Study of Valproic Acid to Treat HIV Infected Adults

May 11, 2012 updated by: University of North Carolina, Chapel Hill

Inhibiting Histone Deacetylase: Toward Eradication of HIV

A histone deacetylase (HDAC) inhibitor is a class of drug that interferes with the function of HDAC, an enzyme that hides HIV within inactive CD4 cells. These drugs are normally used to treat seizures and other nervous system problems but have been found to work against HIV. The purpose of this study is to investigate the efficacy of valproic acid (VPA), an HDAC inhibitor, in treating HIV infected adults using anti-HIV drugs.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

VPA is a type of medication normally used to treat seizures and other nervous system problems. It has been found that VPA works against HIV by releasing the virus from resting CD4 cells, allowing other anti-HIV medications to attack it. The purpose of this study is to assess the efficacy of VPA when used in HIV infected participants using highly active antiretroviral therapy (HAART). The expected duration of participation for individually enrolled participants will depend on which study group the participant is placed in but may range from approximately 24 to 144 weeks.

An initial screening visit will occur about 30 to 120 days prior to study entry. A physical exam, medical and medication history assessment, and blood and urine collection will occur at screening. Leukapheresis and genital secretion collection will occur once 30 to 120 days prior to study entry, separate from the initial screening.

In Step 1, all participants will receive VPA while continuing their current HAART. Doses of VPA will vary by participant. Study visits will occur on Days 0 and 3 and Weeks 1, 2, 4, 8, 12, 16, and 24. A physical exam and blood and urine collection will occur at most visits. Leukapheresis and genital secretion collection will occur at study entry and Weeks 12 and 16. After 24 weeks, participants will enter Step 2. Those participants not responding to VPA in Step 1 will enroll in Step 2A. Participants responding to VPA in Step 1 will enroll in Step 2B.

In Step 2A, participants will discontinue VPA and will receive intensified therapy (enfuvirtide) administered for 24 weeks twice daily. Study visits will occur at Weeks 25, 28, 32, 36, 40, and 48. A physical exam and blood and urine collection will occur at all visits. Leukapheresis will occur at Weeks 36 and 40. Participants who do not respond to intensified therapy in Step 2A will enroll in Step 3A. Participants who respond to intensified therapy in Step 2A will enroll in Step 3B.

In Step 2B, participants will continue to receive VPA for up to 96 weeks. Study visits will occur every 8 weeks until Week 120. A physical exam and blood and urine collection will occur at each visit. Leukapheresis will occur once between Week 72 and Week 120.

In Step 3A, VPA will be added to enfuvirtide for 16 weeks. The study will be discontinued for participants who do not respond. Study visits will occur at screening, entry, Day 0, and Weeks 1, 2, 4, 8, 12, 16, and 22. A physical exam and blood and urine collection will occur at all visits. Leukapheresis will occur after screening, at entry, Day 0 and Weeks 12 and 16.

In Step 3B, participants may continue receiving enfuvirtide for up to 96 weeks. Study visits will occur every 8 weeks until Week 144. A physical exam and blood and urine collection will occur at each visit. Leukapheresis will occur at Week 96 or 144.

Participants may choose to enter an observational period at any time before they start Step 2 or Step 3. During the observational period, participants continue to take HAART but not VPA or enfuvirtide. Upon entering an observational period, study staff will contact the participant every 8 weeks for a review of their medical records. Each participant will have a study visit within 8 weeks of beginning a new step. These interim study screenings include a physical exam, medical history, and blood and urine collection. Participants may be asked to have additional leukapheresis performed if they have discontinued study medications for 12 weeks or more.

Each leukapheresis procedure will take place at the University of North Carolina Apheresis Clinic in Chapel Hill, North Carolina. This study will not provide participants' current HAART regimen medications.

NOTE: As of 05/20/08, the observational period and Steps 1, 2, 2A, 2B, and 3B were discontinued.

Study Type

Interventional

Enrollment (Actual)

14

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • University of North Carolina Memorial Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • HIV-1 infected
  • Adherent to current HAART regimen
  • Adequate vascular access for leukapheresis
  • Receiving HAART, defined as at least two nucleoside reverse transcriptase inhibitors plus at least one protease inhibitor or non-nucleoside reverse transcriptase inhibitor, without changes to the regimen within 24 weeks of study entry
  • Viral load more than 50 copies/ml on two consecutive occasions for more than 6 months, and less than 200 copies/ml on occasion for more than 6 months prior to study entry
  • CD4 count more than 300 cells/mm3
  • Willing and able to comply with all study requirements
  • Willing to use acceptable forms of contraception

Exclusion Criteria:

  • Currently receiving zidovudine or enfuvirtide
  • Require certain medications known to interact with valproate (e.g., lamotrigine; barbiturates; carbamazepine; prescription dosages of salicylates, hydantoins, felbamate, and clonazepam)
  • Any medical, psychiatric, or job-related responsibility that would interfere with the study. More information about this criterion can be found in the protocol.
  • Contraindications to taking VPA (e.g., pregnancy, bleeding disorders, history of pancreatitis, history of hepatitis)
  • Receiving interferon, other immunomodulators, or other experimental medications
  • Abnormal liver enzyme tests
  • Hepatitis B virus infected
  • Symptoms of hepatic decompensation
  • Blood transfusions or hematopoietic growth factors within 90 days prior to study entry
  • Systemic cytotoxic chemotherapy, investigational agents, or immunomodulators within 90 days prior to study entry
  • Current drug or alcohol abuse that, in the opinion of the site investigator, would interfere with the study
  • Serious illness requiring systemic treatment or hospitalization within 90 days prior to study entry
  • Treatment for a current AIDS-defining opportunistic infection within 90 days prior to screening
  • Anemic
  • Involuntarily incarcerated for treatment of either a psychiatric illness or physical illness (e.g., infectious disease)
  • Pregnancy or breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 2A
Discontinuation of VPA and enfuvirtide administered for 24 weeks. As of 05/20/08 this step was discontinued.
Drug: Enfuvirtide
90 mg subcutaneously twice daily
Other Names:
  • T-20
Experimental: 2B
Continuation of VPA for up to 96 weeks. As of 05/20/08 this step was discontinued.
Drug: Valproic acid
500 to 750 mg, taken orally twice daily
Experimental: 3A
VPA may be added to enfuvirtide for 16 weeks. VPA and enfuvirtide will be continued for up to 96 weeks in responders, and the study will be discontinued in nonresponders.
Drug: Enfuvirtide
90 mg subcutaneously twice daily
Other Names:
  • T-20
Drug: Valproic acid
500 to 750 mg, taken orally twice daily
Experimental: 3B
Enfuvirtide may be continued for up to 96 weeks. As of 05/20/08 this step was discontinued.
Drug: Enfuvirtide
90 mg subcutaneously twice daily
Other Names:
  • T-20

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Frequencies of replication-competent HIV detected in resting CD4 cells
Time Frame: At pre-entry and Week 0 to Weeks 12 and 16
At pre-entry and Week 0 to Weeks 12 and 16

Secondary Outcome Measures

Outcome Measure
Time Frame
Change in integrated proviral genomes
Time Frame: Throughout study
Throughout study
Genital tract proviral DNA and viral load
Time Frame: Throughout study
Throughout study
Detectable viral load during VPA therapy and if it remains undetectable after VPA is discontinued
Time Frame: Throughout study
Throughout study
HIV-specific antibody changes and CTL responses
Time Frame: From Week 0 to 16
From Week 0 to 16
Change in replication-competent HIV detected in resting CD4 cells in study participants after intensified HAART, and after extended VPA therapy with or without intensified HAART
Time Frame: Throughout study
Throughout study
Changes in viral load after intensification of HAART with or without VPA
Time Frame: Throughout study
Throughout study

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of North Carolina, Chapel Hill

Investigators

  • Principal Investigator: David M. Margolis, MD, University of North Carolina, Chapel Hill

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2006

Primary Completion (Actual)

April 1, 2009

Study Completion (Actual)

October 1, 2009

Study Registration Dates

First Submitted

April 6, 2006

First Submitted That Met QC Criteria

April 6, 2006

First Posted (Estimate)

April 10, 2006

Study Record Updates

Last Update Posted (Estimate)

May 14, 2012

Last Update Submitted That Met QC Criteria

May 11, 2012

Last Verified

May 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • U01AI067854-02 (U.S. NIH Grant/Contract)
  • CID 0703
  • 7R01AI064074-01A1 (U.S. NIH Grant/Contract)
  • 7R01AI045297-08 (U.S. NIH Grant/Contract)
  • U01A125868

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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