualitative hCG ♀ 
Blood 
 
CBC with differential and platelets 
 
Chemistries (AST/ALT/Creatinine) 
 
Syphilis serology  
 
HIV-1/2 test 
 
Coagulation (PT/INR) 
Pelvic 
 
NAAT for GC/CT/TV♀ 
Anorectal 
 
NAAT for GC/CT 
 
HSV 1/2 detection* 
Study Product/Supplies 
 
Offer condoms 
* If indicated ♀Female participants 


 
 
  
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7.3 Enrollment (Day 0) 
 
The Enrollment Visit can occur up to 45 days after the Screening Visit.  All Enrollment 
procedures must occur on the same day. 
 
Table 12: Enrollment Visit 
Enrollment Visit – Visit 2 
Component 
Procedures 
Administrative and Regulatory 
 
 
Review informed consent/ confirm participant’s willingness 
to participate in study 
 
Assess and confirm eligibility 
 
Review/update locator information 
 
Provide reimbursement 
 
Schedule next visit/contact* 
 
Randomize to rectal tissue sampling schedule 
Behavioral/Counseling 
 
HIV pre- and post-test counseling 
 
HIV/STI risk reduction counseling 
 
Protocol counseling 
 
Behavioral assessment 
Clinical 
 
Review/update medical history 
 
Perform physical examination 
 
Perform male genital examination* 
 
Perform pelvic examination*♀ 
 
Perform rectal examination 
 
Review/update concomitant medications 
 
Treat or prescribe treatment for RTI/UTI, or STIs* 
 
Disclose  available test results 
Laboratory 
 
Pharyngeal 
 
NAAT for GC/CT* 
Urine 
 
NAAT for GC/CT* 
 
Urine dipstick/culture* 

Qualitative hCG ♀ 
Blood 
 
CBC with differential and platelets* 
 
Chemistries (AST/ALT/Creatinine)* 
 
Syphilis serology* 
 
HIV-1/2 test 

Plasma for archive 
Pelvic 

NAAT for GC/CT/TV*♀ 
Anorectal 
 
Anal swab for HPV 
 
Rectal fluid for PD and biomarker 
 
Rectal enema effluent for PD prior to biopsy collection 
 
Rectal tissue for PD, histology, and archive 
 
HSV 1/2 detection* 

NAAT for GC/CT* 
Study Product/Supplies 
 
Offer condoms 
* If indicated ♀Female participants 


 
 
  
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7.4 Follow-up Visits 
 
7.4.1 Dosing – Visits 3, 5, and 7 
 
The first dosing on Visit 3 should occur approximately 14 days after the Enrollment Visit.   
 
After a two-to-six-week washout period (to accommodate scheduling around the 
menstrual cycles of female participants) following each dosing visit, participants will return 
to the clinic for assessment. If no adverse events (AEs) that preclude continuation to the 
next dose are identified (based on product hold criteria in Section 9 and discretion of the 
IoR/designee), participants will receive the next scheduled dose of the study gel. Please 
see the SSP Manual for additional information. 
 
All participants will undergo PK and PD assessments within 24 hours after each gel 
administration. Participants will be randomized 1:1:1:1 to one of the following 4 time 
frames to provide samples of rectal tissue, rectal fluid, vaginal fluid (if applicable), and 
effluent from rectal lavage: 0.5-1 hour, 1.5-3 hours, 3.5-5 hours, and 24 hours following 
PC-1005 gel application. This time frame will remain consistent across gel volumes.. 
Procedures for the day of dosing are listed in  
 
 


 
 
  
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Table 13 below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
  
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Table 13: Dosing Procedures 
Dosing Procedures – Visits 3 , 5, and 7  
Component 
Procedures 
Administrative and Regulatory 
 
 
Review/update locator information 
 
Provide reimbursement 
 
Schedule next visit/contact 
Behavioral/Counseling 
 
Protocol counseling 
 
Behavioral assessment 
Clinical 
 
Review/update medical history 
 
Perform targeted physical examination* 
 
Perform male genital examination* 
 
Perform pelvic examination*♀ 
 
Perform rectal examination 
 
Review/update concomitant medications 
 
Treat or prescribe treatment for RTI/UTI, or STIs* 
 
Disclose available test results 
 
Record/update AEs 
Laboratory 
Pharyngeal 
 
NAAT for GC/CT* 
Urine 
 
NAAT for GC/CT* 
 
Urine dipstick/culture* 

Qualitative hCG ♀ 
Blood 
 
CBC with differential and platelets* 
 
Chemistries (Creatinine only) 
 
Syphilis serology* 

Blood for PK♦ 
Pelvic 
 
Vaginal fluid for PK⌂♀ 

NAAT for GC/CT/TV*♀ 
Anorectal 
 
 
Rectal enema effluent for PD prior to biopsy collection⌂☼ 
 
Rectal fluid for PK and PD⌂ ☼ 
 
Rectal tissue for PK, PD, histology, and archive⌂☼ 
 
HSV 1/2 detection* 

NAAT for GC/CT* 
Study Product/Supplies 
 
Administration of study product▲  

Offer condoms 
* If indicated. ♀Female participants.  
☼ Please reference the MTN-037 SSP Manual for additional details (www.mtnstopshiv.org)   
▲ Participants will receive a single dose of study product (4 mL, 16 mL, or 32 mL) depending on dosing visit.  


 
 
  
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 ⌂= Participants will be randomized  1:1:1:1 to provide samples of rectal tissue, rectal fluid, vaginal fluid (if applicable), 
and effluent from rectal lavage  in one of the following time periods after dose administration across gel volumes: 0.5-
1 hour; 1.5-3 hours; 3.5-5 hours, or 24 hours. (Those assigned to the 24 hour time point to provide samples will do so 
at the  24-hr Post-dose visit instead of the Dosing visit). 
♦ Blood will be collected pre-dose administration and at 1 hour, 2 hours, 3 hours, 4, hours, 5-6 hours and 24 hours after 
dose administration 
NOTE:  Participants will be instructed to call in to the clinic to report any issues related to the collection of samples via 
the flexible sigmoidoscopy. See SSP Manual for additional details. 
 
7.4.2 24-Hour Post-Dosing Visits  
 
Safety laboratory tests and blood for PK will be collected from all participants at the 24 
hour post-dosing visit. Additionally, participants randomized to sample collection at 24 
hours will have PK and PD samples collected.  
 
Table 14: 24-Hour Post-Dosing Visits  
24-Hour Post-Dosing Visits -  Visits 4, 6, and 8  
Component 
Procedures 
Administrative and Regulatory 
 
 
Review/update locator information 
 
Provide reimbursement 
 
Schedule next visit/contact π 
Behavioral/Counseling 
 
HIV pre- and post-test counseling (Visit 8 only) 
 
HIV/STI risk reduction counseling (Visit 8 only) 
 
Protocol counseling  
 
IDI (Visit 8 only) 
Clinical 
 
Review/update medical history 
 
Perform targeted physical examination* 
 
Perform male genital examination* 
 
Perform pelvic examination*♀ 
 
Perform rectal examination 
 
Review/update concomitant medications 
 
Treat or prescribe treatment for RTI/UTI, or STIs* 
 
Disclose available test results 
 
Record/update AEs 
Laboratory 
Pharyngeal 
 
NAAT for GC/CT* 
Urine 
 
NAAT for GC/CT* 
 
Urine dipstick/culture* 
Blood 
 
CBC with differential and platelets 
 
Chemistries (AST/ALT/Creatinine) 
 
Syphilis serology* 
 
HIV-1/2 test (Visit 8 only) 

Blood for PK♦π  
Pelvic 
 
Vaginal fluid for PK⌂♀ 

NAAT for GC/CT/TV*♀ 


 
 
  
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24-Hour Post-Dosing Visits -  Visits 4, 6, and 8  
Component 
Procedures 
Anorectal 
 
 
Anal swab for HPV 
 
Rectal enema effluent for PD prior to biopsy collection⌂π 
 
Rectal fluid for PK and PD⌂π  
 
Rectal tissue for PK, PD, histology, and archive⌂π 
 
HSV 1/2 detection* 

NAAT for GC/CT* 
* If indicated. ♀Female participants. 
 π Please reference the MTN-037 SSP Manual for additional details (www.mtnstopshiv.org) regarding the appropriate 
procedures to complete for an Early Termination Visit. 
 ⌂= Participants will be randomized  1:1:1:1 to provide samples of rectal tissue, rectal fluid, vaginal fluid (if applicable), 
and effluent from rectal lavagein one of the following time periods after dose administration across gel volumes: 0.5-1 
hour; 1.5-3 hours; 3.5-5 hours, or 24 hours. (Those assigned to the 24 hour time point to provide samples will do so at 
the  24-hr Post-dose visit instead of the Dosing visit). 
♦= Blood will be collected pre-dose administration and at 1 hour, 2 hours, 3 hours, 4, hours, 5-6 hours and 24 hours 
after dose administration  
NOTE:  Participants will be instructed to call in to the clinic to report any issues related to the collection of samples 
via the flexible sigmoidoscopy. See SSP Manual for additional details. 
 
7.4.3 48-Hour Post-Dosing Visits 
 
Participants will be randomly assigned 1:1:1 to provide samples of blood, rectal tissue, 
rectal fluid, vaginal fluid (if applicable), and effluent from rectal lavage samples 48 hours 
following PC-1005 administration for one of the 3 gel volume levels (4 mL, 16 mL, or 32 
mL). Participants will only attend one 48-hour visit during the study. 
 
Table 15: 48-Hour Post-Dosing Visits 
48-Hour Post-Dosing Visits -  Visits 4a, 6a, and 8a  
Component 
Procedures 
Administrative and Regulatory 
 
 
Review/update locator information 
 
Provide reimbursement 
 
Schedule next visit/contact 
Behavioral/Counseling 
 
Protocol counseling  
Clinical 
 
Review/update medical history 
 
Perform targeted physical examination* 
 
Perform male genital examination* 
 
Perform pelvic examination*♀ 
 
Perform rectal examination 
 
Review/update concomitant medications 
 
Treat or prescribe treatment for RTI/UTI, or STIs* 
 
Disclose available test results 
 
Record/update AEs 
Laborat
ory 
Pharyngeal 
 
NAAT for GC/CT* 
Urine 
 
Urine dipstick/culture* 
 
NAAT for GC/CT* 


 
 
  
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48-Hour Post-Dosing Visits -  Visits 4a, 6a, and 8a  
Component 
Procedures 
Blood 
 
Blood for PK  
 
Chemistries (AST/ALT/Creatinine)* 
 
CBC with differential and platelets* 
 
Syphilis serology* 
Pelvic 
 
Vaginal fluid for PK♀ 

NAAT for GC/CT/TV*♀ 
Anorectal 
 
 
Rectal enema effluent for PD prior to biopsy collection ☼ 
 
Rectal fluid for PK and PD ☼ 
 
Rectal tissue for PK, PD, histology, and archive ☼ 
 
HSV 1/2 detection* 

NAAT for GC/CT* 
* If indicated. ♀Female participants. 
☼ Please reference the MTN-037 SSP Manual for additional details (www.mtnstopshiv.org)   
NOTE:  Participants will be instructed to call in to the clinic to report any issues related to the collection of samples via 
the flexible sigmoidoscopy. See SSP Manual for additional details.  
 
7.4.4 Final Contact 
 
The Final Contact (Visit 9) will occur either in-person or by phone approximately two to 
six weeks after the third dosing visit (32 mL) of PC-1005 gel application. This contact will 
also serve as the participant’s study termination. 
 
Table 16: Final Contact  
Final Contact – Visit 9  
Component 
Procedures 
Administrative and Regulatory 
 
 
Review/update locator information 
 
Provide reimbursement ~ 
 
Schedule next visit/contact* 
Behavioral/Counseling 
 
HIV pre- and post-test counseling* 
 
HIV/STI risk reduction counseling* 
 
Protocol counseling* 
Clinical 
 
Review/update medical history 
 
Perform targeted physical examination* 
 
Perform male genital examination* 
 
Perform pelvic examination*♀ 
 
Perform rectal examination* 
 
Review/update concomitant medications 
 
Treat or prescribe treatment for RTI/UTI, or STIs* 
 
Disclose available test results 
 
Record/update AEs 
L
a
Pharyngeal 
 
NAAT for GC/CT* 


 
 
  
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Final Contact – Visit 9  
Component 
Procedures 
Urine 
 
NAAT for GC/CT* 
 
Urine dipstick/culture* 

Qualitative hCG* ♀ 
Blood 
 
CBC with differential and platelets* 
 
Chemistries (AST/ALT/Creatinine)* 
 
Syphilis serology* 

HIV-1/2 test* 
Study Product/Supplies 
 
Offer condoms* 
* If indicated. ♀Female participants. ~ Sites to reference SOPs regarding participant reimbursement. 
 
7.5 Follow-up Procedures for Participants Who Permanently Discontinue Study 
Product 
 
7.5.1 Participants Who Become Infected with HIV-1/2 
 
If a participant tests positive for HIV-1/2 after the Enrollment Visit, he/she 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 (please refer to the 
MTN-037 SSP Manual for specific procedures) will be conducted, if the participant is 
willing. Participants who seroconvert after enrollment may be offered additional laboratory 
testing (such as HIV RNA and HIV drug resistance testing), as clinically indicated, per 
discussions between the site IoR and LC.  Please reference the MTN-037 SSP Manual 
for additional details (www.mtnstopshiv.org). 
 
7.5.2 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 will be 
discontinued and the participant will be considered terminated from the study.  An Early 
Termination Visit will be conducted, if the participant is willing. A participant who is 
pregnant at study termination will continue to be followed until the pregnancy outcome is 
ascertained, see Section 9.6 for additional details. 
 
Participants who become pregnant while on study product will be offered enrollment in 
MTN-016 (www.mtnstopshiv.org) which includes follow-up throughout the pregnancy and 
for the first year of the infant’s life. Additionally, for participants who choose not to enroll 
in MTN-016, the study site will make every reasonable effort to contact participants and 
collect infant outcome at approximately one year after delivery for those pregnancies that 
result in live birth. For additional details regarding obtaining pregnancy and infant 
outcomes, please reference the MTN-037 SSP Manual (www.mtnstopshiv.org). 
 


 
 
  
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7.5.3 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 and the PSRT 
should be notified.  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 be conducted, if the participant is willing. 
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.   
 
7.6 Interim Visits 
 
Interim visits may be performed at any time during the study, for the following or other 
reasons: 
 
 For administrative reasons, e.g., a participant may have questions for study staff, 
or may need to re-schedule a follow-up visit or to perform missed procedures. 
 In response to AEs and/or SAEs.  When interim contacts or visits are completed 
in response to participant reports of AEs and/or SAEs, study staff will assess the 
reported event clinically and provide or refer the participant to appropriate medical 
care (see also Section 9). 
 For STI counseling and testing in response to STI symptoms. 
 For HIV counseling and testing in response to participant report of symptoms 
consistent with acute infection or presumed exposure to HIV 
 To provide participants with the results of confirmatory HIV test results, per the 
algorithm in Appendix II. 
 For other reasons at participant request, e.g., social harm. 
 
All interim contacts and visits will be documented in participants' study records.   
 
7.7 Protocol Counseling:  Adherence and Contraception Counseling 
 
At the Dosing Visit, participants will receive study product counseling appropriate to the 
visit.  Study staff will document administration of study product and that the counseling 
was provided.  Protocol adherence counseling will be provided to study participants upon 
enrollment into the study.  Contraception counseling will be provided to female study 
participants beginning at the Screening Visit. Counseling will be provided in accordance 
with standard study methods.  Counseling also will include reminders regarding 
concomitant medication and behavioral restrictions prior to and following collection of 
biopsies.   
 
7.8 Clinical Evaluations and Procedures 
 
Physical Examination 
The physical examination will include the following assessments:  


 
 
  
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 General appearance 
 Weight*  
 Vital signs 
 Temperature 
 Pulse  
 Blood pressure 
 Respirations 
 Height* 
 Abdomen*  
 Head, Eye, Ear, Nose and Throat (HEENT) Examination* 
 Oral mucosa* 
 Lymph nodes*  
 Neck*  
 Heart* 
 Lungs*  
 Extremities* 
 Skin*  
 Neurological* 
 Other components as indicated by participant symptoms 
 
 
* = May be omitted after Enrollment Visit 
 
Rectal Examination 
The rectal examination may include the following:  
 Visual exam 
 Digital exam 
 Anoscopy  
 Flexible sigmoidoscopy  
 
Male Genital Examination 
The male genital examination may include the following: 
 General inspection via naked eye and hand-held magnifying glass of the following: 
o Entire penile surface 
 Glans 
 Urethral meatus 
 Internal and external foreskin (if present) 
 Shaft 
o Scrotum 
o Inguinal lymph nodes 
 
Pelvic Examination 
The pelvic examination may include the following:  
 Visual exam 
 Speculum exam 
 Bimanual exam 


 
 
  
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Note:  Detailed information regarding the pelvic, rectal and male genital examination, as 
well as the associated procedures required for collecting specimens at each visit, can be 
found in the MTN-037 SSP Manual. 
 
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.  
 
7.9 Behavioral Assessments 
 
The behavioral measures of this protocol will focus mainly on the overall acceptability of 
the rectal gel, as well as comparative acceptability across the different volumes of gel 
used during the volume escalation trial. Microbicide acceptability in MTN-037 will be 
assessed considering the following factors: 
 
 Vehicle-associated:  Formulation, amount (tolerability), and perceived product 
texture, viscosity and scent 
 Use-associated:  Perceived post-application side-effects (e.g., odor, leakage, 
lubrication and/or drying effects), perceived satisfaction with product, and 
desirable/appealing elements of product 
 Related Co-variables:  History of anal product use, frequency of anal sex 
 
Participants will respond to brief web-based self-interviews (WSI) at the Enrollment Visit 
(Visit 2) and at the three dosing visits: Visits 3, 5 and 7. The Visit 2 assessment will 
include, among other topics, questions on participants’ prior experience and comfort using 
rectal products as well as douching or other rectal hygiene practices. The Visits for dosing 
(Visits 3, 5 and 7) will explore reactions to product, with an emphasis on identification of 
product attributes likely to challenge and/or facilitate future sustained use when applied 
rectally by participants (secondary objective: acceptability).  Consistent with data 
harmonization efforts, major components of these WSI assessments have been validated 
in prior rectal microbicide trials (e.g., MTN-006, MTN-007, MTN-017) and will be used as 
part of MTN-037. 
  
An in-depth interview is planned 24 hours following the third and final dose of study 
product (Visit 8). 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 during the volume escalation trial, including reactions to the 
BD™  Luer-Lok™ Tip syringe with cap and rectal administration tip, and administration 
method. 
 
7.10 Pharmacokinetics, Pharmacodynamics and Biomarkers of Mucosal Safety  
 
Each participant will have a total of 5 flexible sigmoidoscopies:  
- 
at baseline;  
- 
within 24 hours of each of the three gel applications (to be determined at random 
to be one of the following times after gel administration: 0.5-1 hr, 1.5-3 hours, 3.5-
5 hours, or 24 hours after gel administration), and  


 
 
  
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- 
48 hours after one of the three gel applications (to be determined at random). 
  
During the flexible sigmoidoscopy procedure, approximately 9 tissue samples will be 
taken at 10-15 cm, except at baseline where only 6 samples will be taken. 
 
Table 17: Specimens to be Collected to Assess PK, Ex Vivo Antiviral Activity, Histology 
Visit 
Specimens Collected for 
PK 
Specimens Collected for 
PD 
Specimens Collected to 
Assess Biomarkers of 
Mucosal Safety 
Enrollment (Visit 
2) 
(Baseline 
Samples)  
 
 Rectal sponge 
 Rectal enema effluent 
prior to biopsy collection 
 Rectal tissue (~3 
biopsies) 
 Rectal sponge 
 Rectal tissue for 
histology (1 biopsy) 
 Rectal tissue for 
archive (2 biopsies) 
Dosing Visits  
(Visits 3, 5, and 7) 
 Blood ♦ 
 Rectal fluid ⌂ 
 Rectal tissue (~3 
biopsies) ⌂ 
 Vaginal fluid⌂♀ 
 Rectal fluid ⌂ 
 Rectal enema effluent ⌂ 
 Rectal tissue (~3 
biopsies) ⌂ 
 
 Rectal tissue for 
histology (1 biopsy) ⌂ 
 Rectal tissue for 
archive (2 biopsies) ⌂ 
24h Post-Dosing 
Visits  
(Visits 4, 6, and 8) 
 Blood ♦ 
 Rectal fluid ⌂ 
 Rectal tissue (~3 
biopsies) ⌂  
 Vaginal fluid⌂ ♀ 
 Rectal fluid ⌂ 
 Rectal enema effluent ⌂ 
 Rectal tissue (~3 
biopsies) ⌂ 
 
 Rectal tissue for 
histology (1 biopsy) ⌂ 
 Rectal tissue for 
archive (2 biopsies)  ⌂ 
 48h Post-Dosing 
Visits 
(Visits 4a, 6a, and 
8a) 
 Blood 
 Rectal fluid 
 Rectal tissue (~3 
biopsies) 
 Vaginal fluid♀  
 Rectal fluid  
 Rectal enema effluent  
 Rectal tissue (~3 
biopsies) 
 
 Rectal tissue for 
histology (1 biopsy) 
 Rectal tissue for 
archive (2 biopsies)  
♦= Blood will be collected pre-dose administration and at 1 hour, 2 hours, 3 hours, 4, hours, 5-6 hours and 24 hours 
after dose administration     
♀=Female participants 
⌂= Participants will be randomized 1:1:1:1 to provide samples of rectal tissue, rectal fluid, vaginal fluid (if applicable), 
and effluent from rectal lavage  in one of the following time periods after dose administration across gel volumes: 0.5-
1 hr, 1.5-3 hours, 3.5-5 hours, or 24 hours  
=Participants will be randomly assigned 1:1:1 to provide samples of blood, rectal tissue, rectal fluid, vaginal fluid (if 
applicable), and effluent from rectal lavage samples 48 hours following PC-1005 gel application for one of the 3 gel 
volume levels (4 mL, 16 mL, or 32 mL). 
 
7.11 Laboratory Evaluations 
 
Local Laboratory 
The local laboratory will run the following, as indicated: 
 
 Pharyngeal specimens 
o NAAT for GC/CT 
 Vaginal specimens 
o GC/CT/TV 
 Urine specimens 
o Urine hCG 
o Urine GC/CT by NAAT 


 
 
  
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o Dipstick/culture 
 Anorectal specimens 
o Rectal fluids for:  
 Rectal GC/CT by NAAT  
 HSV 1/2 viral detection 
o Rectal tissue for: 
 PD 
 Blood specimens 
o HIV-1/2 testing, with confirmatory testing as needed 
o CBC with differential and platelets  
o Syphilis serology 
o Creatinine, AST, ALT 
o Coagulation (PT/INR) 
 
Network Laboratory Center (LC) 
 Vaginal specimens  
o Fluid for PK (Pharmacology Core) 
 Blood specimens 
o PK (Pharmacology Core) 
o Plasma archive 
 Anorectal specimens  
o Anal swab for HPV 
o Rectal fluids and/or lavage for:  
 PK (Pharmacology Core) 
 PD (Protocol Support Core) 
o Rectal tissue for: 
 PK (Pharmacology Core) 
 Mucosal safety (archive) 
 Histology 
 
Once all required study analyses of collected specimens are complete, any remaining 
sample may be shipped to the MTN LC for use in study-related quality assurance and 
quality control testing.  If study samples will be used for assay validation or proficiency 
testing that is not study related, all participant identifiers (PTID) will be removed from the 
samples prior to use.  Specimens obtained from participants who do not consent to long 
term storage will not be used for assay validation or proficiency testing purposes. 
 
7.12 Specimen Management 
 
Study sites will adhere to the standards of good clinical laboratory practice 
(https://www.niaid.nih.gov/sites/default/files/gclp.pdf), in accordance with current US 
Division of AIDS (DAIDS) Laboratory Requirements, MTN-037 Study Specific Procedures 
Manual (http://www.mtnstopshiv.org/studies) and site standard operating procedures for 
proper collection, processing, labeling, transport, and storage of specimens to 
standardize procedures.  Specimen collection, testing, and storage at the site laboratories 
will be documented when applicable using the Laboratory Data Management System 


 
 
  
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(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. 
 
7.13 DAIDS Laboratory Oversight 
 
All laboratories participating in DAIDS Sponsored and/or Funded Laboratories in Clinical 
Trials will adhere to the DAIDS Laboratory Policy 
(https://www.niaid.nih.gov/research/daids-clinical-research-policies-us-labs) 
 
7.14 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 
 
Site IoRs are 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, a Population Council 
representative, and MTN Protocol Safety Physicians will serve as the PSRT. The MTN 
Statistical Data and Management Center (SDMC) prepares routine AE and clinical data 
reports for review by the PSRT, which meets via conference call to review safety data, 
discuss product use management, and address any potential safety concerns.  


 
 
  
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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.  
 
MTN SDMC staff will review incoming safety data on an ongoing basis. Events identified 
as questionable, inconsistent, or unexplained will be queried for verification. AE reports 
submitted in an expedited manner to the DAIDS Safety Office will be forwarded to the 
DAIDS Medical Officer and SDMC Clinical Safety & Coding Group 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 10.7), since no Data and Safety Monitoring Board oversight 
is planned for MTN-037. 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 Site IoRs will notify the responsible 
IRB 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.  These reviews will take place 
approximately every 4-6 months, or 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. 
 


 
 
  
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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 through the termination visit. The 
term “investigational product” for this study refers to PC-1005 (0.002% MIV-150/0.3% 
Zinc 
acetate 
[ZA] 
in 
 
3.0% 
 
Carrageenan 
 
[CG] 
 
gel).  
 
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 captured in the study database. 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 in the study database 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, 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).  
 
Please note: 
 Asymptomatic BV and asymptomatic candidiasis will not be reportable AEs; 
 Fetal losses (e.g., spontaneous abortions, spontaneous fetal deaths, stillbirths) will 
not be reported as AEs (however, fetal loss data will be collected); 
 Untoward maternal conditions that either result in or result from fetal losses are 
reported as reproductive system AEs. 
 
Bleeding at the time of BD™ Luer-Lok™ Tip syringe with cap and rectal administration tip 
use, anoscope, flexible sigmoidoscope insertion/removal, and/or biopsy collection that is 
judged by the clinician to be within the range of what is normally anticipated will not be 
reportable as an AE. Bleeding of greater quantity or longer duration than what is typical, 
per clinician assessment, will be reportable as an AE. Fecal urgency, bloating and 


 
 
  
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flatulence associated with rectal procedures deemed to be within the range of what is 
normally expected will not be reportable as AEs. 
 
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:  
 
 Results in death 
 Is life-threatening  
 Results in persistent or significant disability/incapacity  
 Is a congenital anomaly/birth defect 
 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: 
 
 Related: There is a reasonable possibility that the AE may be related to the study 
agent(s) 
 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 AEs are outlined in 
Version 2.0 of the DAIDS EAE Manual, which is available on the DAIDS 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 adverse event (EAE) reporting to DAIDS. In the event 
of system outages or technical difficulties, EAEs may be submitted using the DAIDS EAE 
Form. This form is available on the DAIDS RSC website at http://rsc.tech-res.com/clinical-
research-sites/safety-reporting/daids/paper-eae-reporting. 
 
For 
questions 
about 
DAERS, 
please 
contact 
NIAID 
CRMS 
Support 
at 
CRMSSupport@niaid.nih.gov. Please note that site queries may also be sent from within 
the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety Office at 
(DAIDSRSCSafetyOffice@tech-res.com). 
 
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 agent for which expedited reporting is required is: PC-
1005 (0.002% MIV-150/0.3% zinc acetate [ZA] in 3.0% carrageenan [CG] gel).           
                     
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 2017, and 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 EAE reporting period for this study begins at enrollment 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 
Manual will be reported to DAIDS if the study staff become aware of the events on a 
passive basis (from publicly available information). 
 


 
 
  
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8.5 
Pregnancy and Infant Outcomes 
 
Pregnant women are excluded from this study. 
 
A participant who becomes pregnant after enrollment will continue to be followed until the 
pregnancy and, if applicable, infant outcome is ascertained, see Section 9.6 for additional 
details. Pregnancy outcomes will not be expeditiously reported to the Population Council 
or 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.  
 
A participant who becomes pregnant during the course of study participation will be 
offered participation in MTN-016, HIV Prevention Agent Pregnancy Exposure Registry: 
EMBRACE Study. This registry study captures pregnancy outcomes as well as infant 
health information, (including growth) for the first year of life, to evaluate the safety and 
teratogenic risks of microbicide and oral PrEP exposure in pregnancy. Additionally, for 
participants not enrolled in MTN-016, the study site will make every reasonable effort to 
contact participants and collect infant outcome at approximately one year after delivery 
for those pregnancies that result in live birth. 
 
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 will 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 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 he/she feels that continued product use would 
be harmful to the participant or interfere with treatment deemed clinically necessary. 
IoRs/designees will document all permanent discontinuations on applicable CRFs. 
 


 
 
  
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9.1 Grading System 
 
AE severity grading is described in Section 8.4.3. 
 
9.2 Dose Modification Instructions 
 
No dose modifications will be undertaken in this study. However, participants will not 
proceed to the next sequential dose if they meet any of the criteria for product hold or 
discontinuation as found in Section 9.3 and Section 9.4. 
 
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: 
 Acquisition of HIV infection; for those who acquire HIV, study product should be 
held beginning immediately upon recognition of the first positive/reactive HIV test 
 Pregnancy or breastfeeding 
 Anogenital STIs 
 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. 
 Reported use of PEP or PrEP 
 Anticoagulant use (e.g., heparin, Lovenox, warfarin and Plavix) 
 Use of CYP3A inhibitors and inducers (as specified in MTN-037 SSP Manual) 
 
At the discretion of the IoR/designee, a participant may be permanently discontinued for 
reported use of the following medications 
 Aspirin (greater than 81 mg/day), other non-steroidal anti-inflammatory drugs 
(NSAIDS) 
 Rectally administered products  
   
9.4 Follow-up in Response to Observed Adverse Events 
 
Grade 1 and Grade 2 Unrelated  
In general, a participant who develops a Grade 1 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, 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), regardless of relationship to study product, may 
continue product use. Participants who develop a Grade 2 AE that is judged by the 
IoR/designee to be unrelated to study product may also continue product use. If the 
IoR/designee opts to temporarily hold study product, the PSRT must be notified.  
 


 
 
  
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Grade 2 Related 
For participants who develop a Grade 2 AE that is judged by the IoR/designee to be 
related to product, study product must be held and the IoR must consult with PSRT 
regarding continued study product use. 
 
If a recurrence of the same Grade 2 AE judged to be related to study product recurs at 
any time during the study, study product must be temporarily held until the PSRT can be 
consulted regarding permanent discontinuation or other further management. 
 
Grade 3 or Grade 4 
For participants who develop a Grade 3 or 4 AE study product must be permanently 
discontinued and the PSRT notified. 
 
9.5 HIV-1 Infection 
 
Participants who test positive for HIV-1 must have study product permanently 
discontinued by the IoR/designee.  A participant who is confirmed to be HIV-1 positive 
during the course of the study will have study product discontinued, all follow-up visits will 
be discontinued and the participant will be considered terminated from the study, as per 
Section 7.5.1. Guidance regarding management and referral for participants confirmed to 
be HIV-positive is located in Section 13.10. 
 
9.6 Pregnancy 
 
Female 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 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 7.5.2.  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 and infant outcomes will be 
reported on relevant CRFs; outcomes meeting criteria for EAE reporting also will be 
reported on EAE forms. 
 
A participant who becomes pregnant during the course of study participation will be 
offered participation in MTN-016, HIV Prevention Agent Pregnancy Exposure Registry: 
EMBRACE Study. This registry study captures pregnancy outcomes as well as infant 
health information, (including growth) for the first year of life, to evaluate the safety and 
teratogenic risks of microbicide and oral PrEP exposure in pregnancy. Additionally, for 
participants not enrolled in MTN-016, the study site will make every reasonable effort to 
contact participants and collect infant outcome at approximately one year after delivery 
for those pregnancies that result in live birth.  
 


 
 
  
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9.7 Criteria for Early Termination of Study Participation 
 
Participants may voluntarily withdraw from the study for any reason at any time. 
IoRs/designees 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 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 details regarding the Early 
Termination Visit in Section 7.5). Study staff members will record the reason(s) for all 
withdrawals in participants’ study records. 
 
  
10 
STATISTICAL CONSIDERATIONS 
 
10.1 Overview and General Design 
 
MTN-037 is a phase 1, open label, sequential dose/volume escalation trial designed to 
characterize the PK and safety profiles of a single dose of PC-1005 (0.002% MIV-
150/0.3% zinc acetate [ZA] in 3.0% carrageenan [CG] gel) administered rectally via 
applicator in the clinic. Twelve HIV-uninfected men and women, 18 years or older will 
receive a single dose of each dose/volume (4 mL, 16 mL, and 32 mL) in sequential order 
allowing time for adequate washout before application of the subsequent dose.  
 
10.2 Study Endpoints 
 
Primary Endpoints 
 
Consistent with the primary study objectives to (1) evaluate the safety of PC-1005 gel 
formulation (0.002%MIV-150/0.3% zinc acetate [ZA] in 3.0% carrageenan [CG] gel) when 
applied rectally and (2) characterize the systemic and compartmental pharmacokinetics 
of PC-1005 gel following rectal application, the following endpoints will be assessed: 
 
 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) 
 Pharmacokinetics 
MIV-150 concentrations 
o Plasma 
o Rectal fluid 
o Rectal mucosal tissue homogenates 


 
 
  
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10.3 Primary Study Hypotheses 
 
MTN-037 hypothesizes that PC-1005 gel (0.002% MIV-150/0.3% ZA in 3.0% CG gel) will 
be safe when applied to the rectum and well-tolerated among healthy men and women 
who have a history of receptive anal intercourse (RAI). 
 
10.4 Sample Size and Power Calculations 
 
Safety Endpoints 
 
The proposed total sample size for assessing safety is approximately N=12 participants.  
This sample size is based upon the size of similar Phase 1 studies of microbicides for 
HIV prevention. 
 
As a means to characterize the statistical properties of this study, Table 18 below presents 
the probability of observing zero, at least one, and two or more safety endpoints among 
the 12 participants for various “true” event rates: 
 
Table 18: 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.  Table 19 
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 12 participants receiving a particular 
dose/volume of gel experience a safety event, the 95% exact 2-sided upper confidence 
bound for the true rate of such events for that dose/volume is 26.4%. 
 
Table 19: Exact 2-sided 95% Confidence Intervals Based on Observing a Particular Rate of Safety 
Endpoints for Arms of Size 12 
Observed event rate 
Confidence interval (%) 
0/12 
0.0, 26.4 
1/12 
0.2, 38.4 
2/12 
2.1, 48.4 
  
Additional participants may enroll in the study, at the discretion of the protocol team, to 
replace currently enrolled participants lost to follow-up or to permanent product 
discontinuation. Thus, in the event that additional participants are recruited for this 
purpose, the total sample size at the end of the study may slightly exceed 12 participants 
who received any dose/volume of PC-1005. 
Event Rate 
P (0 events | n=12) 
P (>1 event | n=12) 
P (>2 events | n=12) 
1% 
88.6 
11.4 
0.6 
5% 
54.0 
46.0 
11.8 
10% 
28.2 
71.8 
34.1 
15% 
14.2 
85.8 
55.7 
25% 
3.2 
96.8 
84.2 
35% 
0.6 
99.4 
95.8 


 
 
  
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10.5 Randomization Procedures 
 
There will be no randomization to dose/volume of PC-1005 in this open-label, sequential 
dose/volume escalation trial.  However, upon enrollment a participant will be assigned to 
a randomly selected sequence of pharmacokinetic sampling times for administration of 
flexible sigmoidoscopy biopsy procedures. 
Each participant will have a total of 5 flexible sigmoidoscopies:  
- 
at baseline (1 set of biopsies);  
- 
within 24 hours of each of the three dose/volume gel applications (one of the 
following randomly selected times: 0.5-1 hour, 1.5-3 hours, 3.5-5 hours, or 24 
hours after gel administration for each dose/volume of gel) (total of 3 sets of 
biopsies), and  
- 
48 hours after one of the three dose/volume gel applications (to be determined at 
random) (1 set of biopsies).  
 
The sampling schedule for a participant will be preassigned at the enrollment visit. 
 
The determination of the sample schedule will achieve the following characteristics: 
 All 12 participants will have flexible sigmoidoscopy at enrollment. 
 For the 4 mL, 16 mL, and 32 mL dose/volumes, participants will be randomly 
assigned 1:1:1:1 to one of the following 4 time frames to provide samples of rectal 
tissue, rectal fluid, vaginal fluid (if applicable), and effluent from rectal lavage: 0.5-
1 hour, 1.5-3 hours, 3.5-5 hours, and 24 hours following PC-1005 gel application. 
 There will be 3 sets of biopsies available at each time frame (0.5-1 hour, 1.5-3 
hours, 3.5-5 hours, and 24 hours following PC-1005 gel application) for each 
dose/volume (4 mL, 16 mL, and 32 mL). 
 Across the three dose/volumes (4 mL, 16 mL, and 32 mL), participants will be 
randomly assigned 1:1:1 to provide samples of blood, rectal tissue, rectal fluid, 
vaginal fluid (if applicable), and effluent from rectal lavage48 hours following PC-
1005 gel application for one of the three dose/volumes. 
 There will be 4 sets of biopsies available at 48 hours following PC-1005 gel 
application for each dose/volume (4 mL, 16 mL, and 32 mL). 
 Randomizations will be stratified by gender so as to incorporate 1-2 participants of 
each gender at each of four time frames between 0.5 and 24 hours, and to 
incorporate 2 participants of each gender at 48 hours for each dose/volume. 
 
The randomization scheme will be generated and maintained by the MTN SDMC. 
 
10.6 Participant Accrual, Follow-up and Retention 
 
Based on previous studies of rectal products with similar eligibility requirements, the 
accrual of approximately 12 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 


 
 
  
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complete the regularly scheduled safety evaluations and retain all enrolled participants in 
follow-up to minimize possible bias associated with loss-to-follow-up. 
 
10.7 Data and Safety Monitoring and Analysis 
 
10.7.1 Study Monitoring Committee 
 
No Data and Safety Monitoring Board oversight is planned for this study. The MTN SMC 
will conduct interim reviews of participant safety data and study progress, including rates 
of participant accrual, retention, completion of primary and main secondary endpoint 
assessments, and study or lab issues. These reviews will take place approximately every 
4-6 months, or as needed.  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. 
 
10.7.2 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). 
 
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 dose/volume of gel. Each participant will contribute once 
in each category (i.e., only for highest severity AE for each participant) for the calculation 
of event rates for each dose/volume of gel. 
 
To assess the overall tolerability of the 3 dose/volumes of gel, participants in each 
dose/volume may be compared for characteristics including safety events and laboratory 
measurements using descriptive statistics. Due to the small sample size, formal 
comparisons will not be done.  
 
Pharmacokinetic/Pharmacodynamic Analysis 
 
We will use descriptive statistics such as the mean and median and corresponding 95% 
confidence intervals to describe the MIV-150 concentrations in all biological matrices 
assessed at all scheduled time points.  For each dose/volume of gel, the 0.5 to 48 hour 
time points will be used to describe the concentrations beginning soon after a gel dose 
through time to peak concentrations through initial elimination among different matrices. 


 
 
  
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Concentrations will be compared among and between volume arms using paired 
analyses.  
 
Ex vivo HIV explant data will use cumulative p24 to compare baseline with study product. 
Concentration-response relationships will also be explored using appropriate linear and 
non-linear models. Rectal lavage fluid will be assessed for anti-HIV activity and the 
percent inhibition will be correlated to MIV-150 concentrations. 
 
10.7.3 Missing Data 
 
Every effort will be made to complete the regularly scheduled safety and PK evaluations 
and retain all enrolled participants in follow-up over the three dose/volume evaluations 
lasting 14 to 42 days each, including washout. Based on previous MTN trials, we expect 
to have minimal missing data. If participants are lost to follow-up or to permanent product 
discontinuation, they may be replaced, as mentioned above. If missing data rates are 
higher than anticipated (over 15%) for a particular dose/volume safety evaluation or for 
individual pharmacokinetic measure time points, then additional participants may enroll 
in the study, at the discretion of the protocol team, to replace currently enrolled 
participants. 
 
 
11 
DATA HANDLING AND RECORDKEEPING 
 
11.1 Data Management Responsibilities 
 
Data collection tools will be developed by the MTN SDMC in conjunction with the protocol 
team. Quality control and data integrity are managed manually and systematically with 
reports and queries routinely generated and provided by the SDMC to the study sites for 
verification and resolution.  As part of the study activation process, each study site will 
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, for the 
investigational products tested, IoRs/designees will maintain all study documentation for 
at least two years following the date of marketing approval 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.   


 
 
  
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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 
 
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). 
 
 
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 
study sites to do the following: 
 
 Review informed consent forms, procedures, and documentation 
 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  
 Perform source document verification to ensure the accuracy and completeness 
of study data 
 Verify proper collection and storage of biological specimens 
 Verify proper storage, dispensing, and accountability of investigational study 
products 
 Assess implementation and documentation of internal site quality management 
procedures 
 
IoRs/designees 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. IoRs/designees also will 
allow inspection of all study-related documentation by authorized representatives of the 
MTN LOC, SDMC, LC, the Population Council, NIAID, FDA, OHRP, IRBs and other local, 
US, or international regulatory authorities. A site visit log will be maintained at study sites 
to document all visits. 


 
 
  
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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, IoRs/designees will have obtained IRB approval and the protocol will have been 
submitted to the FDA. IoRs/designees will permit audits by the NIH, the FDA, OHRP, 
MTN LOC, IRBs, SDMC, and other local, US, or international regulatory authorities or any 
of their appointed agents. 
 
13.1 Institutional Review Boards/Ethics Committees 
 
The participating institution is responsible for assuring that this protocol, the associated 
site-specific informed consent forms (ICFs), and study-related documents (such as 
participant education and recruitment materials) are reviewed by an IRB responsible for 
oversight of research conducted at each study site. Any amendments to the protocol must 
be approved by the responsible IRBs prior to implementation. 
 
Subsequent to the initial review and approval, the responsible IRBs must review the study 
at least annually. Each IoR/designee will make safety and progress reports to the IRBs 
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. Study sites will submit 
documentation of continuing review to the DAIDS Protocol Registration Office (PRO) 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, 
sites must have the protocol and the protocol consent forms approved, as appropriate, by 
its local IRB and any other applicable regulatory entity (RE). Upon receiving final 
approval, sites will submit all required protocol registration documents to the DAIDS PRO 
at the RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all of the required documents have been received.  
 
Site-specific informed consent forms (ICFs) will be reviewed and approved by the DAIDS 
PRO and sites will receive an Initial Registration Notification from the DAIDS PRO that 
indicates successful completion of the protocol registration process. A copy of the Initial 
Registration Notification should be retained in the site's regulatory files. 
 
Upon receiving final IRB 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 


 
 
  
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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 site 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. Assignment of 
all sponsor responsibilities for this study will be specified in a Clinical Trials Agreement 
(CTA) executed by NIAID and the Population Council. 
 
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 
implementation will also be guided by a common Study-Specific Procedures (SSP) 
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 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 and 
documentation. 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. 
 
Vaginal Fluid Collection 
Collection of vaginal fluid may cause discomfort or pressure in the vagina or genital area. 
 
Phlebotomy and IV Cannula Placement 
Phlebotomy may lead to discomfort, feelings of dizziness or faintness, and/or bruising, 
swelling, having a blood clot, excessive bleeding, and/or infection.  
 
Pharyngeal Swab 
Pharyngeal (throat) swab collection often causes a momentary gagging reflex. 


 
 
  
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Rectal Enema 
An enema is a 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 
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. Some air may be pumped into the rectum as well, causing 
flatulence. 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 an 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.49  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.50  
 
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 72 hours before and after PK sample collection visits.  
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 or if the participant develops any 
abnormal odor or discharge from the rectum. 
 
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 


 
 
  
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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.  
 
Participation in clinical research includes the risks of loss of confidentiality and discomfort 
with the personal nature of questions when discussing sexual behaviors. 
 
Sexual partner notification in response to diagnosed STI or HIV infection could cause 
problems in participants’ relationships. Participants also could have problems in their 
partner relationships associated with study-required abstinence.   
 
Site staff will make every effort to protect participant privacy while in the study.  Although 
study sites will 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.   
 
Risks Associated With PC-1005 Gel 
AEs among a small number of female participants who dosed vaginally with PC-1005 gel 
included:  
 Metrorrhagia 
 Vaginal discharge 
 Vulvovaginal pruritus 
 Abdominal discomfort 
 Constipation 
 Urinary tract infection 
 Uterine spasm (cramps) 
 
These side effects may or may not be associated with rectal use of PC-1005 gel. 
 
In previously completed studies involving rectally-applied products, the following 
gastrointestinal AEs were common and/or occurred at a Grade 3 or higher: 
 Abdominal distension  
 Abdominal bloating 
 Abdominal pain/cramps 
 Defecation urgency  
 Diarrhea  
 Flatulence  
 Tenesmus 


 
 
  
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Previously tested rectal gels (not the gel being used in this study) have also been 
associated with anal discharge. These side effects may or may not be associated with 
the use of PC-1005 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, HSV-2, and HPV acquisition and transmission. Participants also may 
appreciate the opportunity to contribute to the field of HIV prevention research.  
 
Participants will receive HIV/STI risk reduction counseling, HIV and STI testing, physical 
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, IoRs 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 ICF if they are willing to receive them.  
 
In addition to the ICF, 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 study sites, which will be 
detailed in the 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: 
 
 The unknown safety and unproven efficacy of the study product 
 The need to abstain from sexual intercourse for protocol defined periods 


 
 
  
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 The importance of participants to the success of the study 
 The importance of adherence to the study visit and procedures schedule  
 The potential medical risks of study participation (and what to do if such risks are 
experienced) 
 The potential social harms associated with study participation (and what to do if 
such harms are experienced) 
 The real yet limited benefits of study participation  
 The distinction between research and clinical care 
 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.  Study sites 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.  
 
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, 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’ identification 
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: 
 
 Representatives of the US Federal Government, including the US FDA, the US 
OHRP, NIH, and/or contractors of the NIH, and other local, US, or international 
regulatory authorities 
 PPD 
 Representatives of the Population Council, including study monitors 
 Representatives of the MTN LOC, SDMC, and/or LC Study staff  
 Site IRBs 
 
The MTN has a Certificate of Confidentiality from the US Department of Health and 
Human Services that is applicable to 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. 
 


 
 
  
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13.7 Special Populations 
 
13.7.1 
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 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 ICF. 
 
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 sites and additionally will 
emphasize the unknown efficacy of the study products in preventing HIV-1 and HIV-2 
infection. In accordance with the policies of the NIH, participants must receive their HIV-
1/2 test results to take part in this study.   
 
13.10.2 
Care for Participants Identified as HIV-Positive 
 
An individual who has been identified as infected with HIV-1 will be managed or referred 
for management according to the local standard of care.  Should a participant test positive 
for HIV after the Enrollment Visit, follow-up procedures will be performed as per Section 
7.5.1.   
 
13.11 Study Discontinuation 
 
This study may be discontinued at any time by NIAID, the MTN, the Population Council, 
the US FDA, the OHRP, other government or regulatory authorities, or site IRBs. 
 


 
 
  
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14 
 PUBLICATION POLICY 
 
DAIDS/NIAID and MTN policies and a CTA between NIAID and the Population Council 
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 the Population Council for review prior to 
submission. 
 
 
 


 
 
  
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15 
APPENDICES 
APPENDIX I:  SCHEDULE OF STUDY VISITS AND EVALUATIONS 
Please note: Procedures consistently listed as “If indicated” at study visits will not be listed in Appendix I. 
 
Screenin
g 
Visit 1 
Enrollment 
Visit 2 
Dosing 
Visits 
Visit 3, 5, 7 
24 Hr Post-
Dosing Visits  
Visits 4, 6, 8 
48 Hr Post-
Dosing Visits 
■   
Visits 4a, 6a, 8a 
Final 
Contact 
Visit 9 
ADMINISTRATIVE AND REGULATORY 
  
  
Informed consent 
(SCR/ENR) 
X 
  
  
  
  
  
Assess consent form 
comprehension 
X 
 
 
 
 
 
Assign PTID  
X 
 
 
 
 
 
Assess and/or confirm 
participant eligibility 
X 
 X 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
Locator information 
X 
X 
X 
X 
X 
X 
Provide reimbursement 
X 
X 
X 
X 
X 
X ~ 
Schedule next study 
visit/contact 
* 
* 
X 
X π 
X 
* 
Review informed consent/ 
confirm participant 
willingness to participate in 
study 
  
X 
  
  
  
  
Assign to rectal tissue 
sampling schedule 
  
X 
  
  
  
  
BEHAVIORAL/COUNSELING 
  
  
  
HIV pre-/post-test counseling 
X 
X 
  
 X (Visit 8 only) 
 
*  
HIV/STI risk reduction 
counseling 
X 
X 
  
 X (Visit 8 only) 
 
* 
Protocol counseling  
X 
X 
X 
X 
X 
* 
Behavioral assessment 
 
X 
X 
  
 
 
Behavioral assessment (IDI) 
 
 
 
X (Visit 8 only) 
 
 
CLINICAL 
  
  
  
  
  
  
Medical history 
X 
X 
X 
X 
X 
X 
General/Targeted physical 
exam 
X 
X 
*  
*  
* 
*  
Perform rectal examination 
X 
X 
X 
X 
X 
* 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Provide available test results 
X 
X 
X 
X 
X 
X 
Record/update AEs 
 
 
X 
X 
X 
X 
LABORATORY  
  
  
PHARYNGEAL 
NAAT for GC/CT 
X 
* 
* 
* 
* 
* 
URINE 
NAAT for GC/CT 
X 
* 
* 
* 
* 
* 
Qualitative hCG ♀ 
X 
X 
X 
 
 
* 
BLOOD 
CBC with differential and 
platelets 
X 
* 
* 
X 
* 
* 
Chemistries 
(AST/ALT/Creatinine)  
X 
* 
X  
(creatinine 
only)
X 
* 
* 
Syphilis serology 
X 
* 
* 
* 
* 
* 
HIV-1/2 test 
X 
X 
  
X (Visit 8 only)  
 
* 
Coagulation (PT/INR)  
X 
 
 
 
 
 
Plasma for archive 
  
X 
  
  
 
  
Blood for PK 
  
♦ 
♦ 
X 
 


 
 
  
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Screenin
g 
Visit 1 
Enrollment 
Visit 2 
Dosing 
Visits 
Visit 3, 5, 7 
24 Hr Post-
Dosing Visits  
Visits 4, 6, 8 
48 Hr Post-
Dosing Visits 
■   
Visits 4a, 6a, 8a 
Final 
Contact 
Visit 9 
PELVIC SAMPLES ♀  
Vaginal fluid for PK 
 
 
⌂ 
⌂ 
X 
 
NAAT for GC/CT/TV 
X 
* 
* 
* 
* 
 
ANORECTAL SAMPLES 
Anal swab for HPV 
 
X 
 
X 
 
 
Rectal enema effluent for PD 
prior to biopsy collection 
  
X 
X⌂☼ 
⌂π 
X☼ 
 
Rectal fluid for PK and PD 
  
 X (PD 
only) 
X⌂☼ 
⌂π 
X☼ 
 
Rectal tissue for PD, 
histology, and archive 
 
X 
X⌂☼ 
⌂ π 
X☼ 
 
Rectal tissue for PK  
  
  
X⌂☼ 
⌂π 
X☼ 
 
NAAT for GC/CT 
X 
* 
* 
* 
* 
 
STUDY PRODUCT/SUPPLIES 
  
 
Administration of study 
product  
  
  
▲ 
  
 
 
Offer condoms 
X 
X 
X 
 
 
* 
X = Required.   * = As indicated.  ♀ = For female participants.   
♦ = Blood will be collected pre-dose administration and at 1 hour, 2 hours, 3 hours, 4, hours, 5-6 hours, and 24 hours after dose 
administration.    
⌂ = Participants will be randomized  (1:1:1:1) to provide samples of rectal tissue, rectal fluid, vaginal fluid (if applicable), and 
effluent from rectal lavage in one of the following time periods after dose administration across gel volumes: 0.5-1 hour; 1.5-3 
hours; 3.5-5 hours, or 24 hours. Those assigned to the 24 hour time point to provide samples will do so at the 24-hr Post-dose 
visit instead of the Dosing visit.  
☼ Please reference the MTN-037 SSP Manual for additional details (www.mtnstopshiv.org)   
▲= Participants will receive a single dose of study product (4 mL, 16 mL, or 32 mL) depending on dosing visit.    
■ = Participants will be randomly assigned 1:1:1 to provide samples of blood, rectal tissue, rectal fluid, vaginal fluid (if 
applicable), and effluent from rectal lavage samples  48 hours after one of the three dose administrations.   
~ = Sites to reference SOPs regarding participant reimbursement.  
π =  Please reference the MTN-037 SSP Manual for information regarding Early Termination visit (www.mtnstopshiv.org) 
 
 
 
 
NOTE:  Participants will be instructed to call in to the clinic to report any issues related to the collection of samples via the 
flexible sigmoidoscopy.  
 
  
 
 
 


 
 
  
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APPENDIX II:  ALGORITHM FOR HIV 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-037 
 
A Phase 1 Safety and Pharmacokinetic Study of PC-1005 (MIV-150/Zinc 
Acetate/Carrageenan Gel) Administered Rectally to HIV-1 Seronegative Adults 
 
Version 1.0 
 
November 9, 2017 
 
PRINCIPAL INVESTIGATOR: [Sites to insert] 
PHONE: [Sites to insert] 
Short Title for the Study: Safety and PK Study of PC-1005 Applied Rectally 
 
INFORMED CONSENT 
 
You are being asked to take part in this research study because you are a healthy, HIV-uninfected 
man or woman (cis or transgender) aged 18 or older and reported at least one experience of 
consensual receptive anal sex in your lifetime. Approximately 12 people will participate in this 
study at two sites in the United States. The US National Institutes of Health (NIH) sponsors this 
Microbicide Trials Network (MTN) study. The Population Council supplies product for 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. You may decide to stop being in the study at any time. 
 
What happens if you do not want to take part? 
Before you learn more about the study it is important that you understand: 
 
You do not have to be in this study if you do not want to. 
 
You can stop taking part at any time. This will not affect the service you get at this clinic. 
 
If you decide to stop taking part, you may join another study, if we have one and you 
qualify. 
 
Why is this research being done? 
There are two main purposes of this study. The first is to test if PC-1005 gel is safe when inserted 
into the rectum (the last 6 to 8 inches of the large intestine); the second is to better understand 
how PC-1005 is absorbed by and eliminated from the body when inserted into the rectum via 
applicator.    
 


 
 
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Additionally, researchers would like to understand whether you find it acceptable to use the gel 
when inserted into the rectum via a lubricated applicator. 
 
PC-1005 is a potential multipurpose prevention technology (MPT) microbicide in early 
development that has been shown to be active against human immunodeficiency (HIV), human 
papillomavirus (HPV), and herpes simplex virus type- 2 (HSV-2). 
 
PC-1005 is considered to be investigational. This means it has not been approved by the US 
Food and Drug Administration (FDA) for preventing HIV and other sexually transmitted infections 
(STIs). PC-1005 is a carrageenan-based gel containing MIV-150 and zinc acetate.   
- 
MIV-150 is an anti-retroviral (ARV) drug that has been tested as a treatment for HIV (the 
virus that causes AIDS) in 63 men who took it orally in the form of a tablet in four different 
studies. 
- 
Zinc acetate is a substance used in a number of cosmetic products and over-the-counter 
products, such as calamine lotion and cold medicines. 
- 
Carrageenans come from seaweed and are used in many foods and cosmetics, including 
toothpaste and baby formula. Carrageenan is a Generally Recognized As Safe (GRAS) 
food substance. 
 
PC-1005 has been found to be safe in laboratory testing and has been tested in animal studies. 
It has been tested in and was well-tolerated and found acceptable by 25 women who applied the 
gel vaginally once a day for up to 14 days under close observation. Now researchers would like 
to know more about how PC-1005 is processed within the body when PC-1005 gel is applied 
rectally. In this study, PC-1005 is being tested for the first time in humans as a rectally-applied 
gel.  
 
Who will be in this research study and what will I be asked to do if I join? 
There will be approximately 6 participants enrolled at each site. Approximately 12 participants will 
be enrolled in the MTN-037 study at 2 sites. Each participant will receive three doses of PC-1005, 
the study rectal gel. The dose of gel administered will increase over the course of the study (4mL, 
16mL and 32mL). Participation in this study will last approximately 3-5 months. The study includes 
a total of 9 clinic visits and one contact (via phone or in person), including the Screening Visit 
which is taking place today. Visits will take place here, at this study clinic. Multiple visits may be 
conducted to complete all required screening procedures. The study includes a Screening and an 
Enrollment Visit, three Dosing visits (at which the study gel is administered), three 24-Hour Post-
Dosing Visits and one 48-Hour Post-Dosing Visit (at which rectal and other samples are 
collected), and the Final Contact, which may occur in person or by phone.  
 
After each dose of PC-1005 is administered, you will have more laboratory tests to make sure 
you do not have any side effects. If there are no safety concerns, you will have the next higher 
dose approximately 2-6 weeks after the previous dose. During this time, you will not use any 
product; this is called a washout period.  
 


 
 
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Study Visit Schedule 
  
 
What will happen during study visits? 
 
Screening Visit  
 
The procedures done today will take about [SITES TO INSERT TIME]. 
 
You will:  
 
 
Answer questions to confirm you are able and willing to join the study 
 
Answer questions about where you live, your medical health (including what medications 
you are taking), and your sexual practices   
 
Provide study staff your contact information (i.e. about how we can contact you) 
 
Be asked to abstain from some medications during your participation in the study: 
 
Anticoagulant medications (blood thinners) 
 
Rectally-administered medications  
 
PrEP (oral Truvada® or other PrEP) 
 
PEP (post-exposure prophylaxis) 
 
Have a physical exam 
 
Talk with study staff about sexually transmitted infections (STIs), HIV, HIV/STI testing, and 
ways to avoid HIV and other infections passed through sex, including use of oral Truvada® 
for PrEP   
 
Talk with study staff about the requirements of the study including, but not limited to, 
restrictions on sexual practices: 
 


 
 
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You will be asked to abstain from the following activities at these timepoints during the study: 
 
For males and females: 
Activity: 
Abstain For How Long? 
 
Receptive anal intercourse 
 
Inserting any non-study products or 
objects into your rectum, including:
o 
Fingers 
o 
Rectal medications 
o 
Enemas 
o 
Lubricants 
o 
Sex toys (dildos, anal 
plugs, etc.) 
 
Using aspirin (greater than 81 mg) 
and other non-steroidal anti-
inflammatory drugs (NSAIDS) 
 
72 hours (3 days) prior to each study 
visit at which rectal fluid/tissue is 
scheduled to be collected 
 
72 hours (3 days) following rectal 
fluid/tissue collection 
 
 
Receptive oral anogenital 
stimulation (e.g., partner placing 
their mouth on your anogenital 
area) 
 
72 hours (3 days) following rectal 
fluid/tissue collection 
 
Females will be asked to abstain from the following additional activities: 
Activity: 
Abstain For How Long? 
 
Receptive penile-vaginal 
intercourse 
 
Inserting any non-study products or 
objects into your vagina, including:
o 
Spermicides 
o 
Vaginal medications 
(including hormones) 
o 
Vaginal douches 
o 
Lubricants or moisturizers 
o 
Sex toys (vibrators, dildos, 
etc.) 
o 
Fingers 
 
72 hours (3 days) prior to each study 
visit at which rectal fluid/tissue and/or 
vaginal fluid is scheduled to be 
collected 
 
 
At your Screening Visit, you will also: 
 
Have your urine tested for sexually-transmitted diseases and other infections 
 
Provide 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 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 
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.  


 
 
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 
Have a pharyngeal (throat) swab (like a Q-tip) collected, to test for infections passed 
through sex. 
 
Have a rectal examination. Rectal fluid will be collected with a swab; these will be used to 
test for sexually transmitted infections (STIs). 
 
For females: 
o Your urine will be tested for pregnancy 
 
If you are pregnant you cannot join this study. 
 
Staff will discuss with you ways to avoid getting pregnant. 
o You will have some fluids collected from your cervix using a swab to test for STIs 
and other problems if they feel it necessary.  
 
Be given treatment or a referral for treatment of sexually transmitted infections, if needed. 
 
Be informed about other services, if needed.  
 
Be given the results of your tests, when available. It is expected that all of your results will 
be available by [SITES TO SPECIFY TIMEFRAME].     
 
Be given male condoms, if you need them 
 
Be reimbursed 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-037, 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.]  
 
The following procedures are specific to the Enrollment Visit, which will take place up to 45 days 
after your Screening Visit.  
 
You will: 
 
 
Answer questions to confirm you are able and willing to join the study 
 
Update study staff with your contact information (about where you live and how we can 
contact you) 
 
Be assigned to a study sample collection sequence.  
o During this visit, you will be assigned to specific timepoints to collect rectal fluid 
and tissue (and vaginal fluid if you are female). This may affect how long some of 
your study visits will last. At some of your study visits after the Enrollment Visit, 
these samples may be collected one time at: 30-60 minutes after receiving the 
study gel, between 90 minutes to 3 hours later, between 3 ½ to 5 hours later, or 
24 hours later, depending on the timing of sample collection you have been 
assigned to. You will also be asked to attend one 48-Hour Post-Dosing Visit. 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 to complete these procedures.  
o These samples will help researchers learn how PC-1005 is absorbed by and 
eliminated from the body. 


 
 
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 
Talk with study staff about the following: 
o The instructions and procedures of the study and how to follow the study 
guidelines, including the sexual abstinence requirement and use of non-study 
products/objects. 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.   
 
Discuss any health or medical problems you may have had in the past or since your last 
visit (including what medications you are taking) 
 
Be asked some questions about your experience and comfort using rectal products, as 
well as douching or other rectal hygiene practices, among other things. These questions 
will be asked via computer.  
 
Provide 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 
 
Have a physical exam 
 
Have a rectal exam where 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, 
what effect the drug has, and test for infections passed through sex.  When these samples 
are collected at future visits, similar tests will be done.  
 
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 that 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.   
 
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 (stool).  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 fluid (effluent) left over from the enema will be collected, and then the 
study clinician will collect approximately 6 tissue samples, each about the 
size of a grain of rice. 
 
(For females): 
o Have a urine test for pregnancy and discuss with study staff ways to avoid getting 
pregnant 
 
Be given test results, if available 
 
Be given male condoms, if you need them 
 
Be reimbursed for your visit 
 
Schedule your next visit, if applicable. 
 


 
 
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Dosing Visits (Visits 3, 5, and 7) 
 
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. You will have two 
additional Dosing Visits after the first visit.   
 
All participants will have the same gel dosing visit schedule. All participants will receive PC-1005 
gel; study staff will apply the study gel in your rectum using an applicator (a syringe [not intended 
for injection] with a cap and a rectal administration tip). The dose/volume of gel to be administered 
will increase from visit to visit.   
- 
At Visit 3, 4 mL of PC-1005 gel will be administered.  
- 
At Visit 5, 16 mL of PC-1005 gel will be administered.  
- 
At Visit 7, 32 mL of PC-1005 gel will be administered.  
 
Neither you nor the study staff can choose or change the order in which you will receive the study 
gel doses/volumes. 
 
You will: 
 
 
Update study staff with your contact information 
 
Review the instructions and procedures of the study and how to follow the guidelines, 
including about sexual abstinence and insertion of non-study products or objects 
 
Discuss any health or medical problems you may have had since your last visit (including 
what medications you are taking) 
 
Be asked some questions about your experience receiving the study product. These 
questions will be asked via computer.  
 
Have one dose of study gel inserted by study staff using a lubricated applicator, 
 
Have a rectal examination and have rectal fluid and tissue collected using the anoscope 
and flexible sigmoidoscope. These samples will be collected after each dose of study gel 
is inserted at one of the following time points: 30-60 minutes after inserting the study gel, 
between 90 minutes to 3 hours later, between 3 ½ to 5 hours later, or 24 hours later (at 
your 24-Hour Post-Dosing Visit). You will be randomly assigned to one of these four time 
points at the beginning of the study and will provide samples at the same time point after 
each of the three dose administrations.  
o In preparation for the tissue collection you will have an enema (rectal lavage).  The 
fluid (effluent) left over from the enema will be collected. 
o The study clinician will then collect approximately 9 tissue samples, each about 
the size of a grain of rice 
 
(For females): 
o Your urine will be tested for pregnancy 
o You will provide a small amount of vaginal fluid via swab for research purposes. 
This sample will be collected at the same timepoints as the rectal fluid and tissue 
samples are collected. 
 
Have blood samples collected [SITES TO INSERT AMOUNT]  
o To test your blood for creatinine, a test which shows how well your kidneys are 
functioning 
o At several timepoints including prior to gel administration and at 1 hour, 2 hours, 3 
hours, 4 hours, and 5-6 hours after dose administration.  An intravenous cannula 
(IV tube) may be placed for up to 6 hours after administration of the gel for the 


 
 
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blood draws. These samples will be collected to help researchers better 
understand how the study drug enters and exits the body. 
 
Discuss with study staff about any problems that you may be experiencing as a result of 
administration of the study gel or applicator or as a result of procedures performed during 
your visit 
 
Be provided with any available test results and with treatment or a referral for treatment if 
your test results indicate that you require it. 
 
Be given male condoms, if you need them  
 
Be reimbursed for your visit 
 
Schedule your next visit or contact. 
 
24-Hour Post-Dosing Visits (Visits 4, 6, and 8) 
 
Your 24-Hour Post-Dosing Visits will take place approximately 24 hours (1 day) after you receive 
each dose of the study gel. Each of these visits will take between [SITES TO SPECIFY 
TIMEFRAME] to complete.  
 
At these visits, you will: 
 
 
Update study staff with your contact information 
 
Talk with study staff about the following: 
o The instructions and procedures of the study and how to follow the guidelines, 
including about sexual abstinence and insertion of non-study products or objects 
o Sexually transmitted infections (STIs), HIV, HIV/STI testing, and ways to avoid HIV 
and other infections passed through sex. (Visit 8) 
 
Discuss any health or medical problems you may have had since your last visit (including 
what medications you are taking) 
 
Have a computer-administered interview. This interview may take approximately 30-45 
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 having the gel administered in 
the clinic. (Visit 8) 
 
Have a rectal examination 
 
Provide a rectal fluid sample to test for infections passed through sex. A swab will be used 
to collect the sample. 
 
Provide additional rectal samples (fluid and tissue), if they were not collected at your 
Dosing Visit the day prior. For instance, if you are assigned to give samples at the 24 
hours after dose administration time point. 
 
(For females) 
o Provide a small amount of vaginal fluid via swab for research purposes, if it was 
not collected at your Dosing Visit the day prior. 
 
Provide a blood sample [SITES TO INSERT AMOUNT]: 
o To test the health of your blood, liver and kidneys. 
o To test your blood for HIV, the virus that causes AIDS: (Visit 8) 
 
You will be told your test results as soon as they are available.   
o To help researchers to better understand how the study drug enters and exits the 
body.  


 
 
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 
Speak with study staff about any problems that you may be experiencing as a result of 
administration of the study gel or applicator or as a result of procedures performed during 
your visit 
 
Be given any available test results 
 
Be reimbursed for your visit 
 
Schedule your next visit or contact. 
 
48-Hour Post-Dosing Visits (Visits 4a, 6a, and 8a) 
 
You will be asked to attend one 48-Hour Post-Dosing Visit (Visit 4a, 6a, or 8a). You will be 
randomly assigned at the beginning of the study to which Post-Dose Visit you are to attend. This 
visit will take place approximately 48 hours (2 days) after one of your study gel dosing visits. The 
timing of this visit depends on to which 48-hour post-dosing visit you were assigned. This visit will 
take between [SITES TO SPECIFY TIMEFRAME] to complete.  
 
At these visits, you will: 
 
 
Update study staff with your contact information 
 
Talk with study staff about the instructions and procedures of the study and how to follow 
the guidelines, including about sexual abstinence and insertion of non-study products or 
objects 
 
Discuss any health or medical problems you may have had since your last visit (including 
what medications you are taking) 
 
Have a rectal examination 
 
Provide rectal samples (fluid and tissue). These samples will help researchers to better 
understand how the study drug enters and exits the body and what effect the drug has.   
 
 (For females) 
o Provide a small amount of vaginal fluid via swab for research purposes  
 
Provide a blood sample [SITES TO INSERT AMOUNT]:   
o To help researchers to better understand how the study drug enters and exits the 
body  
 
Discuss with study staff about any problems that you may be experiencing as a result of 
administration of the study gel or applicator or as a result of procedures performed during 
your visit 
 
Be given any available test results 
 
Be reimbursed for your visit 
 
Schedule your next visit or contact. 
 
Final Contact (Visit 9) 
 
Your Final Contact will take place approximately two to six weeks after your final dosing visit.  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: 
 
 
Update study staff with your contact information 
 
Discuss any health or medical problems you may have had since your last visit (including 
what medications you are taking) 


 
 
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 
Discuss any problems that you may be experiencing as a result of using the study gel or 
applicator, or as a result of procedures performed during the study 
 
Talk with study staff about instructions and procedures of the study and how to follow the 
guidelines 
 
Be reimbursed for your visit, if required  
 
Schedule your next visit or contact (if necessary) 
 
Be given any available test results 
 
Be given male condoms, if you need them 
 
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. 
 
Other 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: 
 
Physical exam 
 
Pelvic exam 
 
Genital exam 
 
Rectal exam 
 
Test rectal or throat samples for STIs 
 
Test cervix/vaginal samples for STIs 
 
Test your urine for STIs or other infections 
 
Test your blood for STIs 
 
Test your blood to check the health of your blood, liver and kidneys 
 
Give you treatment or refer you for treatment of STIs or other issues, if needed. 
 
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. 
 
What are the possible risks, side effects, and discomforts of this research study? 
 
Risks from use of rectal gel 
The use of any rectal gel can cause some side effects. We do not yet know all the side effects of 
this gel. Previously tested rectal gels (not the gel being used in this study) have been associated 
with: 
 
Abdominal bloating, feeling full, or a sense of abdominal pressure and/or pain 
 
A sudden, almost uncontrollable, need to relieve the bowels 
 
Diarrhea (loose, frequent stools) 
 
Passing gas from the intestinal tract 
 
Feeling a constant need to pass stools, despite an empty bowel 
 
Anal discharge 
 
These side effects may or may not be associated with rectal use of PC-1005 gel. 
 


 
 
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Risks from study drug 
The gel can cause side effects. We do not yet know the side effects of PC-1005 gel on the rectum. 
The following side effects have been associated with the use of PC-1005 in female participants 
in other studies in which the gel was administered vaginally. These side effects may or may not 
be associated with the use of PC-1005 when the drug is placed into a rectal gel: 
 
Abdominal discomfort 
 
Constipation 
 
Urinary tract infection 
 
Abnormal bleeding from the uterus (metrorrhagia) 
 
Vaginal discharge 
 
Itching of the vagina (vulvovaginal pruritus) 
 
Cramps (uterine spasm) 
 
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. 
 
Risks from phlebotomy and IV cannula placement (blood tests)   
 
You may feel discomfort 
 
You may feel dizzy or faint 
 
You may have a bruise, swelling, small clot, or infection where the needle goes in your 
arm  
 
You may have excessive bleeding 
 
Risks of throat swab 
 
A pharyngeal (throat) swab often causes a momentary gagging reflex. 
 
Risks of rectal enemas 
 
The main risk from having an enema is temporary discomfort.  A hollow plastic tube about 
the thickness of a pencil will be used to administer about 120-125 mL of enema fluid into 
the rectum.  
 
You may experience some mild discomfort and a bloated or “crampy” feeling.  
 
If you have any hemorrhoids or other painful conditions, you might feel anal or rectal 
discomfort. 
 
Some air may be pumped into the rectum as well, causing flatulence.   
 
Risks of finger and anoscope rectal exams 
 
During rectal exams and collection of rectal fluid and tissue samples, insertion of a 
lubricated anoscope will likely cause mild discomfort. 
 
Risks of rectal swab/sponge insertion 
 
Insertion of rectal swabs and sponges may cause mild discomfort, in addition to a slight 
risk of bleeding. 
 
Risks of flexible sigmoidoscopy 
 
A flexible sigmoidoscopy is a commonly practiced medical procedure where a flexible tube 
with a small camera attached 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 


 
 
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sigmoidoscopy performed for clinical indications (for routine medical diagnosis or 
treatment).  
 
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, abnormal odor or discharge from the rectum, as 
well as flatulence (gas passed through the anus/rectum) following the procedure. 
 
Risks of endoscopic biopsy 
 
Endoscopic biopsies (biopsies done using a slender, lighted optical tube) 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 less than once out of every 1,000 procedures (88/100,000 procedures). 
If this extremely rare complication occurs, antibiotics and surgery to repair the tear may 
be necessary. 
 
If you engage in sexual intercourse before the biopsy has healed, there exists the risk of 
temporary discomfort, and increased risk of STIs and HIV acquisition. 
 
Risks from the applicator 
 
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. 
 
(For females) Risks of vaginal swab 
 
During vaginal fluid collection, you may feel discomfort or pressure in your vagina or 
genital area. 
 
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. 
 
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. 
 
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.   
 
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 may choose not to answer any question that makes you 
uncomfortable.   
 
We will make every effort to protect your privacy and confidentiality during the study visits. Your 
visits will take place in private. 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). 


 
 
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What are possible benefits from taking part in this study? 
 
There are no direct benefits for taking part in this study, but you or others may have future 
benefit from information learned in this study.  You may also learn more about HIV and 
other diseases and ways to protect yourself from infection.   
 
It is important that you know that you will not be paid any additional money (beyond the 
reimbursement described below for study participation) if the study product being studied 
is eventually licensed for use.  
 
You will have physical and rectal exams.  You will also have tests to check the overall 
health of your liver, kidneys, and blood cells. If these tests show that you might have any 
health problems, you will be told about medical care and other services available to you. 
This will be available to you even if you do not enroll in this study.  This study cannot 
provide you with general medical care, but study staff will refer you to other available 
sources of care.  
 
You will get counseling and testing for HIV and STIs. If you have infections passed through 
sex, other than HIV infection, you will be offered medicine to treat them or provided 
information for where you may receive treatment, and study staff will discuss options 
available for counseling and treatment of your partner. This treatment or referral for 
treatment is available to you even if you do not enroll in this study.   
 
If you become infected with HIV, you will need to receive care from your own health care 
provider or we will provide you with a referral. This study does not provide medication for 
treatment of HIV/AIDS.    
 
You will receive free male condoms, if you need them. 
 
Will this study drug prevent HIV infection? 
We do not know if the drug contained within the gel works to protect men and women from getting 
HIV. This study is not testing to see if PC-1005 prevents HIV infection. Researchers are continuing 
to study PC-1005 to learn more about how it works in humans to protect against HIV infection. 
There are only two known effective ways to reduce your risk of contracting HIV: the use of 
condoms and/or the use of oral pre-exposure prophylaxis (PrEP) medication, Truvada®.  PrEP is 
an 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. If you are interested in these alternative options you may also 
want to discuss them with your doctor. If you are currently taking PrEP or plan to take PrEP in the 
near future, you will not be eligible for this study.   
 
What if there is new information learned during this study? 
We will tell you about new information from this or other studies that may affect your willingness 
to stay in this study.  You will also be told when study results may be available, and how to learn 
about them. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov.  This website 
will not include information that can identify you.  At most, the website will include a summary of 
the results.  You can search this website at any time. 
 
Is it possible that I may be taken out of the study without my consent? 
A study clinician may need to remove you from the study early without your permission if: 
 
The study is cancelled by the US FDA, US NIH, the Population Council (the nonprofit 
organization that supplies the rectal gel), the US Office for Human Research Protections 
(OHRP), MTN, the local government or regulatory agency, or the Institutional Review 


 
 
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Board (IRB). An IRB is a committee that watches over the safety and rights of research 
participants. 
 
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) 
 
You are found to be infected with HIV (see “If You Become Infected With HIV“ section 
below) or an anogenital STI 
 
(Females) You become pregnant or are breastfeeding (see “If You Become Pregnant“ 
section below)  
 
You report the use of the following prohibited medications: 
 
PEP or PrEP 
 
Anticoagulants (e.g., heparin, Lovenox, warfarin and Plavix) 
 
CYP3A inhibitors or inducers (e.g., grapefruit, Prozac, Zoloft, Prednisone, Prilosec) 
 
A study clinician decides that using the study would be harmful to you, for example you 
have a bad reaction to the study gel 
 
Other reasons that may prevent you from completing the study successfully, such as you 
are not able to reliably keep appointments 
 
 
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. 
 
(For Females) If You Become Pregnant  
The study gel is not a birth control method. 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 only have sex that cannot 
lead to pregnancy (no penile-vaginal intercourse).   
 
We do not know what effect PC-1005 has on pregnancy, including the effect of PC-1005 
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. If you become pregnant and you deliver a baby from that 
pregnancy, we will contact you approximately one year after your delivery to collect 


 
 
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information about the health of your baby. We will also contact you about a study that 
collects information about pregnancy and babies up to one year old. 
 
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 the 24-Hour Post-Dosing Visit, 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. 
 
Will there be any payments if I take part in this research study? 
[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. 
 
What are the costs? 
[SITES TO COMPLETE ACCORDING TO SITE CAPACITY] There is no cost to you for study 
related visits, physical/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. 
 
Are there any other studies if you cannot join this one?  
There may be other studies going on at this study clinic or in the community for which you may 
be eligible.  If you wish, we will tell you about other studies that we know about.  There may also 
be other places where you can go for HIV counseling and testing.  We will tell you about those 
places if you wish.  If you choose not to take part in this study, it will have no effect on the regular 
medical care that is available to you at this clinic or elsewhere. 
 
Who will know about my participation in this research study? 
Any information about you obtained from this research will be kept as private as possible.  All 
records related to your involvement in this research study will be kept in a [SITES TO INSERT].  
Your identity on these records will be indicated by a number rather than by your name, and the 
information linking these numbers with your name will be kept separate from the research records. 
 
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. Any publication of 
this study will not use your name or identify you personally. 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.  
 


 
 
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   November 9, 2017 
 
Your records may be reviewed by: 
 
Study staff 
 
Site Institutional Review Boards 
 
PPD (a contract research organization that monitors clinical trials for safety and data quality) 
 
Representatives of the Population Council, the nonprofit organization that supplies the rectal 
gel 
 
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 
 
Other local, US, or international regulatory authorities 
 
[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]. 
 
[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 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. 
 
What if I am injured as a result of participating in this study? 
[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. 
 
May I withdraw my consent for participation in this research study? 
[SITE 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, nor will the confidentiality of the care provided for you here be 
affected.  You should feel free coming back to this facility even if you decide not to participate in 
this study. If you want the results of the study after the study is over, let the study staff members 
know. 
 
What do I do if I have 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]. 
 


 
 
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   November 9, 2017 
 
If you have questions about your rights as a research participant, you should contact [insert name 
or title of person on the IRB or other organization appropriate for the site] at [insert 
physical address and telephone number]. 
 
CONSENT FOR LONG-TERM STORAGE AND FUTURE TESTING OF SPECIMENS 
There might be a small amount of blood, rectal tissue, rectal fluid, or vaginal 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, such 
as future research to fight HIV and other related diseases. 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.   
 
The 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 
testing, ensuring that the tests work correctly and supply accurate data.  No genetic testing 
on either a limited set or the full set of genes is planned for leftover samples that are stored 
for the purposes of future research. It is important that you know that any future testing or 
studies planned for these specimens must be approved by an Institutional Review Board 
before they can be done.   
 
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 them. 
You can withdraw your consent for the storage and future testing of specimens at 
any time by providing your request in writing 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. 
 
 
 
 


 
 
MTN-037, Version 1.0 
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   November 9, 2017 
 
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 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 
 
 
 
 
 
 
 
 


 
 
MTN-037, Version 1.0 
110 
   November 9, 2017 
 
Reference List 
 
 
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Infectious Diseases 2010;23(1):26-31. 
 
2.  UNAIDS. AIDS By the Numbers-2016.  7-11-2016. 10-21-2016.  
 
 
3.  Leynaert B, Downs AM, de V, I. Heterosexual transmission of human 
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4.  Vittinghoff E, Douglas J, Judson F, McKirnan D, MacQueen KBSP. Per-contact 
risk of human immunodeficiency virus transmission between male sexual partners. 
Am J Epidemiol 1999;150(3):306-311. 
 
5.  Carlos J.A., Bingham TA, Stueve A et al. The role of peer support on condom use 
among Black and Latino MSM in three urban areas. AIDS Educ Prev 
2010;22(5):430-444. 
 
6.  Gorbach PM, Manhart LE, Hess KL, Stoner BP, Martin DH, Holmes KK. Anal 
intercourse among young heterosexuals in three sexually transmitted disease 
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7.  Baral SD, Poteat T, Stromdahl S, Wirtz AL, Guadamuz TE, Beyrer C. Worldwide 
burden of HIV in transgender women: A systematic review and meta-analysis. The 
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8.  Buck CB, Thompson CD, Roberts JN, Muller M, Lowy DR, Schiller JT. 
Carrageenan is a potent inhibitor of papillomavirus infection. PLoS Pathog 
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9.  Chin-Hong PV, Vittinghoff E, Cranston RD et al. Age-specific prevalence of anal 
human papillomavirus infection in HIV-negative sexually active men who have sex 
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 10.  Quinn R, Salvatierra J, Solari V, Calderon M, Ton TGN, Zunt JR. Human 
papillomavirus infection in men who have sex with men in Lima, Peru. AIDS Res 
Hum Retroviruses 2012;28(12):1734-1738. 
 11.  Kizima L, Rodriguez A, Kenney J et al. A Potent Combination Microbicide that 
Targets SHIV-RT, HSV-2 and HPV. PLoS One 2014;9(4):e94547. 
 12.  Rodriguez AKK, Mizenina O, Kizima L et al. In vitro and in vivo evaluation of two 
carrageenan-based formulations to prevent HPV acquisition. Antiviral Res 
2014;108:88-93. 


 
 
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 13.  Marais D, Gawarecki D, Allan B et al. The effectiveness of Carraguard, a vaginal 
microbicide, in protecting women against high-risk human papillomavirus infection. 
Antivir Ther 2011;16(8):1219-1226. 
 14.  Centers for Disease Control and Prevention. Sexually transmitted disease 
surveillance 2014. Atlanta, GA, USA: Centers for Disease Control and Prevention, 
U.S. Department of Health and Human Services, 2015 
 15.  Xu F, Sternberg MR, Markowitz LE. Men who have sex with men in the United 
States: demographic and behavioral characteristics and prevalence of HIV and 
HSV-2 infection: results from National Health and Nutrition Examination Survey 
2001-2006. Sex Transm Dis 2010;37(6):399-405. 
 16.  Celum C, Baeten J. Tenofovir-based pre-exposrure prophylaxis for HIV 
prevention: Evidence and evolving questions. Current Opinion in Infectious 
Diseases 2013;25(1):51-57. 
 17.  Friedland BA, Hoesley CJ, Plagianos M et al. First-in-human trial of MIV-150 and 
zinc acetate coformulated in a carrageenan gel: Safety, pharmacokinetics, 
acceptability, adherence, and pharmacodynamics. Journal of acquired immune 
deficiency syndromes (1999) 2016;73(5):489-496. 
 18.  Zydowsky T, Friedland B. Composition of PC-1005 (Personal Communication). 
Conser E, editor.  1-5-2017. 1-5-2017.  
 
 19.  Population Council. Investigator's Brochure: PC-1005 Gel Formulation (Ver. 2.0).  
1-123. 4-19-2017. New York, NY, Population Council.  
 
 20.  Singer R, Derby N, Rodriguez A et al. The Nonnucleoside Reverse Transcriptase 
Inhibitor MIV-150 in Carrageenan Gel Prevents Rectal Transmission of 
Simian/Human Immunodeficiency Virus Infection in Macaques. J Virol 
2011;85(11):5504-5512. 
 21.  Fenstermacher KJ, DeStefano JJ. Mechanism of HIV reverse transcriptase 
inhibition by zinc: formation of a highly stable enzyme-(primer-template) complex 
with profoundly diminished catalytic activity. The Journal of Biological Chemistry 
2011;286(47):40433-40442. 
 22.  Driessen C, Hirv K, Rink L, Kirchner H. Induction of cytokines by zinc ions in human 
peripheral blood mononuclear cells and separated monocytes. Lymphokine 
Cytokine Res 1994;13(1):15-20. 
 23.  Heterosexual anal sex: Knowledge, attitudes and practice in 5 East African 
communities. 1st International HIV Social Science and Humanities Conference; 
2011. 


 
 
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 24.  Grulich AE, Zablotska I. Probability of HIV transmission through anal intercourse 
(Commentary). Int J Epidemiol 2010;39(4):1064-1065. 
 25.  Giroglou T, Florin L, Schafer F, Streeck RE, Sapp M. Human papillomavirus 
infection requires cell surface heparan sulfate. J Virol 2001;75(3):1565-1570. 
 26.  Fernandez-Romero JA. MTN-037 Draft Version 0.4: Personal Communication. 
Conser E, editor.  1-5-2017. 1-5-2017.  
 
 27.  MZC gel inhibits ex vivo HIV-1 and HSV-2 infection in human cervical mucosa. 
Conference on Retroviruses and Opportunistic Infections (CROI); 15 Feb 23; 2015. 
 28.  Mocchegiani E, Muzzioli M. Therapeutic application of zinc in human 
immunodeficiency virus against opportunistic infections. The Journal of Nutrition 
2000;130(5S Suppl):1424S-1431S. 
 29.  Haaland RE, Chaowanachan T, Evans-Strickfaden T et al. Carrageenan-based gel 
retains limited anti-HIV-1 activity 8-24 hours after vaginal application by HIV-
infected Thai women enrolled in a Phase I safety trial (Letter). J Acquir Immune 
Defic Syndr 2012;61(5):e71-e73. 
 30.  FDA. Select Committee on GRAS Substances (SCOGS) Opinion: Carrageenan.  
1973. Springfield, VA, USA, National Technical Information Service. 10-21-2016.  
 
 31.  Federation of American Societies for Experimental Biology (FASEB). Evaluation 
of the health aspects of carrageenan as a food ingredient (National Technical 
Report prepared for FDA).  1973. 12-6-2016.  
 
 32.  Informatics Inc. GRAS (Generally Recognized as Safe) food ingredients- 
Carrageenan (National Technical Report prepared for FDA).  1972. 12-6-2016.  
 
 33.  Leonard A, Gerber GB, Leonard F. Mutagenicity, carcinogenicity and 
teratogenicity of zinc. Mutat Res 1986;168:343-353. 
 34.  Jean-Pierre N, Barnable P, Kizima L et al. Multipurpose prevention approaches 
with 
antiretroviral-based 
formulations. 
Antimicrob 
Agents 
Chemother 
2016;60(2):1141-1144. 
 35.  Kenney J, Rodriguez A, Kizima L et al. A modified zinc acetate gel, a potential 
nonantiretroviral microbicide, is safe and effective against simian-human 
immunodeficiency virus and herpes simplex virus 2 infection in vivo. Antimicrob 
Agents Chemother 2013;57(8):4001-4009. 
 36.  Turville SG, Aravantinou M, Miller T et al. Efficacy of Carraguard (R)-based 
microbicides in vivo despite variable in vitro activity. PLoS One 2008;3(9):e3162. 


 
 
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 37.  Kenney J, Aravantinou M, Singer R et al. An antiretroviral/zinc combination gel 
provides 24 hours of complete protection against vaginal SHIV infection in 
macaques. PLoS One 2011;6(1):e15835. 
 38.  Kenney J, Singer R, Derby N et al. A single dose of a MIV-150/zinc acetate gel 
provides 24 hours of protection against vaginal simian immunodeficiency virus 
reverse transcriptase infection, with more limited protection rectally 8-24 h after gel 
use. AIDS Research and Human Retroviruses 2012;28(11):1476-1484. 
 39.  Fernandez-Romero JA, Abraham CJ, Rodriguez A et al. Zinc acetate/carrageenan 
gels exhibit potent activity in vivo against high-dose herpes simplex virus 2 vaginal 
and rectal challenge. Antimicrob Agents Chemother 2012;56(1):358-368. 
 40.  Roberts JN. Effect of Pap smear collection and carrageenan on cervicovaginal 
human papillomavirus-16 infection in a rhesus macaque model. J Natl Cancer Inst 
2011;103(9):737-743. 
 41.  Peet MM. 14-Day GLP Rectal Irritation and Toxicity Study of PC-1005 and PC-707 
in Rabbits. 20161726--033.) 
 42.  Barnable P, Calenda G, Ouattera L et al. A MIV-150/zinc acetate gel inhibits SHIV-
RT infection in macaque vaginal explants. PLoS One 2014;9(9):e108109. 
 43.  Skoler-Karpoff S, Ramjee G, Ahmed K et al. Efficacy of Carraguard for prevention 
of HIV infection in women in South Africa: a randomised, double-blind, placebo-
controlled trial. Lancet 2008;372(9654):1977-1987. 
 44.  McGowan I. Rectal microbicides: can we make them and will people use them? 
AIDS Behav 2011;15 Suppl 1:S66-S71. 
 45.  Pines HA, Gorbach PM, Reback CJ, Landovitz RJ, Mutchler MG, Mitsuyasu R. 
Commercial lubricant use among HIV-negative men who have sex with men in Los 
Angeles: Implications for the development of rectal microbicides for HIV 
prevention. AIDS Care 2014;26(12):1609-1618. 
 46.  Carballo-Dieguez A, Stein Z, Saez H, Dolezal C, Nieves-Rosa L, Diaz F. Frequent 
use of lubricants for anal sex among men who have sex with men: The HIV 
prevention potential of a microbicidal gel. Am J Public Health 2000;90(7):1117-
1121. 
 47.  Kinsler JJ, Galea JT, Peinado J, Segura P, Montano SM, Sanchez J. Lubricant 
use among men who have sex with men reporting receptive anal intercourse in 
Peru: Implications for rectal microbicides as an HIV prevention strategy. 
International Journal of STD & AIDS 2010;21:567-572. 


 
 
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 48.  Carballo-Dieguez A, Exner T, Dolezal C, Pickard R, Lin P, Mayer KH. Rectal 
microbicide acceptability: results of a volume escalation trial. Sex Transm Dis 
2007;34(4):224-229. 
 49.  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. 
 50.  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: 
 
Document Type: Template 
 
 
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STATISTICAL ANALYSIS PLAN 
 
MTN-037 
 
A Phase 1 Safety and Pharmacokinetic Study of PC-1005 (MIV-150/Zinc 
Acetate/Carrageenan Gel) Administered Rectally to HIV-1 Seronegative Adults 
 
Microbicide Trials Network 
 
 
 
 
 
 
Statistical Center for HIV/AIDS Research and Prevention 
 
 
 
 
 
Elizabeth Brown, ScD 
Cliff Kelly, MS 
 
 
 
SAP Version 1.0 
September 5, 2019 
 


 
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Approval Signature Page 
 
MTN-037  
Statistical Analysis Plan 
 
A Phase 1 Safety and Pharmacokinetic Study of PC-1005 (MIV-150/Zinc 
Acetate/Carrageenan Gel) Administered Rectally to HIV-1 Seronegative Adults 
 
I have read this Statistical Analysis Plan and approve its contents. 
 
 
 
______________________________ 
 
 
 
_____________________ 
Elizabeth Brown, ScD 
 
 
 
 
 
Date 
Faculty Statistician 
Fred Hutchinson Cancer Research Center 
 
 
 
______________________________ 
 
 
 
_____________________ 
Cliff Kelly, MS  
 
 
 
 
 
Date 
Senior Statistical Analyst 
Fred Hutchinson Cancer Research Center 
 
 
 
 


 
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Page 3 of 15 
TABLE OF CONTENTS 
1. LIST OF ABBREVIATIONS AND ACRONYMS ......................................................................... 4 
2. INTRODUCTION ................................................................................................................. 5 
2.1 STUDY OBJECTIVES AND ENDPOINTS ............................................................................................... 5 
2.2 PRIMARY STUDY HYPOTHESIS ........................................................................................................ 6 
2.3 GENERAL DESIGN CONSIDERATIONS ................................................................................................ 6 
2.3.1 Randomization ................................................................................................................ 7 
2.3.2 Blinding ............................................................................................................................ 8 
2.3.3 Sample Size and Power.................................................................................................... 8 
3. GENERAL DATA ANALYSIS CONSIDERATIONS ...................................................................... 8 
3.1 ANALYSIS SET(S) ......................................................................................................................... 8 
3.2 STATISTICAL ANALYSIS ISSUES ........................................................................................................ 8 
4. INTERIM ANALYSIS AND DATA MONITORING COMMITTEE ................................................. 8 
5. GENERAL ANALYSIS METHODS ........................................................................................... 9 
6. TRIAL PARTICIPANT DISPOSITION ....................................................................................... 9 
6.1 DISPOSITION OF PARTICIPANTS ...................................................................................................... 9 
6.2 TREATMENT EXPOSURE ................................................................................................................ 9 
6.3 PROTOCOL DEVIATIONS .............................................................................................................. 10 
7. BASELINE DATA ............................................................................................................... 10 
8. SAFETY ANALYSES ............................................................................................................ 10 
8.1 PRIMARY SAFETY ANALYSES ........................................................................................................ 10 
8.2 ADVERSE EVENTS ...................................................................................................................... 10 
8.3 LABORATORY EVALUATIONS ........................................................................................................ 11 
8.4 OTHER SAFETY MEASURES .......................................................................................................... 11 
9. PHARMACOKINETIC ANALYSES ........................................................................................ 11 
9.1 METHODS FOR HANDLING MISSING AND BLOQ DATA ..................................................................... 11 
9.2 PRIMARY PK ANALYSES .............................................................................................................. 12 
10. SECONDARY ANALYSES .................................................................................................. 14 
10.1 ACCEPTABILITY ANALYSES ......................................................................................................... 14 
10.2 SECONDARY PK ANALYSES ........................................................................................................ 14 
11. REFERENCES .................................................................................................................. 14 
 


 
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1. LIST OF ABBREVIATIONS AND ACRONYMS  
AE 
 
adverse event 
ALT  
 
Alanine aminotransferase 
AST  
 
Aspartate aminotransferase 
%AUCex  
Percentage of AUC0-∞ obtained by extrapolation, calculated as [(Clast / ke) / AUC0-∞ *100] 
AUC 
 
area under the concentration-time curve 
AUC0-t 
AUC from time zero to the time of the last measurable concentration 
AUC0-∞ 
AUC from time zero extrapolated to infinity, equal to AUC0-t plus AUCt-∞ = (Clast / ke) 
BMI 
 
body mass index 
BLOQ  
below the limit of quantitation 
BP 
 
blood plasma 
Clast  
 
last observed concentration 
Cmax 
 
peak concentration 
CG 
 
carrageenan 
CrCl 
 
creatinine clearance 
h 
 
hour 
ke  
 
terminal elimination rate constant 
LLOQ  
lower limit of quantification 
MedDRA  
Medical Dictionary for Regulatory Activities 
MIV-150 
Urea, N-(5-cyano-2-pyridinyl)-N'-[(1S,2S)-2-[6-fluoro-2-hydroxy-3-(1-
oxopropyl)phenyl]cyclopropyl]-; an NNRTI 
mL 
 
milliliter 
PC-1005  
0.002% MIV-150/0.3% zinc acetate [ZA] in 3.0% carrageenan [CG] gel 
PK 
 
pharmacokinetics 
RAI 
 
receptive anal intercourse 
RF 
 
rectal fluid 
RT 
 
rectal mucosal tissue homogenates 
SAP 
 
statistical analysis plan 
SSP 
 
study specific procedures 
t1/2  
 
half-life of drug elimination in the terminal phase 
tmax 
 
time to peak concentration 
WSI  
 
web-based self-interviews 
ZA 
 
zinc acetate 


 
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2. INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to describe the plan for analyzing data regarding the 
safety, pharmacokinetics, and acceptability among men and women after using a single dose of PC-1005 
(0.002% MIV-150/0.3% zinc acetate [ZA] in 3.0% carrageenan [CG] gel) applied rectally in three 
sequential dose/volumes of 4mL, 16mL, and 32mL.   
2.1 Study Objectives and Endpoints 
Primary Objectives:  
Safety 
To evaluate the safety of PC-1005 gel formulation (0.002% MIV-150/0.3% zinc acetate [ZA] in 
3.0% carrageenan [CG] gel) when applied rectally 
 
Pharmacokinetics 
To characterize the systemic and compartmental pharmacokinetics of MIV-150 following rectal 
gel application 
Primary Endpoints:  
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). 
 
Pharmacokinetics  
MIV-150 concentrations in:  
o 
Plasma 
o 
Rectal fluid 
o 
Rectal mucosal tissue homogenates 
Secondary Objectives:  
Acceptability 
To compare the acceptability of PC-1005 gel formulation across the three doses when 
administered rectally 
 
Pharmacokinetics 
To characterize the compartmental pharmacokinetics of MIV-150 in vaginal fluid following 
rectal gel application 
Secondary Endpoints:  
Acceptability 
Participant self-report of comfort with gel application, liking the product across doses, and 
perceived side-effects 
 
Pharmacokinetics 
MIV-150 concentrations in vaginal fluid 
Exploratory Objectives:  
Biomarkers of Mucosal Safety 
To evaluate the mucosal toxicity of PC-1005 gel formulation when applied rectally 


 
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Ex Vivo Antiviral Activity 
To assess the preliminary (ex vivo) antiviral activity of PC-1005 gel formulation after product is 
applied rectally 
Exploratory Endpoints:  
Biomarkers of Mucosal Safety  
• 
Rectal histology 
• 
Tissue archive 
 
Ex Vivo Antiviral Activity 
• 
Changes in HIV-1 p24 levels in colorectal explant culture supernatant 
• 
Anti-HIV activity in rectal fluid 
2.2 Primary Study Hypothesis 
It is hypothesized that PC-1005 gel (0.002% MIV-150/0.3% ZA in 3.0% CG gel) will be safe when applied 
to the rectum and well-tolerated among healthy men and women (cis or transgender) who have a history 
of receptive anal intercourse (RAI). 
2.3 General Design Considerations 
This section summarizes the protocol and objectives covered in this Statistical Analysis Plan (SAP). 
 
Short Title:  
Safety and PK Study of PC-1005 Applied Rectally 
 
Clinical Phase: 
Phase 1 
 
IND Sponsor: 
DAIDS 
 
Protocol Chair:  
Craig Hendrix, MD 
 
Sample Size: 
MTN-037 will enroll approximately 12 participants.   
 
Study Population:  
HIV-uninfected men and women (cis or transgender) with a history of 
consensual RAI who are 18 years or older at Screening 
 
Study Sites: 
Sites selected by MTN Executive Committee 
 
Study Design: 
Phase 1, open-label, sequential dose/volume escalation study 
 
Study Duration: 
Approximately 3-5 months of follow-up per participant is planned with a 
projected accrual period of 6-8 months. The total duration of the study will 
be approximately 11-13 months.  
 
Study Products: 
PC-1005 (0.002% MIV-150/0.3% zinc acetate [ZA] in 3.0% carrageenan 
[CG] gel) 
 
Study Regimen:  
Each participant will receive a dose of PC-1005 (4mL, 16mL or 32mL) 
rectally administered by clinic staff in the clinic. Safety laboratory tests, PK 
and PD assessments will be performed within 24 hours after each gel 
administration. Each participant will also be randomized to have a 48-hour 
post-dosing visit after one of the three doses. After a washout period of two 


 
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to six weeks (to accommodate scheduling around the menstrual cycles of 
female participants) following each dosing visit, dosing with the next 
sequential escalating volume will be administered. A final study contact will 
occur after the third dosing visit and associated washout period. 
  
Figure 1: MTN-037 Study Visit Schedule 
  
 
 
As displayed in Figure 1, participants will receive the 4mL dose of PC-1005 at Visit 3 and have safety 
laboratory tests, PK and PD assessments performed within 24 hours. After a washout period of two to six 
weeks (to accommodate scheduling around the menstrual cycles of female participants) following the 
4mL dosing visit, participants will receive the 16mL dose of PC-1005 at Visit 5 and have safety laboratory 
tests, PK and PD assessments performed within 24 hours. After a washout period of two to six weeks (to 
accommodate scheduling around the menstrual cycles of female participants) following the 16mL dosing 
visit, participants will receive the 32mL dose of PC-1005 at Visit 7 and have safety laboratory tests, PK 
and PD assessments performed within 24 hours. Participants will be randomized to only one 48-hour 
post-dose sampling visit (Visits 4a, 6a, or 8a). A final study contact will occur after the third dosing visit 
and associated washout period (Visit 9). 
2.3.1 Randomization 
There will be no randomization to dose/volume of PC-1005 in this open-label, sequential dose/volume 
escalation trial. However, upon enrollment a participant will be assigned to a randomly selected sequence 
of pharmacokinetic sampling times for administration of flexible sigmoidoscopy biopsy procedures. 
Each participant will have a total of 5 flexible sigmoidoscopies: 
 
at baseline (1 set of biopsies); 
 
within 24 hours of each of the three dose/volume gel applications (one of the following 
randomly selected times: 0.5-1 hour, 1.5-3 hours, 3.5-5 hours, or 24 hours after gel 
administration for each dose/volume of gel) (total of 3 sets of biopsies), and 
 
48 hours after one of the three dose/volume gel applications (to be determined at random) (1 
set of biopsies). 
 
The sampling schedule for a participant will be preassigned at the enrollment visit. 
 
The determination of the sample schedule will achieve the following characteristics: 
 
All 12 participants will have flexible sigmoidoscopy at enrollment. 
 
For the 4 mL, 16 mL, and 32 mL dose/volumes, participants will be randomly assigned 
1:1:1:1 to one of the following 4 time-frames to provide samples of rectal tissue, rectal fluid, 
vaginal fluid (if applicable), and effluent from rectal lavage: 0.5-1 hour, 1.5-3 hours, 3.5-5 
hours, and 24 hours following PC-1005 gel application. 


 
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 
There will be 3 sets of biopsies available at each time-frame (0.5-1 hour, 1.5-3 hours, 3.5-5 
hours, and 24 hours following PC-1005 gel application) for each dose/volume (4 mL, 16 mL, 
and 32 mL). 
 
Across the three dose/volumes (4 mL, 16 mL, and 32 mL), participants will be randomly 
assigned 1:1:1 to provide samples of blood, rectal tissue, rectal fluid, vaginal fluid (if 
applicable), and effluent from rectal lavage 48 hours following PC- 1005 gel application for 
one of the three dose/volumes. 
 
There will be 4 sets of biopsies available at 48 hours following PC-1005 gel application for 
each dose/volume (4 mL, 16 mL, and 32 mL).  
 
Randomizations will be stratified by gender so as to incorporate 1-2 participants of each 
gender at each of four time-frames between 0.5 and 24 hours, and to incorporate 2 
participants of each gender at 48 hours for each dose/volume. 
2.3.2 Blinding 
There is no blinding in this open-label study. 
2.3.3 Sample Size and Power 
The study is designed for a total accrual of twelve (12) participants, which gives sufficient power for the 
detection of events (adverse events or detection of drug) as described in the protocol. Descriptive safety 
analyses and pharmacokinetic analyses are planned with no formal statistical testing. 
3. GENERAL DATA ANALYSIS CONSIDERATIONS 
3.1 Analysis Set(s) 
The analysis set consists of all participants enrolled in the study who are administered PC-1005 at any 
dosing visit (Visit 3, Visit 5, or Visit 7).  All available safety, PK, and acceptability data will be analyzed on 
this set of participants, as described below. 
3.2 Statistical Analysis Issues 
For the primary safety analyses, safety endpoints will be classified into groups by dose/volume of gel 
based on the amount of gel administered at a dosing visit (Visit 3, Visit 5, and Visit 7).  If a participant was 
not administered a particular dose/volume of gel, then the participant will be excluded from analyses 
describing that particular dose/volume group.   
 
For the primary pharmacokinetics analyses, timing of drug concentration results will be based on the time 
the specimen was actually taken, and not based on timing group as randomized.  Time points may still be 
grouped into categories based the average or targeted time point for specimen collection.  The handling 
of missing data and concentration data below the limit of quantitation (BLOQ) are described in the section 
on pharmacokinetic analyses below. 
4. INTERIM ANALYSIS AND DATA MONITORING COMMITTEE 
No interim statistical analysis was planned or performed for the MTN-037 study. 
 
One study monitoring committee (SMC) review was conducted for MTN-037, on December 10, 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 
When the use of descriptive statistics to assess dose/volume 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). 
 
The following descriptions may be used to distinguish the dose/volume groups: “4 mL Volume”, “16mL 
Volume”, and “32 mL Volume”.  
6. TRIAL PARTICIPANT DISPOSITION 
Enrollment will take place at two sites:  Birmingham and Pittsburgh, USA. 
6.1 Disposition of Participants 
6.1.1 Screening and Enrollment 
 
Dates of site activation, first enrollment, and last enrollment, as well as the number or participants 
screened, number and percentage of participants enrolled, and the screening-to-enrollment ratio will be 
displayed in a table overall and by site.   
 
6.1.2 Retention 
 
A table will display for each visit the number and percentage of participants who are expected, retained, 
missing, and lost-to-follow-up or terminated with respect to that visit, overall and by site.  
 
6.1.3 Treatment Discontinuation 
 
The number and percentage of participants who ended product use early, as well as the reasons for 
terminating product use early, will be presented in a table overall and by site.  
 
6.1.4 Study Discontinuation 
 
The number and percentage of participants who completed the study, as well as the reasons for non-
completion, will be displayed in a table overall and by site. 
 
6.1.5 Completion of Procedures 
 
The completion of required and expected procedures will be displayed in a table overall and by site. The 
table will display the number and percentages of participant-visits for each procedure.  
6.2 Treatment Exposure 
The number and percentage of participants administered each of the three (3) dose/volumes of gel at 
Visits 3, 5, and 7 will be displayed overall and by site.  Participants will be classified into groups by 
dose/volume of gel based on the time from dosing up until just before the next higher dose/volume is 
administered (e.g., for the 4 mL dose/volume group, any safety endpoints which occur between the time 
of gel insertion at Visit 3 up until (but not including) the time the 16 mL dose/volume is administered at 
Visit 5.) 
 


 
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If applicable, the number and percentage of participants who had study product held during follow-up will 
be displayed overall and by site (along with the reasons why product was held). 
6.3 Protocol Deviations 
Protocol deviations occurring in MTN-037 will be summarized in a table of each type of deviation by site 
and overall, and in a listing of deviation events.  
 
These data will be reviewed prior to the analysis of the primary and secondary endpoints to determine if 
any protocol deviations in this study impact participant eligibility or treatment administration and 
subsequently necessitate adjustments to the analysis set. 
7. BASELINE DATA  
Baseline participant demographic characteristics such as age, sex at birth, ethnicity, race, height, weight, 
and body mass index (BMI) will be summarized and displayed in tables overall and by site, and in tables 
overall and by sex at birth.  Descriptive statistics will be presented for age, height, weight, and BMI.  
Frequency counts and percentages will be presented for sex at birth, ethnicity, and race.  No formal 
comparisons are planned. 
 
Individual participant baseline characteristics (medical history and results from baseline anorectal exam 
findings, pelvic exam findings, STI results, hematology, and local laboratory results) will be presented in 
listings. 
8. SAFETY ANALYSES  
All participants enrolled and administered a dose of PC-1005 will be assessed for safety. 
8.1 Primary Safety Analyses  
The primary safety endpoint is defined as follows: 
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). 
The number and the percentage of participants experiencing each safety endpoint will be tabulated by 
dose/volume of gel. This table will display a summary for any primary safety endpoint and for each 
individual safety endpoint. Each participant will contribute once in each category (i.e., only for highest 
severity AE for each participant) for the calculation of event rates for each dose/volume of gel. Exact 
binomial confidence intervals (Clopper-Pearson) will be calculated for each safety endpoint, even if no 
events occur for an endpoint for a particular dose/volume. 
8.2 Adverse Events 
Summaries of adverse events will include a cumulative listing of adverse events, a table displaying the 
total number of adverse events by severity grade and relationship to study product, a table of the 
incidence of adverse events by MedDRA organ system class/preferred term and severity, and a table of 
incidence of adverse events by MedDRA organ system class/preferred term and relationship to study 
product.  Tables will be displayed by dose/volume, and listings will include the dose/volume period when 
the AE occurred. 


 
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8.3 Laboratory Evaluations  
The number and percentage of participants with a positive result for the following laboratory tests will be 
displayed in a table overall and by sex at birth:  hCG for pregnancy and HIV. A listing of participants with 
positive results of STI testing (syphilis, trichomonas, gonorrhea, chlamydia) after dose insertion will be 
presented. 
 
Hematology results after dosing with each dose/volume, including hemogram (hemoglobin, hematocrit, 
MCV, platelets, WBC) and differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils) 
results will be tabulated by dose/volume using descriptive statistics. 
 
Serum chemistries (AST, ALT, and creatinine) after dosing with each dose/volume will be tabulated by 
dose/volume using descriptive statistics. 
8.4 Other Safety Measures  
Additional safety summaries include: 
 
A listing of participants with abnormal findings on rectal examination after dose insertion (with 
dose/volume period when finding occurred) will be presented. 
 
Concomitant medications are defined as any medication taken during the study. A participant listing of all 
concomitant medications will be presented. 
9. PHARMACOKINETIC ANALYSES 
Descriptive statistics will be used to summarize actual PK sample collection times (from dose insertion) 
for plasma, rectal fluid, rectal tissue, and vaginal fluid samples, and these summaries will be provided by 
site and overall.  Plasma samples are expected to be collected pre-dose and at 1h, 2h, 3h, 4h, 5-6h, and 
24h after dose administration.  Samples of rectal fluid, rectal tissue, and vaginal fluid (if applicable) are 
expected to be collected at one of the following time points, 0.5-1h, 1.5-3h, 3.5-5h, or 24h during each 
dose/volume administration (chosen randomly 1:1:1:1).  These samples are also expected to be collected 
at 48h after dose administration for one of the three dose/volume levels (4 mL, 16 mL, or 32 mL; chosen 
randomly 1:1:1).   
 
A table summarizing the number and percentage of plasma, rectal fluid, rectal tissue, and vaginal fluid 
samples collected outside of the windows of the expected time points will be provided overall and by site.  
For samples collected outside of the window, a listing of sample collection times along with the amount of 
time before (-) the window or after (+) the window will be provided.  Allowable windows for the collection 
of plasma, rectal fluid, rectal tissue, and vaginal fluid are detailed in section 5.4.2 and Table 5-1 of the 
MTN-037 SSP Manual. 
9.1 Methods for Handling Missing and BLOQ Data  
Each bioanalytical assay for plasma, rectal fluid, rectal tissue, and vaginal fluid has an assay sensitivity 
described by a lower limit of quantitation (LLOQ).  These LLOQs will be reported for each matrix.  
Concentration values assayed below the LLOQ, as well as those classified as “Not Detected”, are 
identified as below the limit of quantitation (BLOQ).  
 
In individual participant data listings, actual concentration values below the LLOQ will be displayed, if 
provided from the lab, along with the LLOQ for the assay.  For values identified as BLOQ in the data, a 
listing will be provided displaying the assay and time point(s) of the BLOQ values. 
 


 
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Pre-dose samples that are BLOQ or missing will be assigned a numerical value of zero for the calculation 
of area under the concentration-time curve (AUC).  Pre-dose samples that are missing will be excluded 
from the concentration summary calculations at pre-dose.  Any anomalous quantifiable concentration 
values (at or above the LLOQ) observed at pre-dose will be identified in the study report and used for the 
computation of AUC.   
 
Any other BLOQ concentrations that precede quantifiable samples in the initial portion of the profile or a 
BLOQ value that occurs between quantifiable data points, especially prior to Cmax, will be evaluated to 
determine if an assigned concentration of zero makes sense, or if reanalysis or exclusion of the data is 
warranted.  Following Cmax, BLOQ values embedded between two quantifiable data points will be treated 
as missing when calculating AUC.  If BLOQ values occur at the end of the collection interval (after the last 
quantifiable concentration), these will be treated as missing data.  If consecutive BLOQ concentrations 
are followed by quantifiable concentrations in the terminal portion of the concentration curve, these 
quantified values will be excluded from the PK analysis by assigning them a value of missing, unless 
otherwise warranted by the concentration-time profile. 
 
Drug concentration-time data will be listed for each participant and summarized by descriptive statistics at 
each nominal collection time.  BLOQ concentrations will be treated as zero for computation of descriptive 
statistics. Concentrations assigned a value of missing will be omitted from the calculation of descriptive 
statistics.  If the calculated mean concentration is BLOQ, the mean value will be reported as BLOQ, and 
SD will be reported as ND (not determined). Median, quartiles, minimum and maximum may be reported, 
and if any of these values are BLOQ, they will be reported as BLOQ. 
9.2 Primary PK Analyses  
The primary PK analyses describe the concentrations of MIV-150 in the following matrices: 1) blood 
plasma (BP), 2) rectal fluid (RF), and 3) rectal mucosal tissue homogenates (RT) during each of three 
sequential dose/volumes of 4mL, 16mL, and 32mL. 
 
As BP samples are collected among all participants at seven time points and RF and RT samples are 
collected among three participants at each time point up to 24 hours and among four participants at 48 
hours for each dose/volume, there are differences between how the concentration data for these matrices 
will be analyzed and summarized. 
 
In general, due to the small number of concentrations available at sampling time points, a log 
transformation of the concentrations will be considered if the data suggest strong skewness.  In this case, 
figures and tables will report medians with 95% C.I. at each sampling time point and figures will be 
presented on a semi-logarithmic scale (y-axis: logarithmic concentration; x-axis: linear time (h)).  If no log 
transformation of concentration is needed, then figures and tables will report the mean (with 95% 
confidence interval based on a Student’s t-distribution approximation) at each sampling time point and 
figures will be presented on a linear scale. 
 
Blood Plasma Concentrations 
 
For blood plasma, MIV-150 concentrations can be plotted over time for each individual participant and PK 
parameters (defined below) may be calculated for each participant and then summarized across all 
participants. 
 
Displays of blood plasma concentration data include: 
• 
Tables summarizing the distribution of concentrations at each sampling time point for each 
dose/volume (3 tables, or 1 table with a column for each dose/volume). 
• 
Plots of individual participant concentration-time data presented in a panel for each dose/volume 
(3 panels of plots (1 panel for each dose/volume)).   


 
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• 
Individual participant concentration-time data will also be overlaid on a single plot for each 
dose/volume (3 plots). 
• 
Plots of mean/median concentration at each time point (with 95% C.I.) for each dose/volume (3 
plots, or 1 panel with 3 plots (1 for each dose/volume)). 
• 
Listings of individual participant PK parameters for each dose/volume (3 listings). 
• 
Tables summarizing the distributions of PK parameters across all participants for each 
dose/volume (3 tables). 
 
Rectal Fluid and Rectal Tissue Concentrations 
 
For rectal fluid and rectal tissue, the concentration-time profile will consist of data from different 
participants at different sampling time points.  Individual participant PK parameters will not be calculated 
for concentration data from rectal fluid and rectal tissue since data were not collected at each time point 
for each participant.  
 
Displays of rectal fluid and rectal tissue concentration data include: 
• 
For each matrix (RF, RT), tables summarizing the distribution of concentrations at each sampling 
time point for each dose/volume (3 tables per matrix, or 1 table per matrix with a column for each 
dose/volume). 
• 
For each matrix (RF, RT), scatter plots of MIV-150 concentration-time data for each dose/volume 
(3 plots per matrix, or 1 panel per matrix with 3 plots (1 for each dose/volume)).   
• 
For each matrix (RF, RT), plots of mean/median concentration at each time point (with 95% C.I.) 
for each dose/volume (3 plots per matrix, or 1 panel per matrix with 3 plots (1 for each 
dose/volume)). 
• 
For each matrix (RF, RT), tables of PK parameters calculated from mean/median concentrations 
at each sampling time point for each dose/volume (3 tables per matrix). 
 
The PK parameters are: 
 
Cmax  
 
Maximum observed MIV-150 concentration. 
Clast  
 
Last observed MIV-150 concentration. 
tmax  
 
Time of occurrence for Cmax 
AUC0-t 
Area under the MIV-150 concentration-time curve to the time of the last measurable 
concentration. 
AUC0-∞ 
Area under the MIV-150 concentration-time curve to infinite time.  Equal to AUC0-t plus 
AUCt-∞ = (Clast / ke). 
ke  
 
Terminal elimination rate constant. 
t1/2 
 
Half-life of drug elimination in the terminal phase. 
%AUCex  
Percentage of AUC0-∞ obtained by extrapolation, calculated as [(Clast / ke) / AUC0-∞ *100] 
The time, in hours, to each sample collection time is calculated from the time of dose insertion.  The area 
under the curve (AUC) is calculated for each participant using the trapezoidal method from the time of 
dose insertion to the time of the last sample collection (AUC0-t), typically at 24h or 48h.   
Concentrations after Cmax are used to determine the terminal elimination rate constant (ke) and associated 
half-life of MIV-150 elimination in the terminal phase (t1/2), when at least three such concentration values 
are available, according to the following formulas: 
 
ke = ln (C1/C2) / (t2 – t1) 
t1/2 = ln(2) / ke 


 
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where ln is the natural logarithm, C1 is the first MIV-150 concentration value in the elimination 
phase after Cmax, C2 is the last MIV-150 concentration in the elimination phase after Cmax, and t1 
and t2 are the time (hours) of the first and last MIV-150 concentration values in the elimination 
phase after Cmax, respectively, as measured from the time of dose insertion. 
The area under the plasma MIV-150 concentration-time curve to infinite time (AUC0-∞) is calculated by 
extrapolating the area of the curve after the last observed plasma MIV-150 concentration (Clast) by 
dividing Clast by the terminal elimination rate constant (ke) and adding the result to AUC0-t.  The 
percentage of AUC0-∞ obtained by extrapolation (%AUCex) is calculated as [(AUCt-∞ / AUC0-∞ )*100]. 
10. SECONDARY ANALYSES 
10.1 Acceptability Analyses 
Enrolled participants are administered web-based self-interviews (WSI) at Enrollment (Visit 2) and at the 
three dosing visits (Visits 3, 5, and 7).  The WSI at dosing visits explore reactions to product, with an 
emphasis on identification of product attributes likely to challenge and/or facilitate future sustained use 
when applied rectally by participants. 
To address the secondary endpoints of participant self-report of comfort with gel application, liking the 
product across doses, and perceived side-effects, responses to WSI questions in section B (Rectal Gel 
Acceptability) and section C (Experiences Using the Product) of the dosing visits (Visits 3, 5, and 7) will 
be summarized in a table by dose/volume.   
10.2 Secondary PK Analyses  
The secondary PK analyses describe the analyses of MIV-150 concentrations in vaginal fluid and are 
limited to participants identified as female sex at birth. 
 
For these secondary PK analyses, the primary PK analyses for rectal fluid and/or rectal tissue will be 
repeated for MIV-150 concentrations in vaginal fluid. 
11. REFERENCES  
A Phase 1 Safety and Pharmacokinetic Study of PC-1005 (MIV-150/Zinc Acetate/Carrageenan Gel) 
Administered Rectally to HIV-1 Seronegative Adults (MTN-037).  Microbicide Trials Network (MTN) 
clinical study protocol, Version 1.0, November 9, 2017.  
 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 
2.1, July 2017  
 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Publish Date: 
December 2004, Addendum 1, Female Genital Grading Table for Use in Microbicide Studies, Version 1.0, 
November 2007. 
 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Publish Date: 
December 2004, Addendum 2, Male Genital Grading Table for Use in Microbicide Studies, Version 1.0, 
November 2007. 
 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Addendum 3, 
Rectal Grading Table for Use in Microbicide Studies, Clarification dated May 2012. 
 


 
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MTN-037 SSP Manual, Version 1.1, 05 October 2018, Section 5, Page 5-5 and Page 5-6 of 5-10, Section 
5.4.2 Pharmacokinetics, Pharmacodynamics, and Mucosal Safety Assignment.  Table 5-1: PK Sample 
Collection Time-Points following Study Gel Administration.