A Randomized Study of Activity, Safety, and Tolerance of Oral Ro 24-7429 (Tat Antagonist) in Patients With HIV Infection

To study the anti-HIV activity of the various doses of Ro 24-7429 monotherapy based on virologic and immunologic endpoints. To study the safety and tolerance of Ro 24-7429. To explore relationships between exposure to Ro 24-7429 and its metabolites and antiviral activity and drug toxicity. To determine a safe, tolerable, and active dose regimen of Ro 24-7429, and to make preliminary observations of Ro 24-7429 in combination with another antiretroviral nucleoside.

The HIV genome contains a number of genes that regulate viral replication. Control of the activity of these genes and their encoded proteins represents a potential target for development of new antiretroviral drugs. The tat (transactivator of transcription of HIV) antagonist Ro 24-7429 is the first compound for clinical testing that utilizes this approach for therapy of HIV infection.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Zidovudine; Drug: Didanosine; Drug: Ro 24-7429

Detailed Description

The HIV genome contains a number of genes that regulate viral replication. Control of the activity of these genes and their encoded proteins represents a potential target for development of new antiretroviral drugs. The tat (transactivator of transcription of HIV) antagonist Ro 24-7429 is the first compound for clinical testing that utilizes this approach for therapy of HIV infection.

Ninety-six patients (four treatment arms of 24 patients each) are randomized to receive oral Ro 24-7429 at 1 of 3 doses or nucleoside control (either zidovudine or didanosine). The study will be blinded only for the arms receiving Ro 24-7429. Treatment continues for 12 weeks. After 12 weeks, patients on the nucleoside control arm receive the highest tolerated dose of Ro 24-7429 in addition to their nucleoside.

• Study Type: Interventional
• Enrollment: 96
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92103
      • UCSD
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins Hosp
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Harvard (Massachusetts Gen Hosp)
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve Univ

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Concurrent Medication:

Allowed:

• Chemoprophylaxis for P. carinii pneumonia, TB, and mucocutaneous candidiasis.
• Methadone maintenance.
• Hormonal contraceptives.

Patients must have:

• HIV-1 seropositivity.
• CD4 count 50 - 500 cells/mm3.
• Life expectancy of at least 24 weeks.
• Stable weight (+/- 2 kg) by 28 days prior to study entry (by history).

NOTE:

• At least 50 percent of patients must be p24 antigen positive (>= 50 pg/ml).

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms and conditions are excluded:

• Known or suspected hypersensitivity to benzodiazepines.
• Presence of any malignancy other than basal cell carcinoma or limited cutaneous Kaposi's sarcoma (defined as no more than five lesions with no mucosal involvement).
• Ongoing diarrhea, defined as more than 2 liquid stools per day.
• History, physical exam, or laboratory results consistent with a subclinical AIDS-defining opportunistic infection.
• Grade 2 or greater signs and symptoms of AIDS Dementia Complex.
• Evidence of clinically significant cardiac, respiratory, hepatic, gastrointestinal, endocrine, hematologic, psychiatric, neurologic, dermatologic, or allergic disease.

Concurrent Medication:

Excluded:

• Chronic suppressive therapy for CMV, MAI, toxoplasmosis, cryptococcosis, cryptosporidiosis, coccidioidomycosis, and histoplasmosis.
• ddC, ddI, AZT (except for control groups) or other experimental antiretrovirals or immunomodulating agents.
• Other medications excluded from the study.

Patients with the following prior conditions are excluded:

• History of serious adverse reactions to benzodiazepines.
• History of intolerance to AZT at 600 mg/day or less or ddI at 400 mg/day or less.
• History of unexplained fever, defined as a temperature of 38.5 deg C or greater with or without night sweats for more than 7 of the past 28 days.

Prior Medication:

Excluded:

• Benzodiazepines within 14 days prior to study entry.

Active drug or alcohol abuse that would interfere with study compliance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Hoffmann-La Roche
• Investigators: Study Chair: Richman DD; Study Chair: Haubrich R

Publications and helpful links

General Publications

• Haubrich RH, Flexner C, Lederman MM, Hirsch M, Pettinelli CP, Ginsberg R, Lietman P, Hamzeh FM, Spector SA, Richman DD. A randomized trial of the activity and safety of Ro 24-7429 (Tat antagonist) versus nucleoside for human immunodeficiency virus infection. The AIDS Clinical Trials Group 213 Team. J Infect Dis. 1995 Nov;172(5):1246-52. doi: 10.1093/infdis/172.5.1246.
• Haubrich RH. A randomized study of safety, tolerance, pharmacokinetics, and activity of oral Ro 24-7429 (TAT antagonist) in patients with HIV infection. The ACTG 213 Team. Int Conf AIDS. 1993 Jun 6-11;9(1):69 (abstract no WS-B26-5)
• Lathey JL, Marschner IC, Kabat B, Spector SA. Deterioration of detectable human immunodeficiency virus serum p24 antigen in samples stored for batch testing. J Clin Microbiol. 1997 Mar;35(3):631-5. doi: 10.1128/jcm.35.3.631-635.1997.

Study record dates

Study Registration Dates

• First Submitted: November 2, 1999
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (Estimate): August 31, 2001

Study Record Updates

• Last Update Posted (Estimate): August 4, 2008
• Last Update Submitted That Met QC Criteria: July 31, 2008
• Last Verified: November 1, 1998

More Information

Terms related to this study

• Keywords: Acquired Immunodeficiency Syndrome; AIDS-Related Complex; Antiviral Agents; Didanosine; Zidovudine; Gene Products, tat
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Slow Virus Diseases; HIV Infections; Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome; 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; Antimetabolites; Zidovudine; Didanosine
• Other Study ID Numbers: ACTG 213; NV14224A