Clinical trial NCT01687218: Safety and Acceptability Study of Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet and Rectally-Applied Tenofovir Reduced-Glycerin 1% Gel
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV
Lead sponsor: CONRAD
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: National Institute of Mental Health (NIMH)
name: National Institutes of Health (NIH)
First posted: 2012-09-18
Enrollment: 195
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Male or transgender female \> age of 18 at Screening
2. Able and willing to provide written informed consent
3. HIV-1 uninfected at Screening and Enrollment
4. Able and willing to provide adequate locator information, as defined in site SOP
5. Available to return for all study visits, barring unforeseen circumstances and willing to comply with study participation requirements
6. In general good health at Screening and Enrollment, as determined by the site IoR or designee
7. Per participant report, a history of consensual RAI at least once in the past 3 months
8. 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.
9. Willing to use study-provided condoms for the duration of the study for penetrative intercourse
10. 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)
11. 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:

1. 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
2. History of inflammatory bowel disease as reported by participant history
3. 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
4. Known allergy to methylparaben and/or propylparaben
5. Known allergy to any of the study products.
6. 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
7. 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.
8. Symptoms suggestive of acute HIV seroconversion at Screening and Enrollment
9. 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.

Primary outcomes:
measure: Safety: Grade 2 or Higher Adverse Events
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Acceptability: Participant Self-report of Liking the Product. H1-Overall How do You Feel About the Product You Used Recently?
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Acceptability: Participant Self-report of Ease of Use. I1-Overall How Easy or Difficult Was it to Use the Product?
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: 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?
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
Secondary outcomes:
measure: Pharmacokinetics: Tenofovir (TFV) Concentrations (log10 ng/mL) in Blood Plasma
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Pharmacokinetics: End Period Tenofovir (TFV) Concentrations (log10 ng/mg) in Rectal Tissue
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Pharmacokinetics: Tenofovir (TFV) Concentrations (log10 ng/mg) in Rectal Sponge
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Pharmacokinetics: Emtricitabine (FTC) Concentrations (log10 ng/mL) in Blood Plasma
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Pharmacokinetics: End Period Emtricitabine (FTC) Concentrations (log10 ng/mg) in Rectal Tissue
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Pharmacokinetics: Emtricitabine (FTC) Concentrations (log10 ng/mg) in Rectal Sponge
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Pharmacokinetics: End Period Tenofovir-Diphosphate (TFV-DP) Concentrations (log10 ng/mg) in Rectal Tissue
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Adherence: Percentage of Prescribed Doses Taken Orally or Administered Rectally in an 8-week Period
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
Other outcomes:
measure: Pharmacodynamics
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Mucosal Immunity
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Correlation Between PK and Adherence
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Factors Associated With Adherence
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Sexual Activity and Condom Use
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Product Sharing
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
measure: Problem Practices
timeFrame: 27 weeks (three 8-week product use periods with 1-week washout periods between them)
Locations:
city: San Francisco
country: United States
facility: HIV Research Section, San Francisco - Department of Public Health
state: California
city: Boston
country: United States
facility: The Fenway Institute/Fenway Community Health
state: Massachusetts
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center (UPMC)
state: Pennsylvania
city: Lima
country: Peru
facility: Asociacion Civil Impacta Salud y Educacion (IMPACTA)
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico Medical Sciences Campus - Maternal Infant Studies Center (CEMI)
city: Cape Town
country: South Africa
facility: Desmond Tutu HIV Foundation
city: Chiang Mai
country: Thailand
facility: Research Institute for Health Sciences - Chiang Mai University
city: Nonthaburi
country: Thailand
facility: Thailand MOPH - US CDC Collaboration (TUC)
Study officials:
affiliation: University of Pittsburgh Medical Center (UPMC)
name: Ross D. Cranston, MD, FRCP
role: STUDY_CHAIR
affiliation: Asociacion Civil Impacta Salud y Educacion (IMPACTA)
name: Javier R. Lama, MD, MPH
role: STUDY_CHAIR
References:
citation: Cranston RD, Lama JR, Richardson BA, Carballo-Dieguez A, Kunjara Na Ayudhya RP, Liu K, Patterson KB, Leu CS, Galaska B, Jacobson CE, Parikh UM, Marzinke MA, Hendrix CW, Johnson S, Piper JM, Grossman C, Ho KS, Lucas J, Pickett J, Bekker LG, Chariyalertsak S, Chitwarakorn A, Gonzales P, Holtz TH, Liu AY, Mayer KH, Zorrilla C, Schwartz JL, Rooney J, McGowan I; MTN-017 Protocol Team. MTN-017: A Rectal Phase 2 Extended Safety and Acceptability Study of Tenofovir Reduced-Glycerin 1% Gel. Clin Infect Dis. 2017 Mar 1;64(5):614-620. doi: 10.1093/cid/ciw832.
citation: Carballo-Dieguez A, Balan IC, Brown W 3rd, Giguere R, Dolezal C, Leu CS, Marzinke MA, Hendrix CW, Piper JM, Richardson BA, Grossman C, Johnson S, Gomez K, Horn S, Kunjara Na Ayudhya RP, Patterson K, Jacobson C, Bekker LG, Chariyalertsak S, Chitwarakorn A, Gonzales P, Holtz TH, Liu A, Mayer KH, Zorrilla C, Lama J, McGowan I, Cranston RD. High levels of adherence to a rectal microbicide gel and to oral Pre-Exposure Prophylaxis (PrEP) achieved in MTN-017 among men who have sex with men (MSM) and transgender women. PLoS One. 2017 Jul 27;12(7):e0181607. doi: 10.1371/journal.pone.0181607. eCollection 2017.
citation: Giguere R, Brown W III, Balan IC, Dolezal C, Ho T, Sheinfil A, Ibitoye M, Lama JR, McGowan I, Cranston RD, Carballo-Dieguez A. Are participants concerned about privacy and security when using short message service to report product adherence in a rectal microbicide trial? J Am Med Inform Assoc. 2018 Apr 1;25(4):393-400. doi: 10.1093/jamia/ocx081.
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