Safety and Acceptability Study of Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet and Rectally-Applied Tenofovir Reduced-Glycerin 1% Gel

Study Overview
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Brief Summary
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MTN-017 is a Phase 2, multi-site, randomized, six-sequence, two three-period, open label crossover study, examining the effects of oral Truvada and reduced glycerin 1% tenofovir gel. The study population will be sexually active, HIV-uninfected males who are 18 years of age or older, who report a history of receptive anal intercourse in the past 3 months. Each of the study product regimens offers different advantages to participants seeking an effective HIV prevention agent. How these relative advantages will compare in terms of safety, acceptability, systemic and local absorption, and adherence will be examined within this study.

Official Title
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A Phase 2 Randomized Sequence Open Label Expanded Safety and Acceptability Study of Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet and Rectally-Applied Tenofovir Reduced-Glycerin 1% Gel

Conditions
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HIV

Intervention / Treatment
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* Drug: Oral FTC/TDF (Daily Emtricitabine/Tenofovir Disoproxil fumarate Tablet)
* Drug: Rectal Daily TFV RG 1% gel (Rectally applied Tenofovir Reduced Glycerin 1% Gel)
* Drug: Rectal RAI-associated TFV RG 1% gel (Receptive Anal Intercourse Associated rectally applied Tenofovir Reduced Glycerin 1% Gel)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or transgender female > age of 18 at Screening Able and willing to provide written informed consent HIV-1 uninfected at Screening and Enrollment Able and willing to provide adequate locator information, as defined in site SOP Available to return for all study visits, barring unforeseen circumstances and willing to comply with study participation requirements In general good health at Screening and Enrollment, as determined by the site IoR or designee Per participant report, a history of consensual RAI at least once in the past 3 months Per participant report at Screening and Enrollment, agrees not to engage in receptive or insertive sexual activity with another study participant for the duration of study participation. Willing to use study-provided condoms for the duration of the study for penetrative intercourse Willing to not take part in other research studies involving drugs, medical devices, vaccines or genital products for the duration of study participation (including the time between Screening and Enrollment) Men and transgender females who agree to take part in the PK, PD and Mucosal Immunology Subset, must also agree to abstain from: Inserting anything into the rectum, including abstaining from RAI for 72 hours after the collection of biopsies Taking non-steroidal anti-inflammatory drugs (NSAIDs), aspirin and/or other drugs that are associated with increased likelihood of bleeding following mucosal biopsy collection for 72 hours prior to and following the collection of biopsies. Exclusion Criteria: At Screening, participant-reported symptoms, and/or clinical or laboratory diagnosis of active anorectal or reproductive tract infection requiring treatment per current World Health Organization (WHO) guidelines or symptomatic urinary tract infection (UTI). Infections requiring treatment include symptomatic Chlamydia trachomatis (CT) infection, Neisseria gonorrhea (GC), syphilis, active herpes simplex virus (HSV) lesions, anogenital sores or ulcers, or symptomatic genital warts. Note: HSV-1 or HSV-2 seropositive diagnosis with no active lesions is allowed, since treatment is not required. In cases of non-anorectal GC/CT identified at screening, one re-screening 2 months after the screening visit will be allowed History of inflammatory bowel disease as reported by participant history At Screening: Positive for hepatitis B surface antigen Positive for hepatitis C antibody Hemoglobin < 10.0 g/dL Platelet count less than 100,000/mm3 White blood cell count < 2,000 cells/mm3 or > 15,000 cells/mm3 Calculated creatinine clearance less than 60 mL/min by the Cockcroft-Gault formula where creatinine clearance in mL/min = (140 - age in years) x (weight in kg) x (1 for male)/72 x (serum creatinine in mg/dL) Serum creatinine > 1.3 x the site laboratory upper limit of normal (ULN) Alanine transaminase (ALT) and/or aspartate aminotransferase (AST) > 2.5× the site laboratory ULN PK, PD and Immunological Subset only: International normalized ratio (INR) > 1.5× the site laboratory ULN or partial thromboplastin time (PTT) > 1.25× the site laboratory ULN Known allergy to methylparaben and/or propylparaben Known allergy to any of the study products. Per participant report, use of the following medications and/or products within 12 weeks prior to screening, and/or anticipated use or unwillingness to abstain from use throughout study participation: Any investigational products Systemic immunomodulatory medications Use of Heparin, including Lovenox® Warfarin Plavix® (clopidogrel bisulfate) Rectally-administered medications or products, containing N-9 or corticosteroids By participant report, use of post-exposure prophylaxis (PEP) for HIV exposure within the 12 weeks prior to screening or anticipated use during study participation. Symptoms suggestive of acute HIV seroconversion at Screening and Enrollment Has any other condition that, in the opinion of the Investigator of Record (IoR)/designee, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives would make the patient unsuitable for the study or unable/unwilling to comply with the study requirements. Such conditions may include, but are not limited to, colorectal abnormalities, substance abuse, or renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological or psychiatric disease.

Ages Eligible for Study
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Minimum Age: 18 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1<br>Daily Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet (8 weeks); followed by Daily Rectally-Applied Tenofovir Reduced Glycerin 1% Gel (8 weeks); followed by Receptive Anal Intercourse Associated Rectally-Applied Tenofovir Reduced Glycerin 1% Gel (8 weeks) | Drug: Oral FTC/TDF (Daily Emtricitabine/Tenofovir Disoproxil fumarate Tablet)<br> <br> Drug: Rectal Daily TFV RG 1% gel (Rectally applied Tenofovir Reduced Glycerin 1% Gel)<br> <br> Drug: Rectal RAI-associated TFV RG 1% gel (Receptive Anal Intercourse Associated rectally applied Tenofovir Reduced Glycerin 1% Gel)<br> <br> |
| Active Comparator: Group 2<br>Receptive Anal Intercourse Associated Rectally-Applied Tenofovir Reduced Glycerin 1% Gel (8 weeks); followed by Daily Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet (8 weeks); followed by Daily Rectally-Applied Tenofovir Reduced Glycerin 1% Gel (8 weeks) | Drug: Oral FTC/TDF (Daily Emtricitabine/Tenofovir Disoproxil fumarate Tablet)<br> <br> Drug: Rectal Daily TFV RG 1% gel (Rectally applied Tenofovir Reduced Glycerin 1% Gel)<br> <br> Drug: Rectal RAI-associated TFV RG 1% gel (Receptive Anal Intercourse Associated rectally applied Tenofovir Reduced Glycerin 1% Gel)<br> <br> |
| Active Comparator: Group 3<br>Daily Rectally-Applied Tenofovir Reduced Glycerin 1% Gel (8 weeks); followed by Receptive Anal Intercourse Associated Rectally-Applied Tenofovir Reduced Glycerin 1% Gel (8 weeks); followed by Daily Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet (8 weeks) | Drug: Oral FTC/TDF (Daily Emtricitabine/Tenofovir Disoproxil fumarate Tablet)<br> <br> Drug: Rectal Daily TFV RG 1% gel (Rectally applied Tenofovir Reduced Glycerin 1% Gel)<br> <br> Drug: Rectal RAI-associated TFV RG 1% gel (Receptive Anal Intercourse Associated rectally applied Tenofovir Reduced Glycerin 1% Gel)<br> <br> |
| Active Comparator: Group 4<br>Daily Rectally-Applied Tenofovir Reduced Glycerin 1% Gel (8 weeks); followed by Daily Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet (8 weeks); followed by Receptive Anal Intercourse Associated Rectally-Applied Tenofovir Reduced Glycerin 1% Gel (8 weeks) | Drug: Oral FTC/TDF (Daily Emtricitabine/Tenofovir Disoproxil fumarate Tablet)<br> <br> Drug: Rectal Daily TFV RG 1% gel (Rectally applied Tenofovir Reduced Glycerin 1% Gel)<br> <br> Drug: Rectal RAI-associated TFV RG 1% gel (Receptive Anal Intercourse Associated rectally applied Tenofovir Reduced Glycerin 1% Gel)<br> <br> |
| Active Comparator: Group 5<br>Daily Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet (8 weeks); followed by Receptive Anal Intercourse Associated Rectally-Applied Tenofovir Reduced Glycerin 1% Gel (8 weeks); followed by Daily Rectally-Applied Tenofovir Reduced Glycerin 1% Gel (8 weeks) | Drug: Oral FTC/TDF (Daily Emtricitabine/Tenofovir Disoproxil fumarate Tablet)<br> <br> Drug: Rectal Daily TFV RG 1% gel (Rectally applied Tenofovir Reduced Glycerin 1% Gel)<br> <br> Drug: Rectal RAI-associated TFV RG 1% gel (Receptive Anal Intercourse Associated rectally applied Tenofovir Reduced Glycerin 1% Gel)<br> <br> |
| Active Comparator: Group 6<br>Receptive Anal Intercourse Associated Rectally-Applied Tenofovir Reduced Glycerin 1% Gel (8 weeks);followed by Daily Rectally-Applied Tenofovir Reduced Glycerin 1% Gel (8 weeks); followed by Daily Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet (8 weeks) | Drug: Oral FTC/TDF (Daily Emtricitabine/Tenofovir Disoproxil fumarate Tablet)<br> <br> Drug: Rectal Daily TFV RG 1% gel (Rectally applied Tenofovir Reduced Glycerin 1% Gel)<br> <br> Drug: Rectal RAI-associated TFV RG 1% gel (Receptive Anal Intercourse Associated rectally applied Tenofovir Reduced Glycerin 1% Gel)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Grade 2 or Higher Adverse Events | Compare the safety profiles of daily FTC/TDF tablet, daily TFV RG 1% gel, and RAI-associated TFV RG 1% gel. Analysis of the primary endpoint of grade 2 or higher AEs was performed on only the evaluable participants based on the principle of intent-to-treat (ITT) whereby participants who were randomized were included in the analysis regardless of whether or not they received product in a given period (i.e, were lost to follow-up, or terminated early and/or were on a product hold). | 27 weeks (three 8-week product use periods with 1-week washout periods between them) | 
| Acceptability: Participant Self-report of Liking the Product. H1-Overall How do You Feel About the Product You Used Recently? | To evaluate and compare acceptability of daily FTC/TDF tablet, daily TFV RG 1% gel, and RAI-associated TFV RG 1% gel. Consistent with the acceptability endpoint of liking the product, a variable was created by combining from Section H. Liking the Product of the MTN-017 Follow-up Behavioral Questionnaire question 1A and question 1BC. Categories 1 and 2 were combined and categories 3 and 4 were combined to create a dichotomous variable. | 27 weeks (three 8-week product use periods with 1-week washout periods between them) | 
| Acceptability: Participant Self-report of Ease of Use. I1-Overall How Easy or Difficult Was it to Use the Product? | To evaluate and compare acceptability of daily FTC/TDF tablet, daily TFV RG 1% gel, and RAI-associated TFV RG 1% gel. Consistent with the acceptability endpoint of ease of use, a variable was created to compare regimens. This variable combines questions 1A and 1BC from Section I. Ease of Use of the MTN-017 Follow-up Behavioral Questionnaire. Categories 1 and 2 were combined and categories 3 and 4 were combined to create dichotomous variables. | 27 weeks (three 8-week product use periods with 1-week washout periods between them) | 
| Acceptability: Participant Self-report of Likelihood of Product Use if Shown to be Effective. N1-If This Product Provides Some Protection How Likely Would You be to Take it? | To evaluate and compare acceptability of daily FTC/TDF tablet, daily TFV RG 1% gel, and RAI-associated TFV RG 1% gel. Consistent with the acceptability endpoint of likelihood to use product in the future, a variable was created by combining Section N. Likelihood to Use Product in the Future of the MTN-017 Follow-up Behavioral Questionnaire questions 1A, 1B, and 1C. Categories 1 and 2 were combined and categories 3 and 4 were combined to create a dichotomous variable. | 27 weeks (three 8-week product use periods with 1-week washout periods between them) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: Tenofovir (TFV) Concentrations (log10 ng/mL) in Blood Plasma | Compare tenofovir concentrations in blood plasma among daily FTC/TDF tablet, daily TFV RG 1% gel, and RAI-associated TFV RG 1% gel groups. | 27 weeks (three 8-week product use periods with 1-week washout periods between them) | 
| Pharmacokinetics: End Period Tenofovir (TFV) Concentrations (log10 ng/mg) in Rectal Tissue | Compare end period tenofovir concentrations in rectal tissue among daily FTC/TDF tablet, daily TFV RG 1% gel, and RAI-associated TFV RG 1% gel groups. | 27 weeks (three 8-week product use periods with 1-week washout periods between them) | 
| Pharmacokinetics: Tenofovir (TFV) Concentrations (log10 ng/mg) in Rectal Sponge | Compare tenofovir concentrations in rectal sponge specimens among daily FTC/TDF tablet, daily TFV RG 1% gel, and RAI-associated TFV RG 1% gel groups. | 27 weeks (three 8-week product use periods with 1-week washout periods between them) | 
| Pharmacokinetics: Emtricitabine (FTC) Concentrations (log10 ng/mL) in Blood Plasma | Compare emtricitabine concentrations in blood plasma among daily FTC/TDF tablet, daily TFV RG 1% gel, and RAI-associated TFV RG 1% gel groups. | 27 weeks (three 8-week product use periods with 1-week washout periods between them) | 
| Pharmacokinetics: End Period Emtricitabine (FTC) Concentrations (log10 ng/mg) in Rectal Tissue | Compare end period emtricitabine concentrations in rectal tissue among daily FTC/TDF tablet, daily TFV RG 1% gel, and RAI-associated TFV RG 1% gel groups. | 27 weeks (three 8-week product use periods with 1-week washout periods between them) | 
| Pharmacokinetics: Emtricitabine (FTC) Concentrations (log10 ng/mg) in Rectal Sponge | Compare emtricitabine concentrations in rectal sponge among daily FTC/TDF tablet, daily TFV RG 1% gel, and RAI-associated TFV RG 1% gel groups. | 27 weeks (three 8-week product use periods with 1-week washout periods between them) | 
| Pharmacokinetics: End Period Tenofovir-Diphosphate (TFV-DP) Concentrations (log10 ng/mg) in Rectal Tissue | Compare end period tenofovir-diphosphate (TFV-DP) concentrations in rectal tissue among daily FTC/TDF tablet, daily TFV RG 1% gel, and RAI-associated TFV RG 1% gel groups. | 27 weeks (three 8-week product use periods with 1-week washout periods between them) | 
| Adherence: Percentage of Prescribed Doses Taken Orally or Administered Rectally in an 8-week Period | Compare percentage of prescribed doses taken orally or administered rectally in an 8-week period based on the Final Converged Rates. Final Converged Rates were measured first via self-report through Short Message Service (SMS). The clinic staff also reported the most likely number of doses taken. Finally, the MTN Behavioral Research Working Group (BRWG) provided the final estimate of the number of doses taken for each participant for each period based on self-report, staff estimates and PK testing results. Note that these final judgement data are missing if PK results are missing. | 27 weeks (three 8-week product use periods with 1-week washout periods between them) |