BufferGel and PRO 2000/5: Vaginal Gels to Prevent HIV Infection in Women

Phase II/IIb Safety and Effectiveness Study of the Vaginal Microbicides BufferGel and 0.5% PRO 2000/5 Gel (P) for the Prevention of HIV Infection in Women

The majority of HIV infected people worldwide became infected with the virus through heterosexual contact. BufferGel and PRO 2000 Gel are vaginal gels designed to prevent women from becoming infected with HIV during sexual intercourse with an HIV infected partner. This study will test the safety and effectiveness of these gels.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: BufferGel; Drug: PRO 2000/5 Gel; Drug: Placebo gel

Detailed Description

Accessible, usable, and effective vaginal microbicides could significantly decrease the spread of HIV. Vaginal microbicides could be used with condoms to prevent HIV infection; they could also be used in situations in which an individual is unable to negotiate condom use. Vaginal microbicides are potentially bidirectional, preventing both male-to-female and female-to-male HIV transmission. This study will evaluate the safety and effectiveness of two vaginal microbicides, BufferGel and PRO 2000/5, in preventing the transmission of HIV. The study will also evaluate the effectiveness of these gels in preventing other common sexually transmitted infections (STIs).

BufferGel is a buffering agent designed to maintain normal vaginal acidity in the presence of ejaculate. Studies have shown that HIV is inactivated below a pH of 4 to 5.8. Carbopol 974, the major nonaqueous component of BufferGel, is commonly used as a gelling or tableting agent and has a well-documented safety record. BufferGel has proven safe and well tolerated in Phase I studies. PRO 2000/5 inhibits viral entry into susceptible cells. PRO 2000/5 has also been evaluated in Phase I studies and was found to be safe and well tolerated.

Participants in this study will be randomly assigned to receive one of four interventions: BufferGel, PRO 2000/5, placebo gel, or no gel. All participants will receive HIV risk reduction counseling, condoms, and diagnosis and treatment of sexually transmitted diseases. Participants in the three gel arms will be given single-use, prefilled applicators of gel and will be instructed to apply one dose of the product (BufferGel, PRO 2000/5, or placebo gel) intravaginally up to 60 minutes before each vaginal intercourse while in the study.

Participants will be enrolled for approximately 12 to 30 months, depending on when they enter the study. Participants will have two screening study visits and then monthly visits. Monthly study visits may take place at a clinic, the participant's home, or other community site. Monthly visits will include a medical interview; urine testing, including pregnancy testing; HIV and sexually transmitted infection risk reduction counseling; and distribution of study supplies (condoms and gel-filled applicators). Blood collection will occur at selected monthly visits. Four times a year, participants will be seen in the clinic for a more structured medical interview, pelvic exam, and HIV testing. At one of these visits, participants at particular sites who are willing will be asked to complete a behavioral risk assessment. At some visits vaginal fluid swabs will occur. Participants at non-US study sites will be asked for permission for these swabs to be stored for further testing. Assessment interviews will be both face to face and self-reporting.

• Study Type: Interventional
• Enrollment (Actual): 3101
• Phase: Phase 2

Contacts and Locations

Study Locations

• Malawi
  • Central
    • Lilongwe, Central, Malawi
      • University of North Carolina Lilongwe CRS
  • Southern
    • Blantyre, Southern, Malawi
      • College of Med. JHU CRS
• South Africa
  • KwaZulu-Natal
    • Chatsworth, KwaZulu-Natal, South Africa
      • Chatsworth CRS
    • Durban, KwaZulu-Natal, South Africa
      • Med. Research Council-Hlabisa
• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • 3535 Market Street CRS
• Zambia
  • Lusaka, Zambia
    • Kamwala Clinic CRS
• Zimbabwe
  • Chitungwiza, Zimbabwe, 263
    • Seke South CRS
  • Harare, Zimbabwe, 263
    • Spilhaus CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Note: Per the 12/15/06 amendment, all study participants will now enter the Phase IIb study.

Inclusion Criteria:

• HIV uninfected
• Have had sexual intercourse at least once in the 3 months prior to study entry
• Able to provide adequate contact information to study officials for purposes of follow-up

Exclusion Criteria:

• History of adverse reaction to latex
• Nonmedical injection drug use in the 12 months prior to study entry
• Vaginal intercourse more than an average of two times per day in the 2 weeks prior to study entry
• Plan to become pregnant in the 30 months after study entry
• Plan to travel away from the study site for more than 3 consecutive months in the 30 months after study entry
• Plan to relocate away from the study site in the 30 months after study entry
• Participation in another clinical trial of a vaginal product
• Pregnant within 42 days of study entry
• Have a sexually transmitted disease or other reproductive tract infection diagnosed by study staff
• Abnormal pelvic exam indicating deep epithelial disruption
• Condition that, in the opinion of the investigator, may interfere with the study
• Liver or kidney function abnormality of Grade 3 or higher
• Blood or blood clotting abnormality of Grade 4 or higher

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: 4
Experimental: 1; BufferGel	Drug: BufferGel; Participants will be given single-use, prefilled applicators of gel and will be instructed to apply one dose of BufferGel intravaginally up to 60 minutes before each vaginal intercourse while in the study.
Experimental: 2; Pro 2000/5 Gel (P)	Drug: PRO 2000/5 Gel; Participants will be given single-use, prefilled applicators of gel and will be instructed to apply one dose of PRO 2000/5 Gel intravaginally up to 60 minutes before each vaginal intercourse while in the study.
Placebo Comparator: 3; Placeo Gel	Drug: Placebo gel; Participants will be given single-use, prefilled applicators of gel and will be instructed to apply one dose of PRO 2000/5 Gel intravaginally up to 60 minutes before each vaginal intercourse while in the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety of BufferGel and 0.5% PRO 2000/5 Gel (P), as assessed by deep epithelial disruption, other genital symptoms, or other systemic symptoms	Throughout study
HIV infection as measured by seroconversion	Throughout study

Secondary Outcome Measures

Outcome Measure	Time Frame
Bacterial vaginosis	Throughout study
Chlamydia infection	Throughout study
Genital ulcer disease	Throughout study
Gonorrhea infection	Throughout study
Herpes simplex virus-2 infection	Throughout study
Pregnancy	Throughout study
Syphilis infection	Throughout study
Trichomoniasis	Throughout study
Acceptability of study product	At Month 3 and study exit
Number of behavioral risk assessment questions not answered in self-reported interviews	Throughout study
Rates of condom use versus gel use	Throughout study
Establishment of a repository of vaginal swab specimens for long-term storage and future research testing on biomarkers of microbicide safety and effectiveness	Throughout study

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: National Institute on Drug Abuse (NIDA); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH); HIV Prevention Trials Network
• Investigators: Study Chair: Salim Abdool Karim, MBChB, PhD, University of KwaZulu-Natal, Centre for the AIDS Programme of Research in South Africa, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine; Study Chair: Irving Hoffman, PA, MPH, School of Medicine, University of North Carolina; Study Chair: Lisa Maslankowski, MD, University of Pennsylvania; Study Chair: Groesbeck Parham, MD, Centre for Infectious Disease Research in Zambia; Study Chair: Nancy Padian, PhD, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco; AIDS Research Institute; Study Chair: Gita Ramjee, PhD, Medical Research Council, HIV Prevention Research Unit; Study Chair: Taha Taha, MD, Johns Hopkins Bloomberg School of Public Health

Publications and helpful links

General Publications

• Mayer KH, Karim SA, Kelly C, Maslankowski L, Rees H, Profy AT, Day J, Welch J, Rosenberg Z; HIV Prevention Trials Network (HPTN) 020 Protocol Team. Safety and tolerability of vaginal PRO 2000 gel in sexually active HIV-uninfected and abstinent HIV-infected women. AIDS. 2003 Feb 14;17(3):321-9. doi: 10.1097/00002030-200302140-00005.
• Tabet SR, Callahan MM, Mauck CK, Gai F, Coletti AS, Profy AT, Moench TR, Soto-Torres LE, Poindexter III AN, Frezieres RG, Walsh TL, Kelly CW, Richardson BA, Van Damme L, Celum CL. Safety and acceptability of penile application of 2 candidate topical microbicides: BufferGel and PRO 2000 Gel: 3 randomized trials in healthy low-risk men and HIV-positive men. J Acquir Immune Defic Syndr. 2003 Aug 1;33(4):476-83. doi: 10.1097/00126334-200308010-00008. Erratum In: J Acquir Immune Defic Syndr. 2003 Sep 1;34(1):118.
• van De Wijgert J, Fullem A, Kelly C, Mehendale S, Rugpao S, Kumwenda N, Chirenje Z, Joshi S, Taha T, Padian N, Bollinger R, Nelson K. Phase 1 trial of the topical microbicide BufferGel: safety results from four international sites. J Acquir Immune Defic Syndr. 2001 Jan 1;26(1):21-7. doi: 10.1097/00126334-200101010-00003.
• Mayer KH, Peipert J, Fleming T, Fullem A, Moench T, Cu-Uvin S, Bentley M, Chesney M, Rosenberg Z. Safety and tolerability of BufferGel, a novel vaginal microbicide, in women in the United States. Clin Infect Dis. 2001 Feb 1;32(3):476-82. doi: 10.1086/318496. Epub 2001 Jan 26.
• Clarke JG, Peipert JF, Hillier SL, Heber W, Boardman L, Moench TR, Mayer K. Microflora changes with the use of a vaginal microbicide. Sex Transm Dis. 2002 May;29(5):288-93. doi: 10.1097/00007435-200205000-00007.
• D'Cruz OJ, Uckun FM. Clinical development of microbicides for the prevention of HIV infection. Curr Pharm Des. 2004;10(3):315-36. doi: 10.2174/1381612043386374.
• MacQueen KM, Namey E, Chilongozi DA, Mtweve SP, Mlingo M, Morar N, Reid C, Ristow A, Sahay S; HPTN 035 Standard of Care Assessment Team. Community perspectives on care options for HIV prevention trial participants. AIDS Care. 2007 Apr;19(4):554-60. doi: 10.1080/09540120601035284.
• Minces LR, McGowan I. Advances in the Development of Microbicides for the Prevention of HIV Infection. Curr Infect Dis Rep. 2010 Jan;12(1):56-62. doi: 10.1007/s11908-009-0076-5.
• Abdool Karim SS, Richardson BA, Ramjee G, Hoffman IF, Chirenje ZM, Taha T, Kapina M, Maslankowski L, Coletti A, Profy A, Moench TR, Piwowar-Manning E, Masse B, Hillier SL, Soto-Torres L; HIV Prevention Trials Network (HPTN) 035 Study Team. Safety and effectiveness of BufferGel and 0.5% PRO2000 gel for the prevention of HIV infection in women. AIDS. 2011 Apr 24;25(7):957-66. doi: 10.1097/QAD.0b013e32834541d9.
• Guffey MB, Richardson B, Husnik M, Makanani B, Chilongozi D, Yu E, Ramjee G, Mgodi N, Gomez K, Hillier SL, Karim SA; HIV Prevention Trials Network (HPTN) 035 Study Team. HPTN 035 phase II/IIb randomised safety and effectiveness study of the vaginal microbicides BufferGel and 0.5% PRO 2000 for the prevention of sexually transmitted infections in women. Sex Transm Infect. 2014 Aug;90(5):363-9. doi: 10.1136/sextrans-2014-051537. Epub 2014 Jun 4.
• Richardson BA, Kelly C, Ramjee G, Fleming T, Makanani B, Roberts S, Musara P, Mkandawire N, Moench T, Coletti A, Soto-Torres L, Karim SA; HPTN 035 Study Team. Appropriateness of hydroxyethylcellulose gel as a placebo control in vaginal microbicide trials: a comparison of the two control arms of HPTN 035. J Acquir Immune Defic Syndr. 2013 May 1;63(1):120-5. doi: 10.1097/QAI.0b013e31828607c5.

Study record dates

Study Major Dates

• Study Start: January 1, 2005
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): September 1, 2008

Study Registration Dates

• First Submitted: December 11, 2003
• First Submitted That Met QC Criteria: December 12, 2003
• First Posted (Estimate): December 15, 2003

Study Record Updates

• Last Update Posted (Actual): November 8, 2021
• Last Update Submitted That Met QC Criteria: November 3, 2021
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: HIV Seronegativity; Risk Factors; Anti-Infective Agents, Local; Vagina; BufferGel; PRO 2000
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Slow Virus Diseases; HIV Infections; Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome
• Other Study ID Numbers: HPTN 035; 10065 (Registry Identifier: DAIDS ES)