Extended Safety Study of Tenofovir Disoproxil Fumarate (TDF) Among HIV-1 Negative Men

Phase II Extended Safety Study of Tenofovir Disoproxil Fumarate (TDF) Among HIV-1 Negative Men

The purpose of this study is to examine safety and tolerability of daily tenofovir use in HIV-uninfected men.

Study Overview

• Status: Completed
• Conditions: HIV Infection
• Intervention / Treatment: Drug: tenofovir disoproxil fumarate; Drug: placebo

Detailed Description

This study will assess the clinical and behavioral safety and tolerability of oral daily TDF use as pre-exposure prophylaxis (PrEP) to prevent HIV infection in uninfected men.

• Study Type: Interventional
• Enrollment (Actual): 400
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94102
      • San Francisco Department of Public Health
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • AIDS Research Consortium of Atlanta
  • Massachusetts
    • Boston,, Massachusetts, United States, 02115
      • Fenway Community Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy biologic male (male at birth)
• 18-60 years of age
• HIV-1 negative by licensed, commercially available, FDA-approved whole blood rapid enzyme immunoassay (EIA) at screening and enrollment
• Reports any anal sex with a man in the last 12 months
• Able to understand and pass comprehension assessment questionnaire
• Able to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
• Able to understand English
• Adequate renal function: calculated creatinine clearance of at least 70 mL/min
• Hepatic transaminases (AST and ALT) less than or equal to 2x upper limit of normal (ULN)
• Total bilirubin less than or equal to 1.5 mg/dL
• Absolute neutrophil count at least 1,500/mm3;
• Platelets at least 100,000/mm3;
• Hemoglobin at least 9.5 g/dL
• Serum amylase less than or equal to 1.5 x ULN
• Biochemical profile: within normal limits for serum phosphorus, potassium, sodium, and calcium.
• Hepatitis B surface antigen negative
• Normal urine dipstick or urinalysis (UA)

Exclusion Criteria:

• Active untreated syphilis
• Current uncontrolled hypertension (blood pressure > 160/100 mmHg)
• Mutually monogamous for > one year with a known HIV antibody negative partner
• History of chronic renal disease, known osteoporosis, osteomalacia, or osteopenia
• Current or expected participation in other longitudinal HIV behavioral or biomedical research study
• Current HIV antiretroviral use
• Receiving or planning to receive on-going therapy with any nephrotoxic agents or experimental/investigational agents
• Previous or expected requirements for the administration of immunosuppressive/ immunomodulatory therapy (e.g. chronic systemic steroids, interferon, interleukins, chemotherapy, radiation).
• Evidence of a gastrointestinal malabsorption syndrome or chronic nausea or vomiting which may confer an inability to receive an orally administered medication.
• Current alcohol or substance abuse judged by the investigator to potentially interfere with participant compliance.
• Imminently life-threatening medical conditions (malignancy, immunosuppressive disease [e.g. lymphoma]), or other serious disease or conditions (e.g. cardiovascular, renal, diabetes) within the last 5 years or that are unstable and/or require chronic medication that would impede compliance with study requirements and complicate the interpretation of adverse events
• Expected to be non-compliant with study visits or planning to move within 24 months to an area where the study will not be conducted
• Any other clinical or social condition, prior therapy, occupation, or other responsibility, that, in the opinion of the investigator, would interfere with, or serve as a contraindication to study participation or compliance with the dosing requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: active immediate; participants in this arm start study product immediately upon enrollment	Drug: tenofovir disoproxil fumarate; study product taken daily; Other Names: Viread
Placebo Comparator: placebo immediate; participants in this arm start study product immediately upon enrollment	Drug: placebo; study product taken daily
Active Comparator: active delayed; persons in this arm start study product 9 months after enrollment	Drug: tenofovir disoproxil fumarate; study product taken daily; Other Names: Viread
Placebo Comparator: placebo delayed; participants in this arm start study product nine months after enrollment	Drug: placebo; study product taken daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Safety--Creatinine Elevations	Grade 3 or 4 Creatinine elevations (per National Institutes of Health Division of AIDS toxicity scale)	24 months (immediate arm) and 15 months (delayed arm)
Clinical Safety--Hypophosphatemia	Grade 3 or 4 hypophosphatemia (per National Institutes of Health Division of AIDS toxicity scale)	24 months (immediate arm), 15 months (delayed arm)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Breakthrough HIV Infections	Number of participants with HIV seroconversions occuring while on study drug	24 months (immediate arm) and 15 months (delayed arm)
Adherence to Study Drug	Estimated exposure to study drug (active and placebo) as assessed by Medication Event Monitoring System (MEMS) caps.	24 months (immediate arm) and 15 months (delayed arm)
Behavioral Safety--Unprotected Anal Sex (UAS)	Change in percent of participants reporting unprotected anal intercourse--baseline vs. months 3 through 9 on study.	Nine months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
>5% Bone Mineral Density Decline at Femoral Neck	Percent of San Francisco participants in the TDF vs. placebo groups who were found to have >5% decline in Bone Mineral Density at the femoral neck.	24 months (immediate arm), 15 months (delayed arm)

Collaborators and Investigators

• Sponsor: Centers for Disease Control and Prevention
• Collaborators: San Francisco Department of Public Health; AIDS Research Consortium of Atlanta
• Investigators: Principal Investigator: Kata L Chillag, PhD, Centers for Disease Control and Prevention; Principal Investigator: Lisa A Grohskopf, MD, MPH, Centers for Disease Control and Prevention; Principal Investigator: Susan Buchbinder, MD, San Francisco Dept. of Public Health; Principal Investigator: Melanie Thompson, MD, AIDS Research Consortium of Atlanta; Principal Investigator: Kenneth H. Mayer, MD, Fenway Community Health

Publications and helpful links

General Publications

• Baxi SM, Vittinghoff E, Bacchetti P, Huang Y, Chillag K, Wiegand R, Anderson PL, Grant R, Greenblatt RM, Buchbinder S, Gandhi M, Liu AY. Comparing pharmacologic measures of tenofovir exposure in a U.S. pre-exposure prophylaxis randomized trial. PLoS One. 2018 Jan 9;13(1):e0190118. doi: 10.1371/journal.pone.0190118. eCollection 2018.
• Liu AY, Vittinghoff E, Sellmeyer DE, Irvin R, Mulligan K, Mayer K, Thompson M, Grant R, Pathak S, O'Hara B, Gvetadze R, Chillag K, Grohskopf L, Buchbinder SP. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PLoS One. 2011;6(8):e23688. doi: 10.1371/journal.pone.0023688. Epub 2011 Aug 29.

Study record dates

Study Major Dates

• Study Start: February 1, 2005
• Primary Completion (Actual): August 1, 2009
• Study Completion (Actual): August 1, 2009

Study Registration Dates

• First Submitted: August 17, 2005
• First Submitted That Met QC Criteria: August 17, 2005
• First Posted (Estimate): August 19, 2005

Study Record Updates

• Last Update Posted (Estimate): March 10, 2014
• Last Update Submitted That Met QC Criteria: January 22, 2014
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir
• Other Study ID Numbers: CDC-NCHHSTP-4323