A Randomized, Double-Blind, Four-Arm Study Comparing Combination Nucleoside, Alternating Nucleoside, and Triple-Drug Therapy for the Treatment of Advanced HIV Disease (CD4 <= 50/mm3)

This study has been completed.
Sponsor:
Collaborators:
Bristol-Myers Squibb
Glaxo Wellcome
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00000781
First received: November 2, 1999
Last updated: March 30, 2012
Last verified: March 2012
  Purpose

To determine the relative clinical efficacy of zidovudine ( AZT ) plus didanosine (ddI), AZT plus zalcitabine ( ddC ), AZT alternating monthly with ddI, and AZT/ddI plus nevirapine in HIV-infected patients with advanced disease.

The rapid emergence of resistant HIV strains has been observed in patients receiving monotherapy with a nucleoside analog or non-nucleoside reverse transcriptase inhibitor. Use of combination therapy with two nucleoside drugs or convergent combination therapy with two nucleosides and a non-nucleoside RT inhibitor may minimize the evolution of these resistant HIV strains. Since toxicity is a major problem in patients with advanced disease who are receiving combination nucleoside therapy, alternating the two drugs may provide a way of retaining several benefits of combination therapy while minimizing the increased toxicity.


Condition Intervention Phase
HIV Infections
Drug: Nevirapine
Drug: Zidovudine
Drug: Zalcitabine
Drug: Didanosine
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Four-Arm Study Comparing Combination Nucleoside, Alternating Nucleoside, and Triple-Drug Therapy for the Treatment of Advanced HIV Disease (CD4 <= 50/mm3)

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Estimated Enrollment: 1292
Study Completion Date: September 1996
Detailed Description:

The rapid emergence of resistant HIV strains has been observed in patients receiving monotherapy with a nucleoside analog or non-nucleoside reverse transcriptase inhibitor. Use of combination therapy with two nucleoside drugs or convergent combination therapy with two nucleosides and a non-nucleoside RT inhibitor may minimize the evolution of these resistant HIV strains. Since toxicity is a major problem in patients with advanced disease who are receiving combination nucleoside therapy, alternating the two drugs may provide a way of retaining several benefits of combination therapy while minimizing the increased toxicity.

Patients are randomized to receive either AZT/ddC, AZT/ddI, AZT alternating monthly with ddI, or AZT/ddI/nevirapine. Patients are evaluated at week 0 and every 4 weeks thereafter for 2 years. Pharmacologic, virologic, and macroneurologic substudies will be conducted. Patients who are already enrolled on protocol ACTG 193 will be given the option of continuing on their originally assigned ACTG 193 therapy for an additional 6 months or undergoing re-randomization to one of the four treatment arms on ACTG 193A.

  Eligibility

Ages Eligible for Study:   13 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Concurrent Medication:

Required:

  • PCP prophylaxis.

Allowed:

  • Erythropoietin maintenance.
  • G-CSF and GM-CSF.
  • Prophylaxis for Mycobacterium avium intracellulare.
  • Antifungal prophylaxis or treatment with specific drugs.
  • Maintenance therapy for opportunistic infection.
  • Over-the-counter medications or alternative therapies such as vitamins and herbs.
  • Antibiotics as clinically indicated.
  • Steroids for < 21 days for acute problems.
  • Antipyretics, analgesics, allergy medication, antidepressants, sleep medications, oral contraceptives, or other appropriate medications.

Concurrent Treatment:

Allowed:

  • Radiation therapy for cutaneous Kaposi's sarcoma.
  • Acupuncture.

Patients must have:

  • Documented HIV infection.
  • CD4 count <= 50 cells/mm3.
  • Either no prior nucleoside therapy OR a history of prior nucleoside therapy in the absence of high-grade intolerance.
  • Life expectancy of at least 6 months.
  • Consent of parent or guardian if < 18 years of age.
  • Normal chest x-ray at baseline or within 6 months prior to study entry in the absence of new pulmonary or cardiac symptoms (per 12/28/94 amendment).

NOTE:

  • Patients who withdrew from protocol ACTG 193 therapy prior to activation of ACTG 193A are not eligible.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

  • Abnormal baseline chest x-ray.
  • New pulmonary or cardiac symptoms.
  • Psychological or emotional problems sufficient to prevent compliance with study medication.

Concurrent Medication:

Excluded:

  • Systemic chemotherapy for malignancy.
  • Acute or induction therapy for opportunistic infection.
  • Antiretroviral drugs other than study drugs.
  • Biological response modifiers.
  • Erythromycin, phenytoin, phenobarbital, warfarin, or coumadin.

Patients with the following prior conditions are excluded:

  • History of recurrent grade 3 or greater toxicity to AZT, ddI, or ddC on two or more occasions.
  • Evidence of active pulmonary disease within 6 months prior to study entry.
  • History of grade 3 or worse peripheral neuropathy.
  • History of acute or chronic pancreatitis.

Prior Medication:

Excluded:

  • Prior nevirapine.

Excluded within 7 days prior to study entry:

  • Acute therapy for opportunistic infection (maintenance therapy is permitted).
  • Acute systemic therapy for a nonopportunistic infection or other medical condition.
  • Antiretroviral drugs other than AZT, ddI, or ddC.
  • Biological response modifiers.
  • d4T therapy.
  • Nucleosides other than those used in the study.
  • Antibiotics containing clavulanate potassium.

Prior Treatment:

Excluded:

  • More than 4 units of blood in a 30-day period.

Active alcohol or drug abuse.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00000781

  Show 96 Study Locations
Sponsors and Collaborators
Bristol-Myers Squibb
Glaxo Wellcome
Investigators
Study Chair: Henry WK
Study Chair: Kahn JO
Study Chair: Balfour HH
  More Information

Additional Information:
Publications:
Price RW, Yiannoutsos C, Zaborski L, Kmack A, Henry K, Tierney C, Clifford D. Neurological substudies of ACTG protocol 193A: quantitative neurological performance measures and treatment outcomes. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:176 (abstract no 516)
Robinson P, Cotton D, Curry R, Henry K, Hall D, Myers M. Analysis of nevirapine (NVP) effect on clinical endpoints (CEs) of HIV progression or death in ACTG trial 193A. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:210 (abstract no 700)
Henry K, Tierney C, Kahn J, Balfour H, Jiang Q, Kmack A, Fischl M. A randomized, double-blind, placebo-controlled study comparing combination nucleoside and triple therapy for the treatment of advanced HIV disease (CD4 less than or equal to 50/mm(3)). Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:207 (abstract no LB6)
Coplan P, Nikas A, Saah A, Nessly M, Doll L, Leavitt R, Benson J, Guess H. No association observed between indinavir therapy for HIV/AIDS and myocardial infarction in 4 clinical trials with 2,825 subjects. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:191 (abstract no 658)
Erice A, Tierney C, Balfour HH Jr, Liou S, Kahn JO, Henry WK. Virologlc effect of therapy with reverse transcriptase inhibitors (RTIs) in patients with AIDS and less than 50 CD4+ T cells per mm(3): a substudy of ACTG 193a. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:204 (abstract no 662)

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00000781     History of Changes
Other Study ID Numbers: ACTG 193A, 11169
Study First Received: November 2, 1999
Last Updated: March 30, 2012
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Zalcitabine
Didanosine
Drug Therapy, Combination
Acquired Immunodeficiency Syndrome
Zidovudine
Nevirapine

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Zalcitabine
Didanosine
Zidovudine
Nevirapine
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents

ClinicalTrials.gov processed this record on August 19, 2014