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

HIV Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01687218
• Other study ID #: MTN-017
• Secondary ID: 5UM1AI0686331185
• Status: Completed
• Phase: Phase 2
• Start date: September 25, 2013
• Est. completion date: May 26, 2015

Study information

• Verified date: June 2021
• Source: CONRAD
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 195
• Est. completion date: May 26, 2015
• Est. primary completion date: May 26, 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• HIV

Intervention

Drug:
• Oral FTC/TDF (Daily Emtricitabine/Tenofovir Disoproxil fumarate Tablet)

• Rectal Daily TFV RG 1% gel (Rectally applied Tenofovir Reduced Glycerin 1% Gel)

• Rectal RAI-associated TFV RG 1% gel (Receptive Anal Intercourse Associated rectally applied Tenofovir Reduced Glycerin 1% Gel)

Locations

Country	Name	City	State
Peru	Asociacion Civil Impacta Salud y Educacion (IMPACTA)	Lima
Puerto Rico	University of Puerto Rico Medical Sciences Campus - Maternal Infant Studies Center (CEMI)	San Juan
South Africa	Desmond Tutu HIV Foundation	Cape Town
Thailand	Research Institute for Health Sciences - Chiang Mai University	Chiang Mai
Thailand	Thailand MOPH - US CDC Collaboration (TUC)	Nonthaburi
United States	The Fenway Institute/Fenway Community Health	Boston	Massachusetts
United States	University of Pittsburgh Medical Center (UPMC)	Pittsburgh	Pennsylvania
United States	HIV Research Section, San Francisco - Department of Public Health	San Francisco	California

Sponsors (4)

Lead Sponsor	Collaborator
CONRAD	National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Mental Health (NIMH), National Institutes of Health (NIH)

Countries where clinical trial is conducted

United States,  Peru,  Puerto Rico,  South Africa,  Thailand, 

References & Publications (10)

Balán IC, Giguere R, Brown W 3rd, Carballo-Diéguez A, Horn S, Hendrix CW, Marzinke MA, Ayudhya RPKN, Patterson K, Piper JM, McGowan I, Lama JR, Cranston RD; MTN-017 Protocol Team. Brief Participant-Centered Convergence Interviews Integrate Self-Reports, P — View Citation

Brown W 3rd, Giguere R, Sheinfil A, Ibitoye M, Balan I, Ho T, Brown B, Quispe L, Sukwicha W, Lama JR, Carballo-Diéguez A, Cranston RD. Challenges and solutions implementing an SMS text message-based survey CASI and adherence reminders in an international — View Citation

Carballo-Diéguez A, Balán 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, — View Citation

Carballo-Diéguez A, Giguere R, Dolezal C, Leu CS, Balán IC, Brown W 3rd, Rael C, Richardson BA, Piper JM, Bekker LG, Chariyalertsak S, Chitwarakorn A, Gonzales P, Holtz TH, Liu A, Mayer KH, Zorrilla CD, Lama JR, McGowan I, Cranston RD; MTN-017 Protocol Te — View Citation

Cranston RD, Carballo-Diéguez A, Gundacker H, Richardson BA, Giguere R, Dolezal C, Siegel A, KunjaraNaAyudhya RP, Gomez K, Piper JM, Lama JR, McGowan I; MTN-017 Protocol Team. Prevalence and determinants of anal human papillomavirus infection in men who h — View Citation

Cranston RD, Lama JR, Richardson BA, Carballo-Diéguez 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 — View Citation

Giguere R, Brown W III, Balán IC, Dolezal C, Ho T, Sheinfil A, Ibitoye M, Lama JR, McGowan I, Cranston RD, Carballo-Diéguez A. Are participants concerned about privacy and security when using short message service to report product adherence in a rectal m — View Citation

Giguere R, Rael CT, Sheinfil A, Balán IC, Brown W 3rd, Ho T, Dolezal C, Leu CS, Liu A, Mayer KH, Lama JR, McGowan I, Carballo-Diéguez A, Cranston RD; MTN-017 Protocol Team. Factors Supporting and Hindering Adherence to Rectal Microbicide Gel Use with Rece — View Citation

Leu CS, Giguere R, Bauermeister JA, Dolezal C, Brown W 3rd, Balán IC, Richardson BA, Piper JM, Lama JR, Cranston RD, Carballo-Diéguez A. Trajectory of use over time of an oral tablet and a rectal gel for HIV prevention among transgender women and men who — View Citation

Liu AY, Norwood A, Gundacker H, Carballo-Diéguez A, Johnson S, Patterson K, Bekker LG, Chariyalertsak S, Chitwarakorn A, Gonzales P, Holtz TH, Mayer KH, Zorrilla C, Buchbinder S, Piper JM, Lama JR, Cranston RD. Brief Report: Routine Use of Oral PrEP in a — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pharmacodynamics	To characterize pharmacodynamic responses following oral and rectal exposure to antiretroviral drugs	27 weeks (three 8-week product use periods with 1-week washout periods between them)
Other	Mucosal Immunity	To characterize changes in mucosal immunity between baseline and the end of the daily FTC/TDF and TFV RG 1% gel product use	27 weeks (three 8-week product use periods with 1-week washout periods between them)
Other	Correlation Between PK and Adherence	To assess correlation of PK with adherence measures	27 weeks (three 8-week product use periods with 1-week washout periods between them)
Other	Factors Associated With Adherence	To identify factors associated with product adherence and whether they differ by product used (FTC/TDF or TFV RG 1% gel) or regimen (daily use or RAI-associated use)	27 weeks (three 8-week product use periods with 1-week washout periods between them)
Other	Sexual Activity and Condom Use	To examine whether sexual activity or condom use varies by product used	27 weeks (three 8-week product use periods with 1-week washout periods between them)
Other	Product Sharing	To determine the level of sharing of study products with non-participants and to assess with whom products are shared	27 weeks (three 8-week product use periods with 1-week washout periods between them)
Other	Problem Practices	To determine the prevalence of behavioral practices associated with anal intercourse that may affect microbicide use	27 weeks (three 8-week product use periods with 1-week washout periods between them)
Primary	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)
Primary	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)
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)