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| Name | Class |
|---|---|
| CONRAD | OTHER |
| Gilead Sciences | INDUSTRY |
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The investigators propose a randomized, double blind, placebo-controlled, cross-over trial to evaluate the effect of oral and topical (vaginal gel) tenofovir on genital herpes simplex virus (HSV) shedding among herpes simplex virus type-2 (HSV-2) seropositive, human immunodeficiency virus (HIV) seronegative women. The investigators hypothesize that tenofovir will reduce genital HSV shedding compared to placebo.
The investigators propose a randomized, double-blind, placebo-controlled, cross-over study of 55 adult, healthy women who are HSV-2 seropositive and HIV-1 seronegative. Women will first participate in a run-in phase with twice daily swabbing. Following 4 weeks of swabbing, participants will be randomized 2:2:1 to one of three groups: 1) oral tenofovir and placebo gel, 2) oral placebo and tenofovir gel, or 3) oral placebo and placebo gel. Participants will begin treatment and swab the genital region twice daily for 5 more weeks. Study drug will be administered daily.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Run-in Phase | No Intervention | Women will first participate in a run-in phase with twice daily swabbing. | |
| Study Drug Phase: TDF | Experimental | Participants will take tenofovir disoproxil fumarate (TDF) tablets and apply a placebo vaginal gel. Participants will begin treatment and swab the genital region twice daily for 5 more weeks. Study drugs will be administered once daily. |
|
| Study Drug Phase: Vaginal TFV Gel | Experimental | Participants will take oral placebo tablets and apply a tenofovir 1% (TFV) vaginal gel. Participants will begin treatment and swab the genital region twice daily for 5 more weeks. Study drugs will be administered once daily. |
|
| Study Drug Phase: Double Placebo | Placebo Comparator | Participants will take oral placebo tablets and apply a placebo vaginal gel. Participants will begin treatment and swab the genital region twice daily for 5 more weeks. Study drugs will be administered once daily. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TDF | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo | 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. | Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase |
| Measure | Description | Time Frame |
|---|---|---|
| Within-person Changes in Log-copy Numbers of HSV | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Anna Wald, MD, MPH | University of Washington | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Washington Virology Research Clinic | Seattle | Washington | 98104 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26265463 | Derived | Johnston C, Harrington R, Jain R, Schiffer J, Kiem HP, Woolfrey A. Safety and Efficacy of Combination Antiretroviral Therapy in Human Immunodeficiency Virus-Infected Adults Undergoing Autologous or Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies. Biol Blood Marrow Transplant. 2016 Jan;22(1):149-56. doi: 10.1016/j.bbmt.2015.08.006. Epub 2015 Aug 8. | |
| 26044291 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Observational Group | All enrolled participants completed 28 days of twice-daily genital swabbing for HSV DNA. Only women completing >90% of requested swabs were randomized. |
| FG001 | Oral TDF + Vaginal Placebo Gel | Women received daily TDF tablets at 300mg + "universal" placebo gel for daily application |
| FG002 | Oral Placebo + Vaginal Tenofovir 1% Gel | Participants received a matching oral placebo to study product and 40mg of TFV gel both to be used daily |
| FG003 | Placebo Oral + Placebo Vaginal Gel | This group received the matching placebos to both study products |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Lead-In (Observational Phase) |
|
| ||||||||||||||||||
| Study Drug (Treatment Phase) |
|
Participants were randomized 2:2:1 to one of the 3 treatment arms after completing the lead-in phase
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| ID | Title | Description |
|---|---|---|
| BG000 | Oral TDF + Vaginal Placebo Gel | Participants randomized to receive 300mg Tenofovir Disaproxil Fumarate (TDF) 1 tab daily + the universal placebo vaginal gel (4ml) to be used daily. |
| BG001 | Oral Placebo + Vaginal TFV Gel |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | HSV Shedding Rate in Those Receiving Oral TDF, Vaginal TFV, or Double Placebo | 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. | This is the intent-to-treat population (all randomized participants returning at least 1 swab in each phase of study) | Posted | Number | 95% Confidence Interval | percentage of swabs positive (%) | Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase |
|
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.
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Observational Group | All enrolled participants completed 28 days of twice-daily genital swabbing for HSV DNA. Only women completing >90% of requested swabs were randomized. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Rachel Bender Ignacio, MD MPH | University of Washington | 2065204340 | rbi13@uw.edu |
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| ID | Term |
|---|---|
| D000068698 | Tenofovir |
| D014622 | Vaginal Creams, Foams, and Jellies |
| ID | Term |
|---|---|
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D009930 | Organic Chemicals |
| D000225 | Adenine |
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|
|
| Placebo Vaginal Gel | Drug | 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. |
|
|
| Vaginal TFV Gel | Drug | 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) 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 | Drug | 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. |
|
|
| Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase |
| Genital Lesion Rate | 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. | Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase |
| Asymptomatic Shedding (Shedding on Days Without Genital Lesions) | 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. | Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase |
| Derived |
| Bender Ignacio RA, Perti T, Magaret AS, Rajagopal S, Stevens CE, Huang ML, Selke S, Johnston C, Marrazzo J, Wald A. Oral and Vaginal Tenofovir for Genital Herpes Simplex Virus Type 2 Shedding in Immunocompetent Women: A Double-Blind, Randomized, Cross-over Trial. J Infect Dis. 2015 Dec 15;212(12):1949-56. doi: 10.1093/infdis/jiv317. Epub 2015 Jun 4. |
| Collected <90% of required swabs |
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
Participants randomized to receive matching oral placebo tab once daily + tenofovir (TFV) 1% vaginal gel (40mg in 4ml) to be used daily
| BG002 | Oral Placebo + Vaginal Placebo Gel | Participants received matching oral tab and placebo gel both to be used daily |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
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.
| OG001 | Oral Placebo + Vaginal TFV Gel | 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. |
| OG002 | Oral Placebo + Vaginal Placebo | 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. |
|
|
|
| Secondary | Within-person Changes in Log-copy Numbers of HSV | 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. | Analysis is within person changes such that the observational group contributed to analyses of those persons in each treatment randomization group | Posted | Mean | 95% Confidence Interval | log-copy number of HSV DNA shed | Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase |
|
|
|
|
| Secondary | Genital Lesion Rate | 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. | Posted | Number | 95% Confidence Interval | percentage of days with lesions (%) | Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase |
|
|
|
|
| Secondary | Asymptomatic Shedding (Shedding on Days Without Genital Lesions) | 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. | 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. | Posted | Number | 95% Confidence Interval | % days with asymptomatic shedding | Comparison of 4 weeks of treatment phase with 4 weeks of lead-in phase |
|
|
|
|
| 0 |
| 73 |
| 11 |
| 73 |
| EG001 | Oral TDF + Vaginal Placebo Gel | Women received daily TDF tablets at 300mg + "universal" placebo gel for daily application | 0 | 24 | 12 | 24 |
| EG002 | Oral Placebo + Vaginal Tenofovir 1% Gel | Participants received a matching oral placebo to study product and 40mg of TFV gel both to be used daily | 0 | 27 | 11 | 27 |
| EG003 | Placebo Oral + Placebo Vaginal Gel | This group received the matching placebos to both study products | 0 | 13 | 3 | 13 |
| Headache | Nervous system disorders | MedDRA (10.0) | Systematic Assessment | Including previously diagnosed migraine |
|
| Nausea | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Candida Intertrigo | Infections and infestations | MedDRA (10.0) | Systematic Assessment |
|
| Vulvovaginitis | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Vulvovaginal pruritis | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Vulvovaginal burning | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Skin Irritation | Skin and subcutaneous tissue disorders | MedDRA (10.0) | Systematic Assessment |
|
| Abdominal Pain | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Upper Respiratory Viral Illness | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
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| D011687 |
| Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
| D053566 | Feminine Hygiene Products |
| D004864 | Equipment and Supplies |
|
| 0.008 |
| Change in log copies |
| -0.50 |
| 2-Sided |
| 95 |
| -0.86 |
| -0.13 |
| Superiority or Other (legacy) |
| Intent to treat analysis | Linear Mixed Effects Model | 0.45 | Change in log copies | 0.16 | 2-Sided | 95 | -0.27 | 0.60 | Superiority or Other (legacy) |
|
| 0.25 |
| Risk Ratio (RR) |
| 0.80 |
| 2-Sided |
| 95 |
| 0.54 |
| 1.18 |
| Superiority |
| Poisson GLM | 0.82 | Risk Ratio (RR) | 0.95 | 2-Sided | 95 | 0.57 | 1.57 | Superiority |
|
| Risk Ratio (RR) |
| 1.30 |
| 2-Sided |
| 95 |
| 0.9 |
| 1.76 |
| Superiority |
| Intent to treat analysis | Poisson GLM | 0.47 | Risk Ratio (RR) | 0.90 | 2-Sided | 95 | 0.67 | 1.22 | Superiority |