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Trial record 79 of 126 for:    HSV-2

Effect of Tenofovir on Genital Herpes Simplex Virus (HSV) Shedding

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ClinicalTrials.gov Identifier: NCT01448616
Recruitment Status : Completed
First Posted : October 7, 2011
Results First Posted : January 12, 2016
Last Update Posted : January 12, 2016
Sponsor:
Collaborators:
CONRAD
Gilead Sciences
Information provided by (Responsible Party):
Anna Wald, University of Washington

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Herpes Simplex Type II
Interventions Drug: TDF
Drug: Placebo Vaginal Gel
Drug: Vaginal TFV Gel
Drug: Placebo Tablets
Enrollment 73
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Observational Group Oral TDF + Vaginal Placebo Gel Oral Placebo + Vaginal Tenofovir 1% Gel Placebo Oral + Placebo Vaginal Gel
Hide Arm/Group Description All enrolled participants completed 28 days of twice-daily genital swabbing for HSV DNA. Only women completing >90% of requested swabs were randomized. Women received daily TDF tablets at 300mg + "universal" placebo gel for daily application Participants received a matching oral placebo to study product and 40mg of TFV gel both to be used daily This group received the matching placebos to both study products
Period Title: Lead-In (Observational Phase)
Started 73 0 [1] 0 [1] 0 [1]
Completed 64 [2] 0 [3] 0 0
Not Completed 9 0 0 0
Reason Not Completed
Collected no genital swabs             3             0             0             0
Collected <90% of required swabs             6             0             0             0
[1]
N/A during observational phase as participants randomized subsequently
[2]
Participants who swabbed >90% completed this phase and were randomized to treatment 2:2:1.
[3]
completed >90% of sample collection to qualify for randomization for next phase
Period Title: Study Drug (Treatment Phase)
Started 0 [1] 24 27 13
Completed 0 22 23 9
Not Completed 0 2 4 4
Reason Not Completed
Adverse Event             0             1             1             0
Never initiated study drug             0             0             1             2
Withdrawal by Subject             0             1             2             2
[1]
All qualifying participants from this group moved to treatment group.
Arm/Group Title Oral TDF + Vaginal Placebo Gel Oral Placebo + Vaginal TFV Gel Oral Placebo + Vaginal Placebo Gel Total
Hide Arm/Group Description Participants randomized to receive 300mg Tenofovir Disaproxil Fumarate (TDF) 1 tab daily + the universal placebo vaginal gel (4ml) to be used daily. Participants randomized to receive matching oral placebo tab once daily + tenofovir (TFV) 1% vaginal gel (40mg in 4ml) to be used daily Participants received matching oral tab and placebo gel both to be used daily Total of all reporting groups
Overall Number of Baseline Participants 24 27 13 64
Hide Baseline Analysis Population Description
Participants were randomized 2:2:1 to one of the 3 treatment arms after completing the lead-in phase
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 27 participants 13 participants 64 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
24
 100.0%
27
 100.0%
13
 100.0%
64
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 24 participants 27 participants 13 participants 64 participants
39.1
(20.8 to 50.8)
36.7
(21.1 to 50.7)
41.0
(19.2 to 48.7)
37.3
(20.8 to 50.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 27 participants 13 participants 64 participants
Female
24
 100.0%
27
 100.0%
13
 100.0%
64
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 24 participants 27 participants 13 participants 64 participants
24 27 13 64
1.Primary Outcome
Title HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo
Hide Description The within-person changes in rate of HSV shedding during study drug administration (treatment phase) compared with the rate of HSV shedding during lead-in observation phase in the same participants. We evaluated only weeks 2-5 of HSV shedding during the treatment phase in comparison with the 4 weeks of the lead-in phase. We excluded the first week of samples from the treatment phase in order to allow for physiologic run-in of the treatment. This is analyzed separately for each treatment arm and not compared between arms.
Time Frame Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase
Hide Outcome Measure Data
Hide Analysis Population Description
This includes intent to treat, ( all randomized participants) and per-protocol analyses (persons receiving 30 or more days of treatment with >90% compliance as recorded by returned product counts)
Arm/Group Title Oral TDF + Vaginal Placebo Gel Oral Placebo + Vaginal TFV Gel Oral Placebo + Vaginal Placebo
Hide Arm/Group Description:

tenofovir disoproxil fumarate (TDF): Oral tenofovir will be administered as tablets. TDF (Viread®) tablets contain 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil. Study participants are instructed to take the one tablet, by mouth, once each day without regard to meals.

placebo gel: Study participants are instructed to insert one dose (the entire contents of one applicator) of product into the vagina once each day. They are instructed to insert their gel as close to the same time each day as possible.

The placebo gel (known as the 'universal' placebo gel) is formulated to minimize any possible effects — negative or positive — on study endpoints.

Tenofovir: Tenofovir 1% gel (w/w) is a gel formulation of tenofovir. Study participants are instructed to insert one dose (the entire contents of one applicator 40mg/4ml) of product into the vagina once each day. They are instructed to insert their gel as close to the same time each day as possible.

placebo tablets: TDF placebo tablets are film-coated and contain denatonium benzoate, a bittering agent, in addition to other inactive ingredients. Study participants are instructed to take the one tablet, by mouth, once each day without regard to meals.

placebo tablets: TDF placebo tablets are film-coated and contain denatonium benzoate, a bittering agent, in addition to other inactive ingredients. Study participants are instructed to take the one tablet, by mouth, once each day without regard to meals.

placebo gel: Study participants are instructed to insert one dose (the entire contents of one applicator) of product into the vagina once each day. They are instructed to insert their gel as close to the same time each day as possible.

The placebo gel (known as the 'universal' placebo gel) is formulated to minimize any possible effects — negative or positive — on study endpoints.

Overall Number of Participants Analyzed 24 27 13
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of swabs positive (%)
Lead-in Phase
22.9
(20.6 to 25.2)
13.8
(12.1 to 15.7)
21.3
(18.4 to 24.5)
Treatment Phase
19.5
(17.4 to 21.8)
12.0
(10.3 to 13.9)
20.4
(17.0 to 24.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oral TDF + Vaginal Placebo Gel
Comments For per protocol analysis
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments For per protocol analysis
Method Poisson GLME
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.60 to 0.91
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Oral Placebo + Vaginal TFV Gel
Comments This is the per-protocol analysis including only persons who completed >30 days of study drug with 90% or better compliance by returned product count
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.69
Comments For per protocol analysis
Method Poisson GLME
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.95
Confidence Interval (2-Sided) 95%
0.74 to 1.22
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Oral Placebo + Vaginal Placebo
Comments This is the per-protocol analysis including only persons who completed >30 days of study drug with 90% or better compliance by returned product count
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.11
Comments [Not Specified]
Method Poisson GLME
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.78
Confidence Interval (2-Sided) 95%
0.57 to 1.07
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Within-person Changes in Log-copy Numbers of HSV
Hide Description

The within-person changes in mean log-copy numbers of HSV shed during treatment phase (oral TDF, vaginal TFV, or double placebo) compared with the lead-in (observation) phase in the same participants. Each treatment arm is analyzed separately without comparison between arms.

We evaluated only weeks 2-5 of HSV shedding during the treatment phase in comparison with the 4 weeks of the lead-in phase. We excluded the first week of samples from the treatment phase in order to allow for physiologic run-in of the treatment.

Time Frame Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis is within person changes such that the observational group contributed to analyses of those persons in each treatment randomization group
Arm/Group Title Oral TDF + Vaginal Placebo Gel Oral Placebo + Vaginal Tenofovir 1% Gel Placebo Oral + Placebo Vaginal Gel
Hide Arm/Group Description:
Women received daily TDF tablets at 300mg + "universal" placebo gel for daily application
Participants received a matching oral placebo to study product and 40mg of TFV gel both to be used daily
This group received the matching placebos to both study products
Overall Number of Participants Analyzed 24 27 13
Mean (95% Confidence Interval)
Unit of Measure: log-copy number of HSV DNA shed
Lead-in Phase
4.02
(3.21 to 5.29)
4.47
(2.92 to 6.24)
3.71
(2.78 to 5.54)
Treatment Phase
4.11
(3.23 to 5.39)
4.40
(3.37 to 5.13)
4.22
(3.35 to 5.45)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oral TDF + Vaginal Placebo Gel
Comments For per protocol analysis
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method Linear Mixed Effects Model
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Oral Placebo + Vaginal Tenofovir 1% Gel
Comments For per protocol analysis
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method Linear Mixed Effects Model
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo Oral + Placebo Vaginal Gel
Comments for Per protocol only
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.42
Comments [Not Specified]
Method Linear Mixed Effects Model
Comments [Not Specified]
3.Secondary Outcome
Title Genital Lesion Rate
Hide Description

The within person change in proportion of days with lesions between the lead-in (observational) and study drug (treatment) phase for each arm separately. No between arm comparisons were performed. We include intent to treat with all randomized participants as well as per protocol (persons receiving study drug for at least 30 days with 90% or better reported compliance per returned product counts).

We evaluated only weeks 2-5 of HSV shedding during the treatment phase in comparison with the 4 weeks of the lead-in phase. We excluded the first week of samples from the treatment phase in order to allow for physiologic run-in of the treatment.

Time Frame Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Oral TDF + Vaginal Placebo Gel Oral Placebo + Vaginal Tenofovir 1% Gel Placebo Oral + Placebo Vaginal Gel
Hide Arm/Group Description:
Women received daily TDF tablets at 300mg + "universal" placebo gel for daily application
Participants received a matching oral placebo to study product and 40mg/4ml of TFV gel both to be used daily
This group received the matching placebos to both study products
Overall Number of Participants Analyzed 24 27 13
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of days with lesions (%)
Lead-in Phase
11.8
(9.5 to 14.5)
8.7
(6.8 to 10.9)
13.6
(10.3 to 17.5)
Treatment Phase
11.6
(9.3 to 13.3)
7.1
(5.3 to 9.2)
14.7
(10.7 to 19.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oral TDF + Vaginal Placebo Gel
Comments Per protocol analysis
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.032
Comments [Not Specified]
Method Poisson GLME
Comments [Not Specified]
4.Secondary Outcome
Title Asymptomatic Shedding (Shedding on Days Without Genital Lesions)
Hide Description

Within person changes in shedding on days without lesions between the lead-in (observational) phase and the study drug (treatment) phase. Each arm is evaluated separately and no inter arm comparisons are made.

We evaluated only weeks 2-5 of HSV shedding during the treatment phase in comparison with the 4 weeks of the lead-in phase. We excluded the first week of samples from the treatment phase in order to allow for physiologic run-in of the treatment.

Time Frame Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants are included in ITT analysis. Per protocol analysis includes persons receiving 30 or more days of study drug with >90% adherence as documented by returned product counts.
Arm/Group Title Oral TDF + Vaginal Placebo Gel Oral Placebo + Vaginal Tenofovir 1% Gel Placebo Oral + Placebo Vaginal Gel
Hide Arm/Group Description:
Women received daily TDF tablets at 300mg + "universal" placebo gel for daily application
Participants received a matching oral placebo to study product and 40mg of TFV gel both to be used daily
This group received the matching placebos to both study products
Overall Number of Participants Analyzed 24 27 13
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: % days with asymptomatic shedding
Lead-in Phase
17.5
(15.4 to 19.9)
7.6
(6.2 to 9.1)
14.4
(11.7 to 17.4)
Treatment Phase
13.7
(11.8 to 15.8)
8.2
(6.8 to 9.9)
12.1
(9.2 to 15.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oral TDF + Vaginal Placebo Gel
Comments per protocol only here
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.032
Comments [Not Specified]
Method Poisson GLME
Comments [Not Specified]
Time Frame Adverse Events were collected during the course of the lead-in phase (4 weeks) and the treatment (study drug) phase (5 weeks) and final AEs were recorded at a post-treatment follow up telephone visit 2 weeks after completing the study products.
Adverse Event Reporting Description

Unscheduled study visits were conducted as needed to evaluate potential adverse events.

Adverse events were systematically collected in daily participant diaries and queried at each biweekly study visit.

 
Arm/Group Title Observational Group Oral TDF + Vaginal Placebo Gel Oral Placebo + Vaginal Tenofovir 1% Gel Placebo Oral + Placebo Vaginal Gel
Hide Arm/Group Description All enrolled participants completed 28 days of twice-daily genital swabbing for HSV DNA. Only women completing >90% of requested swabs were randomized. Women received daily TDF tablets at 300mg + "universal" placebo gel for daily application Participants received a matching oral placebo to study product and 40mg of TFV gel both to be used daily This group received the matching placebos to both study products
All-Cause Mortality
Observational Group Oral TDF + Vaginal Placebo Gel Oral Placebo + Vaginal Tenofovir 1% Gel Placebo Oral + Placebo Vaginal Gel
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Observational Group Oral TDF + Vaginal Placebo Gel Oral Placebo + Vaginal Tenofovir 1% Gel Placebo Oral + Placebo Vaginal Gel
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/73 (0.00%)   0/24 (0.00%)   0/27 (0.00%)   0/13 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Observational Group Oral TDF + Vaginal Placebo Gel Oral Placebo + Vaginal Tenofovir 1% Gel Placebo Oral + Placebo Vaginal Gel
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   11/73 (15.07%)   12/24 (50.00%)   11/27 (40.74%)   3/13 (23.08%) 
Gastrointestinal disorders         
Diarrhea  1  0/73 (0.00%)  5/24 (20.83%)  0/27 (0.00%)  0/13 (0.00%) 
Nausea  1  0/73 (0.00%)  3/24 (12.50%)  0/27 (0.00%)  0/13 (0.00%) 
Abdominal Pain  1  0/73 (0.00%)  3/24 (12.50%)  0/27 (0.00%)  0/13 (0.00%) 
Infections and infestations         
Candida Intertrigo  1  0/73 (0.00%)  0/24 (0.00%)  0/27 (0.00%)  1/13 (7.69%) 
Nervous system disorders         
Headache  1 [1]  0/73 (0.00%)  3/24 (12.50%)  4/27 (14.81%)  0/13 (0.00%) 
Reproductive system and breast disorders         
Vulvovaginitis  1  2/73 (2.74%)  1/24 (4.17%)  2/27 (7.41%)  1/13 (7.69%) 
Vulvovaginal pruritis  1  1/73 (1.37%)  1/24 (4.17%)  1/27 (3.70%)  2/13 (15.38%) 
Vulvovaginal burning  1  0/73 (0.00%)  0/24 (0.00%)  2/27 (7.41%)  0/13 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Upper Respiratory Viral Illness  1  8/73 (10.96%)  4/24 (16.67%)  2/27 (7.41%)  0/13 (0.00%) 
Skin and subcutaneous tissue disorders         
Skin Irritation  1  0/73 (0.00%)  0/24 (0.00%)  0/27 (0.00%)  1/13 (7.69%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (10.0)
[1]
Including previously diagnosed migraine
The study was not powered to detect differences in lesion rate; the study was appropriately powered to detect a 50% decrease in viral shedding only, and therefore may have been underpowered to detect significant findings for secondary outcomes.
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
Layout table for Results Point of Contact information
Name/Title: Rachel Bender Ignacio, MD MPH
Organization: University of Washington
Phone: 2065204340
EMail: rbi13@uw.edu
Layout table for additonal information
Responsible Party: Anna Wald, University of Washington
ClinicalTrials.gov Identifier: NCT01448616     History of Changes
Other Study ID Numbers: 41250-J
First Submitted: September 14, 2011
First Posted: October 7, 2011
Results First Submitted: August 5, 2015
Results First Posted: January 12, 2016
Last Update Posted: January 12, 2016