An Open Label Demonstration Project and Phase II Safety Study of Pre-Exposure Prophylaxis Use Among 15 to 17 Year Old Young Men Who Have Sex With Men (YMSM)

Study Overview
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Brief Summary
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Approximately 100 HIV-uninfected YMSM at high risk of acquiring HIV infection, between the ages of 15 and 17 inclusive will be enrolled across all participating Adolescent Medicine Trial Units (AMTUs). Subjects will complete the behavioral intervention selected by all participating sites, Personalized Cognitive Counseling (PCC), and will then be provided with open label emtricitabine (FTC)/tenofovir (TDF) (Truvada®) as pre-exposure prophylaxis (PrEP). Behavioral and biomedical data will be collected at baseline and at 0, 4, 8, 12, 24, 36 and 48 weeks. Any subject who becomes HIV infected during the course of the study will be discontinued from the study agent and be followed for an additional 24 weeks after the study visit at which HIV infection is confirmed. Those subjects who meet specific bone or renal criteria at the Week 48 visit or the 24-Week HIV Seropositive visit will be followed for an additional 48 weeks in the Extension Phase to monitor longer-term outcomes of potential concerns.

Detailed Description
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The aims of the study are to obtain additional data on the safety of FTC/TDF (Truvada®) and to evaluate acceptability, patterns of use, rates of adherence, and measured levels of drug exposure when YMSM are provided with open label FTC/TDF (Truvada®) and information regarding safety and efficacy of FTC/TDF (Truvada®) as PrEP based on prior studies in adults. The study will also examine patterns of sexual risk behavior among HIV-uninfected YMSM in the U.S. at high risk of acquiring HIV infection who are provided with open label FTC/TDF (Truvada®) as PrEP. The study will also explore the feasibility and acceptability of implementing an efficacious risk reduction behavioral intervention prior to the provision of PrEP- PCC. The inclusion of a behavioral intervention in this project not only addresses the ethical responsibility of providing at least the minimum risk reduction education to all subjects given the high HIV risk of the study population, but also builds behavioral skills to assist subjects in reducing their risk when not taking PrEP. Furthermore, the study will evaluate the process of protocol implementation to better understand how to best implement PrEP research and program practice at adolescent medicine sites, including an evaluation of consent procedures and the acceptability/feasibility of allowing youth minors to consent for their own participation in HIV prevention intervention, to the extent allowable by local laws and regulations, and to allow youth minor participation in a clinical trial without requiring disclosure of their sexual orientation and risk behaviors to their parents or legal guardians.

Official Title
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Project PrEPare - An Open Label Demonstration Project and Phase II Safety Study of Pre-Exposure Prophylaxis Use Among 15 to 17 Year Old Young Men Who Have Sex With Men (YMSM) in the United States

Conditions
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HIV Infection

Intervention / Treatment
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* Behavioral: PCC
* Drug: Emtricitabine/tenofovir (FTC/TDF (Truvada®))


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent; Male gender at birth; Age 15 years and 0 days through 17 years and 364 days, inclusive, at the time of signed informed consent; Self reports evidence of high risk for acquiring HIV infection including at least one of the following: At least one episode of unprotected anal intercourse with an HIV-infected male partner or a male partner of unknown HIV status during the last 6 months; Anal intercourse with 3 or more male sex partners during the last 6 months; Exchange of money, gifts, shelter, or drugs for anal sex with a male partner during the last 6 months; Sex with a male partner and has had a sexually transmitted infection (STI) during the last 6 months or at screening; Sexual partner of an HIV-infected man with whom condoms were not consistently used in the last 6 months; or At least one episode of anal intercourse where the condom broke or slipped off during the last 6 months; Tests HIV antibody negative at time of screening; Willing to provide locator information to study staff; Willing to take PrEP; Willing to participate in behavioral intervention; Reports intention not to relocate out of AMTU study area during the course of the study; and Does not have a job or other obligations that would require long absences from AMTU study area (greater than 4 weeks at a time). Exclusion Criteria: Appears visibly distraught or presence of active serious psychiatric symptoms (e.g., active hallucinations, suicidal, homicidal, or exhibiting violent behavior) at the time of consent; Intoxicated or under the influence of alcohol or other drugs at the time of consent; Any significant uncontrolled, active or chronic disease process that, in the judgment of the site investigator, would make participation in the study inappropriate. (Appropriately managed conditions, like well-controlled diabetes, would not preclude enrollment; the site is encouraged to contact the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) 113 Protocol Team if they are having difficulty making the judgment.); History of bone fractures not explained by trauma; Acute or chronic hepatitis B infection as indicated by positive hepatitis B surface antigen (sAg) test at time of screening; Confirmed renal dysfunction (Creatinine Clearance (CrCl) < 75 ml/min calculated based on bedside Schwartz formula: Glomerular filtration rate (GFR) = (0.413 x (height in centimeters)) / (serum creatinine in mg/dl)), or serum creatinine > upper limit of normal (ULN), or history of renal parenchymal disease or presence of only one kidney at time of screening; Confirmed ≥ Grade 2 hypophosphatemia at time of screening; Confirmed ≥ Grade 2 hematologic system abnormality (White Blood Count (WBC), Absolute Neutrophil Count (ANC), hemoglobin, or platelets) at time of screening; Confirmed ≥ Grade 2 hepatobiliary system abnormality (Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), or bilirubin) at time of screening; Confirmed proteinuria as indicated by urine dipstick result ≥ 1+ at time of screening, regardless of urine protein to creatinine ratio (UP/C); UP/C > 0.37 g/g at time of screening, regardless of urine dipstick protein result; Confirmed normoglycemic glucosuria as indicated by urine dipstick result ≥ 1+ in the presence of normal serum glucose (<120 mg/dL) at time of screening; A confirmed Grade ≥ 3 toxicity on any screening evaluations; Known allergy/sensitivity to the study agent or its components; Concurrent participation in an HIV vaccine study or other investigational drug study, including oral or topical PrEP (microbicide) studies; Use of disallowed medications; or Inability to understand spoken English.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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Male

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PCC Behavioral Intervention Group<br>PCC Behavioral Intervention combined with open label FTC/TDF (Truvada®) as PrEP | Behavioral: PCC<br>* Personalized Cognitive Counseling (PCC) is based on the Model of Relapse Prevention and Gold's Self-Appraisal of Risk Behavior. PCC is a 1-hour, single-session, individual level intervention administered by a trained counselor in a clinic setting. Counselors ask the client to recall and describe a recent encounter of unprotected anal sex with another man of unknown or sero-discordant HIV status. The client then identifies and expresses thoughts, feelings, or attitudes that might have led to the high-risk behavior. The client and counselor examine and identify thoughts that may have led the client to decide to engage in high transmission risk sex. The client and counselor agree on strategies that can be used to deal with similar situations in the future.<br>* Other names: Personalized Cognitive Counseling;Drug: Emtricitabine/tenofovir (FTC/TDF (Truvada®))<br>* All subjects will be provided with daily FTC/TDF (Truvada®) as Pre-exposure prophylaxis (PrEP) for 48 weeks.<br>* Other names: PrEP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serum Creatinine Event of Grade 1 or Higher Over the Course of the Study | This represents one of the indicators associated with the objective: Additional safety data regarding FTC/TDF (Truvada®) use among HIV-uninfected YMSM. Participants were assessed for any serum creatinine event of Grade 1 or higher over the course of the study (Week 0 through Week 48). | 48 weeks | 
| Lumbar Spine Bone Mineral Density: Percent Change From Baseline to Week 48 | The percent change in lumbar spine BMD from baseline measurement to Week 48 is calculated as: Percent change= [(Value at Week 48 - Value at Baseline)/(Value at Baseline)] x 100 This represents one of the indicators associated with the objective: Additional safety data regarding FTC/TDF (Truvada®) use among HIV-uninfected YMSM. | Baseline, Week 48 | 
| Femoral Neck Bone Mineral Density: Percent Change From Baseline to Week 48 | The percent change in femoral neck BMD from baseline measurement to Week 48 is calculated as: Percent change= [(Value at Week 48 - Value at Baseline)/(Value at Baseline)] x 100 This represents one of the indicators associated with the objective: Additional safety data regarding FTC/TDF (Truvada®) use among HIV-uninfected YMSM. | Baseline, Week 48 | 
| Total Body Bone Mineral Density: Percent Change From Baseline to Week 48 | The percent change in total body BMD from baseline measurement to Week 48 is calculated as: Percent change= [(Value at Week 48 - Value at Baseline)/(Value at Baseline)] x 100 This represents one of the indicators associated with the objective: Additional safety data regarding FTC/TDF (Truvada®) use among HIV-uninfected YMSM. | Baseline, Week 48 | 
| Total Hip Bone Mineral Density: Percent Change From Baseline to Week 48 | The percent change in total hip BMD from baseline measurement to Week 48 is calculated as: Percent change= [(Value at Week 48 - Value at Baseline)/(Value at Baseline)] x 100 This represents one of the indicators associated with the objective: Additional safety data regarding FTC/TDF (Truvada®) use among HIV-uninfected YMSM. | Baseline, Week 48 | 
| Number of Participants With Decrease in Bone Mineral Density | The proportion of subjects with DXA data through Week 48 who experienced varying degrees of decrease in absolute BMD in at least one region (spine, hip, or whole body). This represents one of the indicators associated with the objective: Additional safety data regarding FTC/TDF (Truvada®) use among HIV-uninfected YMSM. | 48 weeks | 
| Behavioral Disinhibition/Risk Compensation: Number of Participants Reporting Unprotected Sex | Behavioral disinhibition/risk compensation was assessed based on a number of questions, including the following related to unprotected sex from the participant ACASI: Of these males [male partners], how many did you have unprotected oral or anal sex with since the last time you took this survey? An event is defined as an answer of greater than 0. This represents one of the indicators associated with the objective: Additional safety data regarding FTC/TDF (Truvada®) use among HIV-uninfected YMSM. | Week 48 | 
| Behavioral Disinhibition/Risk Compensation: Number of Male Sexual Partners | Behavioral disinhibition/risk compensation was assessed based on a number of questions, including the following related to related to number of male sexual partners from the participant ACASI: Since the last time you took this survey, how many male partners have you had sexual contact with (oral or anal)? This represents one of the indicators associated with the objective: Additional safety data regarding FTC/TDF (Truvada®) use among HIV-uninfected YMSM. | Week 48 | 
| Acceptability of PrEP Regimen and Study Visits | This represents one of the indicators associated with the objective: Acceptability when YMSM are provided open label FTC/TDF (Truvada®) and information regarding the safety and efficacy of PrEP from prior studies. Acceptability of PrEP as measured by the acceptability assessment that includes questions on usability of PrEP, user-friendliness of the medication regimen, including an assessment of side effects and delivery format, and acceptability of behavioral intervention sessions. | Week 12 | 
| Estimation of Medication Adherence by Dried Blood Spot (DBS) Results | This outcome addresses the objective: Rates of adherence and measured levels of drug exposure when YMSM are provided open label FTC/TDF (Truvada®) and information regarding the safety and efficacy of PrEP from prior studies. Medication adherence is estimated by factors including levels of drug exposure as measured by DBS red blood cell (RBC) samples. The TFV dosing level was translated into number of dosing days per week for week 8 onwards using lab estimates as follows: '<2 days' is defined as <350 (fmol/punch), '2 days' as 350 to 700 (fmol/punch), '4 days' as >700 to 1250 (fmol/punch), and 'Daily' as >1250 (fmol/punch). The TFV dosing level was translated into number of dosing days for week 4 using lab estimates as follows: '<2 days' is defined as <275 (fmol/punch), '2 days' as 275 to 525 (fmol/punch), '4 days' as >525 to 950 (fmol/punch),and 'Daily' as >950 (fmol/punch) | Week 4, Week 12, Week 24, Week 36, Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acceptability and Feasibility of Two Types of Efficacious Sexual Risk Reduction Interventions as Measured by Session Evaluation | Study subjects were given a brief Session Evaluation Form at the end of the behavioral intervention session consisting of ten items on a 4-point response scale aimed at eliciting information about the subject's experience with the session (i.e., was session interesting, was it relevant to their life, and did they learn from the session) | 48 weeks | 
| Number of Participants Using Text Messaging Reminders | This represents one of the indicators associated with the objective: Acceptability and feasibility of text message reminders. | Baseline through Week 48 | 
| Rating of the Reasons for Missing Medications on a 4-point Likert Scale. | This represents one of the indicators associated with the objective: Acceptability and feasibility of text message reminders, as measured by subject rating of the reasons for missing medications on a 4-point Likert scale. Subjects were asked to rate various measures as Never, Rarely, Sometimes, or Often the reason for missing taking study pills. Data shown for Week 48. Question: In the past month, how often have you missed taking your study pills because you: | 48 weeks | 
| Demographic and/or Behavioral Difference Between Study Groups. Behavioral Disinhibition/Risk Compensation Endpoints Will be Compared. |  | 48 weeks | 
| Evaluation of the Process of Protocol Implementation | Brief phone interviews and review of written institutional review board (IRB) correspondence will be conducted for all sites whether the study is approved at that site or not. If approved, the steps needed for approval and how barriers were addressed will be examined. If the study was rejected, the reasons for disapproval, the IRB's interpretation of the risk of PrEP, and other barriers will be examined. In addition, data from a survey specific to each site's IRB's responses of minor YMSM inclusion in PrEP studies will be evaluated. NOTE: Data collected to address this outcome were primarily qualitative in nature, and as such are not presented here. For more information on this outcome, refer to: Gilbert AL, Knopf AS, Fortenberry JD, Hosek SG, Kapogiannis BG, Zimet GD. Adolescent Self-Consent for Biomedical Human Immunodeficiency Virus Prevention Research. J Adolesc Health. 2015 Jul;57(1):113-9. | 48 weeks | 
| Demographic and/or Behavioral Differences Between Youth Who Are Interested in Participating in a PrEP Study Versus Those Who Are Not. | Behavioral disinhibition/risk compensation endpoints will be compared. | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, PrEP, FTC/TDF, Truvada®