The ADAPT Study: Use of Emtricitabine and Tenofovir Disoproxil Fumarate for Pre-Exposure Prophylaxis (PrEP)

Study Overview
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Brief Summary
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Pre-exposure prophylaxis (PrEP) is a method of preventing HIV infection through the use of antiretroviral (ARV) medications before exposure to HIV. This study will examine the feasibility of different methods of dosing for a PrEP regimen. Three methods of delivery will be compared: daily, time-based, and event-based.

Detailed Description
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No single strategy for the prevention of HIV has emerged as consistently used and successful, so multiple strategies have been developed. PrEP involves delivering ARV medications to people before they are exposed to HIV, in order to prevent infection. The optimal method of delivering PrEP has not yet been determined. This study will examine the feasibility of delivering PrEP in three methods. Daily dosing involves receiving ARV medications every day; time-driven dosing involves receiving ARV medications twice weekly plus a post-exposure dose; and event-driven dosing involves receiving ARV medications before and after a potential exposure to HIV. The ARV medication that will be used in this study is a combination pill that contains emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). Recent research studies have shown that, if taken consistently, a daily oral dose of FTC/TDF can reduce the risk of HIV infection. This study will enroll HIV-uninfected men who have sex with men and transgender women (MSM/TGW) and women who have sex with men (WSM). Participation will last 34 weeks. All participants will be given a combination pill that contains FTC/TDF. For the first 5 weeks, all participants will come to the study clinic weekly to receive a single dose of FTC/TDF. At Week 6, participants will be randomly assigned to one of three groups. In the daily dosing group, participants will take FTC/TDF once a day. In the time-dosing group, participants will take FTC/TDF twice per week and another dose after sexual intercourse (a post-exposure dose). In the event-dosing group, participants will take FTC/TDF before and after sexual intercourse. During this part of the study, participants will be given FTC/TDF to take on their own. Every week, from Week 6 to Week 29, study officials will call to ask questions about how many pills participants have taken and when they have had sexual intercourse. Participants will also complete computer-assisted self-interviews (CASIs). Study visits will occur at enrollment, once a week for the first 5 weeks, and then once a month until Week 34. Assessment will include recording of medical history, completing an interview about sexual practices and background, and collection of blood, urine, and hair samples. Select study visits will include vaginal practices assessment (including use of lubricants and vaginal cleansing practices), family planning assessments (for women), and sex hormones assessments (for men). Participants who acquire HIV infection during the study will discontinue study product. These participants will continue to be followed after enrollment at Weeks 4, 6, 10, 14, 18, 22, 26, 30, and every 12 weeks thereafter, as appropriate, until the last study participant completes follow-up at the study site. Participants whose first reactive HIV rapid test is at Week 34 who are later confirmed to be HIV infected will also be followed every 12 weeks after their Week 30 visit until the last study participant completes follow-up at the study site. Participants who acquire HIV infection during the study will undergo select protocol procedures and will receive counseling and referrals for HIV treatment.

Official Title
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The ADAPT Study: A Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use of Intermittent Oral Emtricitabine/Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis (PrEP) Pre-Exposure Prophylaxis (PrEP)

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Daily dosing
* Drug: Time-driven dosing
* Drug: Event-driven dosing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Literacy in one of the study languages (Thai, Xhosa, and/or English) Able to provide written informed consent Able to provide weekly telephonic updates Within 70 days of enrollment: Serum creatinine less than or equal to the upper limit of normal (ULN) and calculated creatinine clearance of at least 70 mL/min by the Cockcroft-Gault formula. More information on this criterion can be found in the protocol. Serum phosphate greater than or equal to the lower limit of normal (LLN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2 times ULN Hemoglobin greater than 10 g/dL Hepatitis B surface antigen (HBsAg)-negative Willing and able to provide adequate locator information Inclusion Criteria for MSM/TGW: Male at birth Reporting anal intercourse and/or receptive neovaginal intercourse with at least one man or transgender woman in the past 6 months One or more of the following risk factors for HIV acquisition in the past 6 months according to self-report: sexual intercourse with more than one man or transgender woman; history of an acute sexually transmitted infection (STI); sex in exchange for money, goods, or favors; condomless intercourse (oral, anal, vaginal, or neovaginal) with a partner known to be HIV-infected or of unknown HIV infection status according to self report Inclusion Criteria for Women Who Have Sex With Men (WSM): Female at birth or self identify as female Not pregnant or breastfeeding Not able to or not intending to become pregnant during the next year If able to become pregnant, self reported use of an effective method of contraception at Enrollment, and intending to use an effective method for the next 34 weeks One or more of the following risk factors for HIV acquisition in the past 6 months according to self report: sexual intercourse with more than one man; history of an acute STI; sex in exchange for money, goods or favors; condomless intercourse (oral, anal, or vaginal) with a partner known to be HIV-infected or of unknown HIV infection status Exclusion Criteria: Proteinuria 2+ or greater at screening Glucosuria 2+ or greater at screening Serious and active medical or mental illness One or both HIV rapid tests is reactive at screening or enrollment, regardless of subsequent HIV diagnostic test results Signs or symptoms suggestive of acute HIV infection Use of hypoglycemic agents for diabetes or agents with known nephrotoxic potential Use of ARV therapy (e.g., for post-exposure prophylaxis [PEP] or PrEP) in the 90 days prior to study entry Serum phosphate level below site laboratory LLN Current participation (or participation within 3 months of screening) in any HIV prevention study Previous or current participation in the active arm of an HIV vaccine trial Acute or chronic hepatitis B (HBV) infection (refers to chronic active HBV infection evidenced by a positive test for hepatitis B surface antigen (HBsAg) Presence of a psychological or social condition or an addictive disorder that would preclude compliance with the protocol Any other reason or condition that in the opinion of the investigator would interfere with participation, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: One arm is daily TDF/FTC. One arm is twice weekly TDF/FTC with a post-exposure dose. One arm is as needed TDF/FTC with a post-exposure dose.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Daily dosing<br>Participants will receive oral FTC/TDF daily. | Drug: Daily dosing<br>* A fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate.<br>* Other names: TDF/FTC;|
| Experimental: Time-driven dosing<br>Participants will receive oral FTC/TDF twice weekly with a post-exposure dose. | Drug: Time-driven dosing<br>* TDF/FTC twice weekly with a post-exposure dose<br>* Other names: A fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate.;|
| Experimental: Event-driven dosing<br>Participants will receive oral FTC/TDF before and after a potential exposure to HIV infection. | Drug: Event-driven dosing<br>* TDF/FTC as needed with a post exposure dose<br>* Other names: A fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Sexual Exposures Covered by Pre- and Post-exposure Dosing | Coverage will be determined based on the adjusted electronic and self-reported pill-use data. Specifically, a sex act will be considered as covered if at least one pill is taken 96 hours prior the sexual activity and at least one additional pill is taken within 24 hours after the sexual activity. If participant only took pill before the sexual activity (within 96 hours), but no pill taken after sexual activity (within 24 hours), then we considered it as pre-exposure covered. likewise, if participant only took pill after sexual activity (within 24 hours), but did not taken pill before sexual activity (within 96 hours), then we considered it as post-exposure covered. If participant did not taken pill before and after sexual activity, then it was considered as not covered. Note that the same pill can be both pre-exposure dose and a post-exposure dose if events are closely spaced. At no time should a participant in the intermittent arm be taking more pills than the daily arm. | From week 6 (randomization week) to week 30 (end of self-administered dosing) | 
| The (Minimum) Total Number of Pills Needed for 100% Coverage Over the Follow-up Period (Based on Randomization Arm and Self-reported Sexual History in the Weekly Interviews) | Below I reported the number of sex acts as reported based on the adjusted electronic and self-reported sexual activity data, also the number of pills needed for 100% coverage. 100% coverage means all sex events (excluding oral sex) are covered; Note: sex act is considered as covered if at least one pill is taken 96 hours prior the sexual activity and at least one additional pill is taken within 24 hours after the sexual activity (same coverage definition for all three arms) | From week 6 (randomization week) to week 30 (end of self-administered dosing) | 
| The Total Pills Actually Used Over the Follow-up Period | The total pills actually used over the follow-up period was calculated based on the adjusted electronic and self-reported pill-use data. It could be more or less than required by study design | From week 6 (randomization week) to week 30 (end of self-administered dosing) | 
| Self-reported Side Effect or Symptom Scores | The self-reported symptom/side effect scores for common symptoms/side effects including headache, dizziness, cramping, abdominal pain, and flatulence. Collected during clinic visits. All the presented numbers are the percent of visits with each side effects | From week 6 (randomization week) to week 30 (end of self-administered dosing) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of TFV-DP (Tenofovir Diphosphate) in PBMC (Peripheral Blood Mononuclear Cell) | Below we presented the percentages of total cohort with TFV-DP concentrations consistent with >=2 pills/week in women who also report sex in the last 7 day for each arm. For Cape Town and Bangkok, TFV-DP in PBMC was analyzed, for Harlem site, the TFV-DP in DBS (dried blood spot) was analyzed. Note: PBMC >5.2 fmol/10^6 cells is considered as participants taken >=2 tablets per week; DBS >=326 fmol/punch is considered as participants taken >=2 tablets per week | week 10, 18 and 30, which is 4 weeks, 12 weeks, and 24 weeks after randomization | 
| A Listing of Adverse Events (AEs) by Grade, Relationship to Study Product, and Arm | Only the listing of adverse events (AEs) by grade and arm are presented here. See outcome measure 10 for the listing of AE by relationship to study product | From week 6 (randomization week) to week 30 (end of self-administered dosing) | 
| A Listing, by Arm, of Drug Resistance Test Results and Plasma HIV RNA Levels Among All Participants Who Seroconvert While on Study | Only the cross table between drug resistance by arm are presented here. See outcome measure 11 for the listing of plasma HIV RNA levels, and outcome measure 12 for the listing of drug resistance test by arm among all participants who seroconvert while on study. | From enrollment to week 30 (end of self-administered dosing) | 
| The Percentage of Correctly Timed Adherence (Number of Pills Taken Within the Recommended Time Frame/Number of Pills Recommended) During 24 Weeks of Follow-up Based on Weekly Interviews and Adjusted EDM (Electronic Drug Monitoring) Data |  | From week 6 (randomization week) to week 30 (end of self-administered dosing) | 
| The Proportion of Participants Who Discontinue All PrEP Use Based on Self-report Via CASI or Weekly Interviews |  | From Week 6 to Week 30 | 
| A Listing of Adverse Events (AEs) by Grade, Relationship to Study Product, and Arm | Only the listing of AE related to study product are presented here. See outcome measure 6 for the listing of adverse events (AEs) by grade and arm. | From week 6 (randomization week) to week 30 (end of self-administered dosing) | 
| A Listing, by Arm, of Drug Resistance Test Results and Plasma HIV RNA Levels Among All Participants Who Seroconvert While on Study | Only the listing of plasma HIV RNA levels among all participants who seroconvert while on study are presented here. See outcome measure 12 for the listing of drug resistance test by arm. | From Enrollment to week 30 (end of self-administered dosing) | 
| A Listing, by Arm, of Drug Resistance Test Results and Plasma HIV RNA Levels Among All Participants Who Seroconvert While on Study | Only the listing of drug resistance test by arm among all participants who seroconvert while on study are presented here. See outcome measure 11 for the listing of plasma HIV RNA levels | From Enrollment to week 30 (end of self-administered dosing) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Administration Schedule, Nucleoside Reverse Transcriptase Inhibitors, Pharmacokinetics