Safety and Pharmacokinetic Study of Tenofovir Alafenamide (TAF)/Elvitegravir (EVG) Administered Rectally

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and pharmacokinetics of rectal administration of a tenofovir alafenamide (TAF)/elvitegravir (EVG) insert at two dose levels in HIV-uninfected individuals.

Detailed Description
-----------------
This study will evaluate the safety and pharmacokinetics of rectal administration of a tenofovir alafenamide (TAF)/elvitegravir (EVG) insert at two dose levels in HIV-uninfected individuals. All participants will receive a single TAF/EVG Insert at Study Visit 3. After a washout period of at least 7 days, participants will receive two TAF/EVG Inserts at Study Visit 7. The inserts will be administered rectally by study staff. After each dosing visit, samples will be collected over a 3-day period. Participants will attend 10 study visits and will be followed for approximately 6 to 13 weeks. Study visits may include physical and rectal examinations; collection of blood, urine, rectal and vaginal fluid; and interviews. The total duration of the study will be approximately 11 months.

Official Title
-----------------
A Phase 1 Open Label Safety and Pharmacokinetic Study of Rectal Administration of a Tenofovir Alafenamide/Elvitegravir Insert at Two Dose Levels

Conditions
-----------------
HIV Infections

Intervention / Treatment
-----------------
* Drug: TAF/EVG Insert


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Individuals who are 18 years of age or older at Screening, verified per site standard operating procedure (SOP) Able and willing to provide written informed consent to be screened for and enrolled in MTN-039 HIV-1/2 uninfected at Screening and Enrollment, per applicable algorithm in the study protocol and willing to receive HIV test results Able and willing to provide adequate locator information, as defined in site SOP Able to communicate in spoken and written English Available for all visits and able and willing to comply with all study procedural requirements In general good health at Screening and Enrollment, as determined by the site Investigator of Record (IoR) or designee At Screening, history of consensual receptive anal intercourse (RAI) at least once in lifetime per participant report Willing not to take part in other research studies involving drugs, medical devices, genital or rectal products, or vaccines for the duration of study participation (including the time between Screening and Enrollment) Willing to comply with abstinence and other protocol requirements as outlined in the study protocol For participants of childbearing potential: a negative pregnancy test at Screening and Enrollment For participants of childbearing potential: Per participant report at Enrollment, using an effective method of contraception for at least 30 days (inclusive) prior to Enrollment and intending to use an effective method for the duration of study participation. Effective methods include: Hormonal methods Intrauterine device (IUD) inserted at least 30 days prior to Enrollment (but not past the maximum length of recommended usage according to package instructions) Sterilization (of participant or partner, as defined in site SOPs) Sexually abstinent as defined by abstaining from penile-vaginal intercourse for 90 days prior to Enrollment and intending to remain abstinent for the duration of study participation; this includes having sex exclusively with individuals assigned female sex at birth Exclusion Criteria: At Screening: Hemoglobin Grade 1 or higher* Platelet count Grade 1 or higher* Aspartate aminotransferase (AST) or alanine transaminase (ALT) Grade 1 or higher* Serum creatinine greater than 1.3 times the site laboratory upper limit of normal (ULN) International normalized ratio (INR) greater than 1.5 times the site laboratory ULN History of inflammatory bowel disease by participant report Positive hepatitis B surface antigen (HBsAg) test result *As per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1, July 2017. Note: Otherwise eligible participants with an exclusionary test result (other than HIV) can be re-tested during the screening process. If a participant is re-tested and a non-exclusionary result is documented within 45 days of providing informed consent for screening, the participant may be enrolled. Anticipated use of and/or unwillingness to abstain from the following medications during study participation: Anticoagulant medications Non-study rectally-administered medications and any products containing nonoxynol-9 (N-9) Known adverse reaction to any of the components of the study product Use of approved or other investigational pre-exposure prophylaxis (PrEP) for HIV prevention within 3 months prior to Enrollment, and/or anticipated use and/or unwillingness to abstain from PrEP during trial participation Use of post-exposure prophylaxis (PEP) for potential HIV exposure within 6 months prior to Enrollment Condomless RAI and/or penile-vaginal intercourse with a partner who is known to be HIV-positive or whose status is unknown in the 6 months prior to Enrollment History of transactional sex in the 12 months prior to Enrollment Non-therapeutic injection drug use or use of non-therapeutic, non-injection stimulant drugs in the 12 months prior to Enrollment Participation in research studies involving drugs, medical devices, genital or rectal products, or vaccines within 30 days of the Enrollment Visit Per participant report, medical records, clinical diagnosis and/or diagnostic testing at either Screening or Enrollment: Diagnosis or treatment of an anogenital sexually transmitted infection (STI) in the 3 months prior to enrollment (including window between Screening and Enrollment). Symptoms, clinical or laboratory diagnosis of active pharyngeal, anorectal, or reproductive tract infection (RTI) requiring treatment per current Centers for Disease Control and Prevention (CDC) guidelines (http://www.cdc.gov/std/treatment). Current symptomatic urinary tract infection (UTI). Infections requiring treatment include Neisseria gonorrhea (GC), Chlamydia trachomatis (CT) infection, syphilis, active herpes simplex virus (HSV) lesions, or symptomatic genital warts, chancroid, pelvic inflammatory disease (PID), bacterial vaginosis (BV), symptomatic vaginal candidiasis, and trichomoniasis. Note: Otherwise eligible participants with an exclusionary UTI, BV and/or candida finding may be re-tested during the screening process. For participants of childbearing potential: Pregnant or breastfeeding at either Screening or Enrollment or planning to become pregnant during study participation Note: A documented negative pregnancy test performed by study staff is required for inclusion; however, a self-reported pregnancy is adequate for exclusion from screening/enrollment into the study. For participants of childbearing potential: Last pregnancy outcome 90 days or less prior to Screening Has any other condition that, in the opinion of the IoR/designee, would preclude informed consent, make study participation unsafe, complicate the interpretation of study outcome data, or otherwise interfere with achieving the study objectives including any significant uncontrolled active or chronic medical condition.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenofovir Alafenamide (TAF)/Elvitegravir (EVG) Insert<br>On the first dosing visit (Visit 3), participants will receive a single TAF/EVG Insert for rectal administration. On the second dosing visit (Visit 7), after a washout period of at least 7 days, participants will receive two TAF/EVG Inserts for rectal administration. Each participant will be on study for approximately 6-13 weeks. | Drug: TAF/EVG Insert<br>* TAF/EVG Insert (20/16 mg) administered rectally by study staff<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 2 and Higher Adverse Events (AEs) | Graded per the Division of AIDS (DAIDS) Table for Grading Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 and/or Addenda 1, 2 and 3 (Female Genital [Dated November 2007], Male Genital [Dated November 2007] and Rectal [Clarification Dated May 2012] Grading Tables for Use in Microbicide Studies). | Measured from Enrollment through Final Contact at Visit 11 with a median (IQR) of 76 (47, 292) days. COVID restrictions delayed first dosing 9-10 months in 5 participants. Follow-up time from first dosing was a median (IQR) of 34 (22, 39) days. | 
| Elvitegravir (EVG) Concentration in Blood | Based on laboratory evaluations on samples collected at baseline (pre dose), 1, 2, 4, 6, 24, 48, and 72 hours post dose | Samples collected at baseline (pre dose), 1, 2, 4, 6, 24, 48, and 72 hours after each dose (up to 9 weeks after first dose) | 
| Elvitegravir (EVG) Concentration in Rectal Fluid | Based on laboratory evaluations on samples collected at 2, 4, 6, 24, 48, and 72 hours post dose | Samples collected at 2, 4, 6, 24, 48, and 72 hours after each dose (up to 9 weeks after first dose) | 
| Elvitegravir (EVG) Concentration in Rectal Mucosal Tissue Homogenates | Based on laboratory evaluations on samples collected at 2, 24, 48, and 72 hours post dose | Samples collected at 2, 24, 48, and 72 hours after each dose (up to 9 weeks after first dose) | 
| Tenofovir Alafenamide (TAF) Concentration in Blood | Based on laboratory evaluations on samples collected at baseline (pre dose), 1, 2, 4, 6, 24, 48, and 72 hours post dose | Samples collected at baseline (pre dose), 1, 2, 4, 6, 24, 48, and 72 hours after each dose (up to 9 weeks after first dose) | 
| Tenofovir Alafenamide (TAF) Concentration in Rectal Fluid | Based on laboratory evaluations on samples collected at 2, 4, 6, 24, 48, and 72 hours post dose | Samples collected at 2, 4, 6, 24, 48, and 72 hours after each dose (up to 9 weeks after first dose) | 
| Tenofovir Alafenamide (TAF) Concentration in Rectal Mucosal Tissue Homogenates | Based on laboratory evaluations on samples collected at 2, 24, 48, and 72 hours post dose | Samples collected at 2, 24, 48, and 72 hours after each dose (up to 9 weeks after first dose) | 
| Tenofovir (TFV) Concentration in Blood | Based on laboratory evaluations on samples collected at baseline (pre dose), 1, 2, 4, 6, 24, 48, and 72 hours post dose | Samples collected at baseline (pre dose), 1, 2, 4, 6, 24, 48, and 72 hours after each dose (up to 9 weeks after first dose) | 
| Tenofovir (TFV) Concentration in Rectal Fluid | Based on laboratory evaluations on samples collected at 2, 4, 6, 24, 48, and 72 hours post dose | Samples collected at 2, 4, 6, 24, 48, and 72 hours after each dose (up to 9 weeks after first dose) | 
| Tenofovir (TFV) Concentration in Rectal Mucosal Tissue Homogenates | Based on laboratory evaluations on samples collected at 2, 24, 48, and 72 hours post dose | Samples collected at 2, 24, 48, and 72 hours after each dose (up to 9 weeks after first dose) | 
| Tenofovir Diphosphate (TFV-DP) Concentration in Rectal Mucosal Tissue Cell Isolates | Based on laboratory evaluations on samples collected at 2, 24, 48, and 72 hours post dose | Samples collected at 2, 24, 48, and 72 hours after each dose (up to 9 weeks after first dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant Self-report Rectal Insert Acceptability - Ease of Use | Response for Overall, how easy or difficult was it to use the study product when inserted by clinic staff? | 24 hours after each dose (Visits 4 and 8) (up to 9 weeks after first dose) | 
| Participant Self-report Rectal Insert Acceptability - Feeling When Inserted | Response for How did it feel to have the insert inside you? | 24 hours after each dose (Visits 4 and 8) (up to 9 weeks after first dose) | 
| Participant Self-report Rectal Insert Acceptability - Problems With Rectal Insert | Responses for questions related to problems with Rectal Insert | 24 hours after each dose (Visits 4 and 8) (up to 9 weeks after first dose) |