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Safety and Effectiveness of TFV 1% Gel, TDF Tablets, and FTC/TDF Tablets in Preventing HIV in Women

This study has been completed.
Sponsor:
Collaborator:
Microbicide Trials Network
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00705679
First received: June 24, 2008
Last updated: February 15, 2016
Last verified: February 2016
Results First Received: January 12, 2016  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Pharmacokinetics Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Prevention
Condition: HIV Infections
Interventions: Drug: Emtricitabine/tenofovir disoproxil fumarate
Drug: Emtricitabine/tenofovir disoproxil fumarate placebo
Drug: Tenofovir disoproxil fumarate
Drug: Tenofovir disoproxil fumarate placebo
Drug: Tenofovir 1% vaginal gel
Drug: Tenofovir placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Women were recruited from September 2009 through June 2011 from 15 sites in South Africa, Uganda, and Zimbabwe.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
12,320 women were assessed for eligibility and 7,291 were excluded for various reasons, including 2,308 women who were HIV-positive. 5,029 women were randomized.

Reporting Groups
  Description
Oral TDF

TDF 300 mg tablet taken orally once daily and one FTC/TDF placebo tablet taken orally once daily for 12 to 36 months

Emtricitabine/tenofovir disoproxil fumarate placebo: placebo tablet

Tenofovir disoproxil fumarate: 300 mg tablet

Oral TDF-FTC

TDF placebo tablet taken orally once daily and one FTC 200 mg/TDF 300 mg tablet taken orally once daily for 12 to 36 months

Emtricitabine/tenofovir disoproxil fumarate: 200 mg/300 mg tablet

Tenofovir disoproxil fumarate placebo: placebo tablet

Oral Placebo

TDF placebo tablet taken orally once daily and one FTC/TDF placebo tablet taken orally once daily for 12 to 36 months

Emtricitabine/tenofovir disoproxil fumarate placebo: placebo tablet

Tenofovir disoproxil fumarate placebo: placebo tablet

TFV Gel

Application of tenofovir 1% vaginal gel once daily

Tenofovir 1% vaginal gel: 1 gm/100 ml of 1% gel

Gel Placebo

Application of tenofovir placebo gel once daily

Tenofovir placebo: placebo gel


Participant Flow:   Overall Study
    Oral TDF     Oral TDF-FTC     Oral Placebo     TFV Gel     Gel Placebo  
STARTED     1007     1003     1009     1007     1003  
COMPLETED     942     864     894     927     934  
NOT COMPLETED     65     139     115     80     69  
Adverse Event                 1                 1                 0                 0                 0  
Death                 0                 0                 3                 2                 1  
Lost to Follow-up                 32                 60                 44                 30                 35  
Physician Decision                 0                 1                 0                 1                 0  
Withdrawal by Subject                 32                 77                 68                 47                 33  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Includes all participants enrolled and randomized to a study arm

Reporting Groups
  Description
Oral TDF

TDF 300 mg tablet taken orally once daily and one FTC/TDF placebo tablet taken orally once daily for 12 to 36 months

Emtricitabine/tenofovir disoproxil fumarate placebo: placebo tablet

Tenofovir disoproxil fumarate: 300 mg tablet

Oral TDF-FTC

TDF placebo tablet taken orally once daily and one FTC 200 mg/TDF 300 mg tablet taken orally once daily for 12 to 36 months

Emtricitabine/tenofovir disoproxil fumarate: 200 mg/300 mg tablet

Tenofovir disoproxil fumarate placebo: placebo tablet

Oral Placebo

TDF placebo tablet taken orally once daily and one FTC/TDF placebo tablet taken orally once daily for 12 to 36 months

Emtricitabine/tenofovir disoproxil fumarate placebo: placebo tablet

Tenofovir disoproxil fumarate placebo: placebo tablet

TFV Gel

Application of tenofovir 1% vaginal gel once daily

Tenofovir 1% vaginal gel: 1 gm/100 ml of 1% gel

Gel Placebo

Application of tenofovir placebo gel once daily

Tenofovir placebo: placebo gel

Total Total of all reporting groups

Baseline Measures
    Oral TDF     Oral TDF-FTC     Oral Placebo     TFV Gel     Gel Placebo     Total  
Number of Participants  
[units: participants]
  1007     1003     1009     1007     1003     5029  
Age  
[units: years]
Mean (Standard Deviation)
  25.5  (5.1)     25.2  (5.2)     25.3  (5.2)     25.3  (5.2)     25.3  (5.1)     25.3  (5.2)  
Gender  
[units: participants]
           
Female     1007     1003     1009     1007     1003     5029  
Male     0     0     0     0     0     0  
Race/Ethnicity, Customized [1]
[units: participants]
           
Chichewa     4     10     7     7     2     30  
Lombwe     0     0     0     0     1     1  
Yao     1     0     0     0     1     2  
Tumbuka     0     1     1     0     1     3  
Other African tribe     76     75     83     92     84     410  
White     0     0     0     0     0     0  
Zulu     601     587     595     585     571     2939  
Xhosa     85     75     74     72     92     398  
Indian     21     28     22     22     22     115  
Colored     0     3     3     4     1     11  
Black     64     64     65     65     64     322  
Bemba     0     0     0     0     0     0  
Chewa     1     1     0     0     0     2  
Tonga     0     0     0     0     0     0  
Lozi     0     0     0     0     0     0  
Shona     123     108     111     111     117     570  
Ndebele     14     27     18     25     22     106  
Other     17     24     30     24     25     120  
Region of Enrollment [2]
[units: participants]
           
South Africa     816     812     815     818     816     4077  
Uganda     64     64     65     65     64     322  
Zimbabwe     127     127     129     124     123     630  
Some secondary school education or higher [3]
[units: participants]
           
Some secondary school education or higher     924     929     926     920     923     4622  
Complete primary school education or lower     82     74     83     85     79     403  
Missing     1     0     0     2     1     4  
Earns own income [4]
[units: participants]
           
Yes     569     569     586     587     570     2881  
No     438     434     423     420     432     2147  
Missing     0     0     0     0     1     1  
Live births [5]
[units: children]
Mean (Standard Deviation)
  1.6  (1.1)     1.5  (1.1)     1.5  (1.2)     1.5  (1.1)     1.5  (1.2)     1.5  (1.1)  
Currently married [6]
[units: participants]
           
Yes     207     209     211     210     215     1052  
No     800     794     798     797     788     3977  
At least 2 male sex partners in the past 3 months [7]
[units: participants]
           
Yes     236     208     244     217     199     1104  
No     761     782     754     779     793     3869  
No response     10     13     11     11     11     56  
Episodes of vaginal intercourse in the past 7 days  
[units: episodes]
Mean (Standard Deviation)
  2.5  (2.8)     2.5  (3.4)     2.5  (2.6)     2.6  (3.6)     2.6  (2.9)     2.5  (3.1)  
Condom use during last vaginal intercourse  
[units: participants]
           
Yes     763     760     742     768     733     3766  
No     242     239     263     239     268     1251  
Missing     2     4     4     0     2     12  
Anal sex in the previous 3 months [8]
[units: participants]
           
Yes     164     175     174     179     176     868  
No     827     812     823     814     810     4086  
Missing     16     16     12     14     17     75  
Injectable contraception use [9]
[units: participants]
           
Yes     709     723     700     707     726     3565  
No     298     280     309     300     277     1464  
Oral pills contraception [9]
[units: participants]
           
Yes     226     223     238     238     215     1140  
No     781     780     771     769     788     3889  
Infection by Chlamydia trachomatis [10]
[units: participants]
           
Yes     122     117     127     116     129     611  
No     884     886     882     891     874     4417  
Missing     1     0     0     0     0     1  
Infection by Neisseria gonorrhoeae [10]
[units: participants]
           
Yes     42     27     34     24     36     163  
No     964     976     975     983     967     4865  
Missing     1     0     0     0     0     1  
Infection by Trichomonas vaginalis [11]
[units: participants]
           
Yes     68     54     66     62     51     301  
No     939     948     943     943     949     4722  
Missing     0     1     0     2     3     6  
Syphilis infection [12]
[units: participants]
           
Yes     12     15     16     14     11     68  
No     994     988     993     993     992     4960  
Missing     1     0     0     0     0     1  
HSV-2 infection [13]
[units: participants]
           
Yes     482     449     455     438     465     2289  
No     520     548     551     566     531     2716  
Missing     5     6     3     3     7     24  
Bacterial vaginosis infection [14]
[units: participants]
           
Yes     422     410     401     397     393     2023  
No     578     592     607     606     604     2987  
Missing     7     1     1     4     6     19  
[1] Response to the question: What is your ethnic group or tribe?
[2] Country at time of enrollment
[3] Response to question: What is your highest level of education?
[4] Response to question: Do you earn an income of your own?
[5] Response to question: How many children have you given birth to who were alive at birth?
[6] Response to question: Are you currently married?
[7] Includes primary partner and at least 1 other male partner with which the participant has had vaginal sex in the past 3 months
[8] A response of 1 or more to the question: In the past 3 months how many times have you had anal sex?
[9] Response to question: What method(s) of contraception/family planning is the participant currently using? (Participant could indicate more than one method.)
[10] Testing was performed with the use of a strand-displacement amplification assay
[11] Testing was performed with the use of the OSOM Trichomonas Rapid Test
[12] Testing was performed with the use of a rapid plasma reagin screening test followed by a confirmatory microhemagglutinin assay
[13] HSV-2 seropositivity was determined with the use of the HerpeSelect 2 enzyme immunoassay at the time of enrollment; an index value of 3.5 or greater was considered to be a positive result.
[14] Bacterial vaginosis was determined by the Nugent score on Gram's staining of vaginal fluid (Nugent score 7-10).



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Person-years of Follow-up of Tenofovir 1% Gel and Vaginal Placebo Gel Arms   [ Time Frame: For up to 30 months of follow-up ]

2.  Primary:   Number of HIV-1 Infections of Tenofovir 1% Gel and Vaginal Placebo Gel Arms   [ Time Frame: For up to 30 months of follow-up ]

3.  Primary:   Incidence Rate of HIV-1 Infections of Tenofovir 1% Gel and Vaginal Placebo Gel Arms   [ Time Frame: For up to 30 months of follow-up ]

4.  Primary:   Person-years of Follow-up of Oral TDF and Oral Placebo Arms   [ Time Frame: For up to 30 months of follow-up ]

5.  Primary:   Number of HIV-1 Infections of Oral TDF and Oral Placebo Arms   [ Time Frame: For up to 30 months of follow-up ]

6.  Primary:   Incidence Rate of HIV-1 Infections of Oral TDF and Oral Placebo Arms   [ Time Frame: For up to 30 months of follow-up ]

7.  Primary:   Person-years of Follow-up of Oral TDF-FTC and Oral Placebo Arms   [ Time Frame: For up to 30 months of follow-up ]

8.  Primary:   Number of HIV-1 Infections of Oral TDF-FTC and Oral Placebo Arms   [ Time Frame: For up to 30 months of follow-up ]

9.  Primary:   Incidence Rate of HIV-1 Infections of Oral TDF-FTC and Oral Placebo Arms   [ Time Frame: For up to 30 months of follow-up ]

10.  Primary:   Extended Safety of Daily Tenofovir 1% Gel, Oral TDF, and Oral FTC/TDF in Women at Risk for Sexually Transmitted HIV Infection Based on Occurrence of Grade 2, 3, and 4 Adverse Events   [ Time Frame: Throughout study, up to 2.5 years ]

11.  Secondary:   Frequency of HIV-1 Drug Resistance in Women Who Acquire HIV-1 Infection While Using Study Product   [ Time Frame: Throughout study, up to 2.5 years ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
In September 2011, the oral TDF arm was discontinued for futility; in November 2011, the TFV gel and gel placebo arms were discontinued for futility. The TDF-FTC and oral placebo arms continued follow-up until the end of study in August 2012.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.


Results Point of Contact:  
Name/Title: Jeanne Marrazzo, MD, MPH, FACP, FIDSA
Organization: University of Washington
phone: 206-744-3679
e-mail: jmm2@uw.edu


Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00705679     History of Changes
Other Study ID Numbers: MTN-003 (VOICE)
10622 ( Registry Identifier: DAIDS ES )
MTN-003 ( Other Identifier: Microbicide Trials Network )
5U01AI068633-05 ( US NIH Grant/Contract Award Number )
VOICE ( Other Identifier: Microbicide Trials Network )
Study First Received: June 24, 2008
Results First Received: January 12, 2016
Last Updated: February 15, 2016
Health Authority: United States: Food and Drug Administration