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Safety and Effectiveness of Tenofovir Gel in the Prevention of Human Immunodeficiency Virus (HIV-1) Infection in Women and the Effects of Tenofovir Gel on the Incidence of Herpes Simplex Virus (HSV-2) Infection

Primary Purpose

HIV Prevention

Status
Completed
Phase
Phase 3
Locations
South Africa
Study Type
Interventional
Intervention
Tenofovir gel
Universal placebo gel
Sponsored by
CONRAD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for HIV Prevention

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria:

  • Confirmed age 18-40 years (inclusive)
  • Able and willing to provide written informed consent
  • Able and willing to provide adequate locator information for study retention and safety purposes
  • Sexually active, defined as having had vaginal intercourse at least twice in the past 30 days prior to screening
  • HIV negative on two rapid tests performed by study staff within 30 days of enrolment (see algorithm in Appendix 3).
  • No evidence of glycosuria
  • No evidence of proteinuria greater than trace*
  • No history of pathological bone fractures
  • Have a negative pregnancy test
  • Women currently breastfeeding may be enrolled in the study
  • Agree to use a study-approved effective non-barrier form of contraception
  • Agree to adhere to study visits and procedures
  • Willing to use study gel as advised

  • Not using or taking any of the following groups of medications:

    • Nephrotoxic agents
    • Drugs that slow renal excretion
    • Immune system modulators
    • Other antiretrovirals

Exclusion Criteria:

  • History of adverse reaction to latex.

  • Plans any of the following during the study period

    • To travel away from the study site for more than 30 consecutive days.
    • To relocate away from the study site.
    • To become pregnant.
    • To enrol in any other study of an investigational product or behaviour modification related to HIV prevention.
  • If in the opinion of the examining clinician, is not sexually active
  • Inadequate renal function (serum creatinine greater than 1.5mg/dl and creatinine clearance less than 50ml/min, as estimated using the method of Cockcroft and Gault96 )
  • Grade 3 and above ALT and AST at screening or any clinical sign of liver disease ( e.g. ascites, hepatomegaly, jaundice)
  • Abnormal serum phosphate levels (Grade 3 and above)
  • Has a clinically apparent finding on speculum pelvic examination (observed by study staff) involving deep epithelial disruption. Otherwise eligible participants with speculum pelvic examination findings involving deep epithelial disruption may proceed with enrolment after the findings have resolved and the inclusion/exclusion are met.
  • Received previously or receiving an experimental HIV vaccine
  • Currently participating in another HIV prevention intervention study or participation in any other clinical trial with a biomedical intervention in the last six months
  • Has current STI symptoms and/or other reproductive tract infection requiring treatment, as assessed by study staff. Otherwise eligible participants diagnosed during screening with infection(s) requiring treatment may be enrolled provided that treatment has been completed.
  • Any clinical evidence of untreated cervical abnormalities
  • Has any other condition that, based on the opinion of the Investigator or designee, would preclude provision of informed consent, make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

Sites / Locations

  • MatCH Edendale Research Center
  • Desmond Tutu HIV Centre / University of Cape Town
  • Perinatal HIV Research Unit / University of the Witwatersrand
  • Wits Reproductive Health and HIV Institute / University of the Witwatersrand
  • Qhakaza Mbokodo Research Clinic
  • Medunsa Clinical Research Unit / Ga-Ra
  • The Aurum Institute (Rustenburg)
  • Setshaba Research Centre
  • The Aurum Institute, Tembisa Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Tenofovir 1% vaginal gel

Universal placebo gel

Arm Description

Participants will be required to insert a single dose of assigned gel intravaginally up to 12 hours before coitus and a second dose within 12 hours after coitus but no more than 2 applications within a 24 hour period.

Participants will be required to insert a single dose of assigned gel intravaginally up to 12 hours before coitus and a second dose within 12 hours after coitus but no more than 2 applications within a 24 hour period.

Outcomes

Primary Outcome Measures

Effectiveness
Incidence of HIV-1 infection: HIV incidence will be determine by detection of HIV antibodies using two HIV rapid tests (of which one will be FDA approved) according to algorithm in protocol. One of the rapid tests will detect both HIV-1 and HIV-2; the other will be specific for HIV-1. All endpoints will be reviewed by an expert committee (the Endpoint Adjudication Committee). In carrying out this review, the Committee will use guidelines prepared by the protocol committee for this purpose and recorded in the Manual of Procedures
Safety
Grade 2, 3, and 4 clinical and laboratory adverse events as defined by the DAIDS toxicity table

Secondary Outcome Measures

Incidence of HSV-2 infection
HSV-2 status will be established at enrollment according to a testing algorithm in the protocol. At product discontinuation samples of all those that were HSV-2 seronegative at enrollment will be tested. To identify and confirm incident HSV-2 infections and the timing of these infections, blood samples that were stored will be tested to determine the earliest equivocal or positive result. These samples will be then be tested by HSV Western blot. Samples positive on HSV Western blot will be deemed to be incident HSV-2 infections.
Pregnancy
Incidence of pregnancy loss, prematurity, low birth weight, and major and minor congenital anomalies will be determined
Gel and condom use
HIV-1 incidence after product withdrawal
HIV testing will be conducted 3 months after product discontinuation and if HIV positive, the last stored sample will be tested to ascertain timing of infection and viral tenofovir resistance testing will be performed

Full Information

First Posted
June 28, 2011
Last Updated
April 16, 2015
Sponsor
CONRAD
Collaborators
Follow-on African Consortium for Tenofovir Studies (FACTS), United States Agency for International Development (USAID)
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1. Study Identification

Unique Protocol Identification Number
NCT01386294
Brief Title
Safety and Effectiveness of Tenofovir Gel in the Prevention of Human Immunodeficiency Virus (HIV-1) Infection in Women and the Effects of Tenofovir Gel on the Incidence of Herpes Simplex Virus (HSV-2) Infection
Official Title
A Phase III, Multi-Centre, Randomized Controlled Trial to Assess the Safety and Effectiveness of the Vaginal Microbicide 1% Tenofovir Gel in the Prevention of Human Immunodeficiency Virus Type 1 Infection in Women, and to Examine Effects of the Microbicide on the Incidence of Herpes Simplex Virus Type 2 Infection
Study Type
Interventional

2. Study Status

Record Verification Date
April 2015
Overall Recruitment Status
Completed
Study Start Date
October 2011 (undefined)
Primary Completion Date
August 2014 (Actual)
Study Completion Date
August 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
CONRAD
Collaborators
Follow-on African Consortium for Tenofovir Studies (FACTS), United States Agency for International Development (USAID)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of the study is to assess the safety and effectiveness of intravaginal 1% tenofovir gel in preventing Human Immunodeficiency Virus (HIV-1) infection and Herpes Simplex Virus (HSV-2) infection in sexually active women.
Detailed Description
This is a phase III, multicenter trial to assess the safety and effectiveness of 1% tenofovir gel, administered vaginally by approximately 2900 sexually active women at high risk for sexually transmitted HIV. Approximately 2600 women aged 18-30 years old will be enrolled to achieve the required number of endpoints to show an effect on HIV-1 infection, while up to 300 additional women aged 31-40 years old will be enrolled to collect more safety information in this age group. This is an event driven study that plans to randomize seronegative women. Participants will be randomized to a 1:1 ratio to receive 1% tenofovir gel or placebo gel. Each will be asked to insert a dose of the assigned study product within 12 hours prior to a coital event and another dose as soon as possible within 12 hours after a coital event. Participants will be advised to use only two doses of gel in a 24 hour period. All women will be evaluated for the rates of adverse events and the rate of HIV seroconversion. In addition, the study will evaluate several secondary endpoints that bear directly on potential risks and benefits of vaginal tenofovir gel use.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Prevention

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
2059 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tenofovir 1% vaginal gel
Arm Type
Experimental
Arm Description
Participants will be required to insert a single dose of assigned gel intravaginally up to 12 hours before coitus and a second dose within 12 hours after coitus but no more than 2 applications within a 24 hour period.
Arm Title
Universal placebo gel
Arm Type
Placebo Comparator
Arm Description
Participants will be required to insert a single dose of assigned gel intravaginally up to 12 hours before coitus and a second dose within 12 hours after coitus but no more than 2 applications within a 24 hour period.
Intervention Type
Drug
Intervention Name(s)
Tenofovir gel
Intervention Description
Tenofovir gel is a clear, transparent, viscous gel at concentrations of 1% formulated in purified water with edentate disodium, citric acid, glycerin, methylparaben, propylparaben, HEC, and pH adjusted to 4-5. Tenofovir gel will be supplies in a 4 ml single use applicator containing approximately 4 grams of gel, equivalent to approximately 40mg of tenofovir.
Intervention Type
Drug
Intervention Name(s)
Universal placebo gel
Intervention Description
The placebo gel is an inert gel containing HEC as the gelling agent, purified water, sodium chloride, sorbic acid and sodium hydroxide. Each applicator contains approximately 4ml of placebo gel
Primary Outcome Measure Information:
Title
Effectiveness
Description
Incidence of HIV-1 infection: HIV incidence will be determine by detection of HIV antibodies using two HIV rapid tests (of which one will be FDA approved) according to algorithm in protocol. One of the rapid tests will detect both HIV-1 and HIV-2; the other will be specific for HIV-1. All endpoints will be reviewed by an expert committee (the Endpoint Adjudication Committee). In carrying out this review, the Committee will use guidelines prepared by the protocol committee for this purpose and recorded in the Manual of Procedures
Time Frame
30 months
Title
Safety
Description
Grade 2, 3, and 4 clinical and laboratory adverse events as defined by the DAIDS toxicity table
Time Frame
30 months
Secondary Outcome Measure Information:
Title
Incidence of HSV-2 infection
Description
HSV-2 status will be established at enrollment according to a testing algorithm in the protocol. At product discontinuation samples of all those that were HSV-2 seronegative at enrollment will be tested. To identify and confirm incident HSV-2 infections and the timing of these infections, blood samples that were stored will be tested to determine the earliest equivocal or positive result. These samples will be then be tested by HSV Western blot. Samples positive on HSV Western blot will be deemed to be incident HSV-2 infections.
Time Frame
30 months
Title
Pregnancy
Description
Incidence of pregnancy loss, prematurity, low birth weight, and major and minor congenital anomalies will be determined
Time Frame
30 months
Title
Gel and condom use
Time Frame
30 months
Title
HIV-1 incidence after product withdrawal
Description
HIV testing will be conducted 3 months after product discontinuation and if HIV positive, the last stored sample will be tested to ascertain timing of infection and viral tenofovir resistance testing will be performed
Time Frame
3 months after product withdrawal

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Confirmed age 18-40 years (inclusive) Able and willing to provide written informed consent Able and willing to provide adequate locator information for study retention and safety purposes Sexually active, defined as having had vaginal intercourse at least twice in the past 30 days prior to screening HIV negative on two rapid tests performed by study staff within 30 days of enrolment (see algorithm in Appendix 3). No evidence of glycosuria No evidence of proteinuria greater than trace* No history of pathological bone fractures Have a negative pregnancy test Women currently breastfeeding may be enrolled in the study Agree to use a study-approved effective non-barrier form of contraception Agree to adhere to study visits and procedures Willing to use study gel as advised Not using or taking any of the following groups of medications: Nephrotoxic agents Drugs that slow renal excretion Immune system modulators Other antiretrovirals Exclusion Criteria: History of adverse reaction to latex. Plans any of the following during the study period To travel away from the study site for more than 30 consecutive days. To relocate away from the study site. To become pregnant. To enrol in any other study of an investigational product or behaviour modification related to HIV prevention. If in the opinion of the examining clinician, is not sexually active Inadequate renal function (serum creatinine greater than 1.5mg/dl and creatinine clearance less than 50ml/min, as estimated using the method of Cockcroft and Gault96 ) Grade 3 and above ALT and AST at screening or any clinical sign of liver disease ( e.g. ascites, hepatomegaly, jaundice) Abnormal serum phosphate levels (Grade 3 and above) Has a clinically apparent finding on speculum pelvic examination (observed by study staff) involving deep epithelial disruption. Otherwise eligible participants with speculum pelvic examination findings involving deep epithelial disruption may proceed with enrolment after the findings have resolved and the inclusion/exclusion are met. Received previously or receiving an experimental HIV vaccine Currently participating in another HIV prevention intervention study or participation in any other clinical trial with a biomedical intervention in the last six months Has current STI symptoms and/or other reproductive tract infection requiring treatment, as assessed by study staff. Otherwise eligible participants diagnosed during screening with infection(s) requiring treatment may be enrolled provided that treatment has been completed. Any clinical evidence of untreated cervical abnormalities Has any other condition that, based on the opinion of the Investigator or designee, would preclude provision of informed consent, make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Helen Rees, Prof
Organizational Affiliation
University of Witwatersrand, South Africa
Official's Role
Study Chair
Facility Information:
Facility Name
MatCH Edendale Research Center
City
Pietermaritzburg
State/Province
Kwa-Zulu NAtal
ZIP/Postal Code
316
Country
South Africa
Facility Name
Desmond Tutu HIV Centre / University of Cape Town
City
Cape Town
Country
South Africa
Facility Name
Perinatal HIV Research Unit / University of the Witwatersrand
City
Diepkloof
Country
South Africa
Facility Name
Wits Reproductive Health and HIV Institute / University of the Witwatersrand
City
Hillbrow
Country
South Africa
Facility Name
Qhakaza Mbokodo Research Clinic
City
Ladysmith
ZIP/Postal Code
3370
Country
South Africa
Facility Name
Medunsa Clinical Research Unit / Ga-Ra
City
Pretoria
Country
South Africa
Facility Name
The Aurum Institute (Rustenburg)
City
Rustenburg
Country
South Africa
Facility Name
Setshaba Research Centre
City
Soshanguve
Country
South Africa
Facility Name
The Aurum Institute, Tembisa Hospital
City
Tembisa
Country
South Africa

12. IPD Sharing Statement

Citations:
PubMed Identifier
30507409
Citation
Delany-Moretlwe S, Lombard C, Baron D, Bekker LG, Nkala B, Ahmed K, Sebe M, Brumskine W, Nchabeleng M, Palanee-Philips T, Ntshangase J, Sibiya S, Smith E, Panchia R, Myer L, Schwartz JL, Marzinke M, Morris L, Brown ER, Doncel GF, Gray G, Rees H. Tenofovir 1% vaginal gel for prevention of HIV-1 infection in women in South Africa (FACTS-001): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018 Nov;18(11):1241-1250. doi: 10.1016/S1473-3099(18)30428-6. Epub 2018 Oct 24.
Results Reference
derived

Learn more about this trial

Safety and Effectiveness of Tenofovir Gel in the Prevention of Human Immunodeficiency Virus (HIV-1) Infection in Women and the Effects of Tenofovir Gel on the Incidence of Herpes Simplex Virus (HSV-2) Infection

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