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)

HIV Infections Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00000781
• Other study ID #: ACTG 193A
• Secondary ID: 11169
• Status: Completed
• Phase: Phase 2
• Est. completion date: September 1996

Study information

• Verified date: October 2021
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1292
• Est. completion date: September 1996
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections

Intervention

Drug:
• Nevirapine

• Zidovudine

• Zalcitabine

• Didanosine

Locations

Country	Name	City	State
Puerto Rico	Univ of Puerto Rico	San Juan
United States	Adirondack Med Ctr at Saranac Lake	Albany	New York
United States	Albany Med College / Division of HIV Medicine A158	Albany	New York
United States	Mid - Hudson Care Ctr	Albany	New York
United States	Univ of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess - West Campus	Boston	Massachusetts
United States	Boston Med Ctr	Boston	Massachusetts
United States	Harvard (Massachusetts Gen Hosp)	Boston	Massachusetts
United States	Bronx Municipal Hosp Ctr/Jacobi Med Ctr	Bronx	New York
United States	Bronx Veterans Administration / Mount Sinai Hosp	Bronx	New York
United States	Comprehensive Health Care Ctr / Bronx Municipal Hosp	Bronx	New York
United States	Jack Weiler Hosp / Bronx Municipal Hosp	Bronx	New York
United States	Montefiore Drug Treatment Ctr / Bronx Municipal Hosp	Bronx	New York
United States	Montefiore Family Health Ctr / Bronx Municipal Hosp	Bronx	New York
United States	Montefiore Med Ctr / Bronx Municipal Hosp	Bronx	New York
United States	Montefiore Med Ctr Adolescent AIDS Program	Bronx	New York
United States	North Central Bronx Hosp / Bronx Municipal Hosp	Bronx	New York
United States	Samaritan Village Inc / Bronx Municipal Hosp	Bronx	New York
United States	SUNY / Health Sciences Ctr at Brooklyn	Brooklyn	New York
United States	SUNY / Erie County Med Ctr at Buffalo	Buffalo	New York
United States	Univ of North Carolina	Chapel Hill	North Carolina
United States	Med Univ of South Carolina / UNC	Charleston	South Carolina
United States	Cook County Hosp	Chicago	Illinois
United States	Louis A Weiss Memorial Hosp	Chicago	Illinois
United States	Northwestern Univ Med School	Chicago	Illinois
United States	Rush Presbyterian - Saint Luke's Med Ctr	Chicago	Illinois
United States	Univ of Cincinnati	Cincinnati	Ohio
United States	Univ of Kentucky Lexington	Cincinnati	Ohio
United States	Case Western Reserve Univ	Cleveland	Ohio
United States	MetroHealth Med Ctr	Cleveland	Ohio
United States	Columbus Children's Hosp	Columbus	Ohio
United States	Denver Dept of Health and Hosps	Denver	Colorado
United States	Mountain States Reg Hemo Ctr / Univ of Colorado	Denver	Colorado
United States	Rose Med Ctr	Denver	Colorado
United States	Univ of Colorado Health Sciences Ctr	Denver	Colorado
United States	City Hosp Ctr at Elmhurst / Mount Sinai Hosp	Elmhurst	New York
United States	Univ of Texas Galveston	Galveston	Texas
United States	Northern Wisconsin Hemophilia Ctr / Saint Vincent's Hosp	Green Bay	Wisconsin
United States	Moses H Cone Memorial Hosp	Greensboro	North Carolina
United States	Milton S Hershey Med Ctr	Hershey	Pennsylvania
United States	Saint Michael's Med Ctr / Milton S Hershey Med Ctr	Hershey	Pennsylvania
United States	Univ of Hawaii	Honolulu	Hawaii
United States	Univ Texas Health Science Ctr / Univ Texas Med School	Houston	Texas
United States	Indiana Univ Hosp	Indianapolis	Indiana
United States	Methodist Hosp of Indiana / Life Care Clinic	Indianapolis	Indiana
United States	Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr	Knoxville	Tennessee
United States	Dartmouth - Hitchcock Med Ctr / Med Ctr Cntrl Massachusetts	Lebanon	New Hampshire
United States	Children's Hosp of Los Angeles	Los Angeles	California
United States	Univ of Southern California / LA County USC Med Ctr	Los Angeles	California
United States	Univ of Louisville / East Tennesee Comprehensive Hem Ctr	Louisville	Kentucky
United States	North Shore Univ Hosp	Manhasset	New York
United States	Univ of Miami School of Medicine	Miami	Florida
United States	Hennepin County Med Clinic	Minneapolis	Minnesota
United States	Univ of Minnesota	Minneapolis	Minnesota
United States	Meharry Med College	Nashville	Tennessee
United States	Robert Wood Johnson Med School / Hershey Med Ctr	New Brunswick	New Jersey
United States	Yale Univ / New Haven	New Haven	Connecticut
United States	Bellevue Hosp / New York Univ Med Ctr	New York	New York
United States	Beth Israel Med Ctr	New York	New York
United States	Columbia Presbyterian Med Ctr	New York	New York
United States	Cornell Univ Med Ctr	New York	New York
United States	Harlem Hosp Ctr	New York	New York
United States	Mem Sloan - Kettering Cancer Ctr	New York	New York
United States	Mount Sinai Med Ctr	New York	New York
United States	Mount Sinai Med Ctr / Hemophilia Treatment Ctr	New York	New York
United States	Saint Clare's Hosp and Health Ctr	New York	New York
United States	Univ of Medicine & Dentistry of New Jersey / Univ Hosp	Newark	New Jersey
United States	Univ of Nebraska Med Ctr	Omaha	Nebraska
United States	Huntington Memorial Hosp / Children's Hosp of Los Angeles	Pasadena	California
United States	Girard Med Ctr	Philadelphia	Pennsylvania
United States	Thomas Jefferson Univ Hosp	Philadelphia	Pennsylvania
United States	Univ of Pennsylvania at Philadelphia	Philadelphia	Pennsylvania
United States	Univ of Rochester Medical Center	Rochester	New York
United States	St Louis Regional Hosp / St Louis Regional Med Ctr	Saint Louis	Missouri
United States	St Paul Ramsey Med Ctr	Saint Paul	Minnesota
United States	Univ of California / San Diego Treatment Ctr	San Diego	California
United States	San Francisco AIDS Clinic / San Francisco Gen Hosp	San Francisco	California
United States	San Francisco Gen Hosp	San Francisco	California
United States	Stanford at Kaiser / Kaiser Permanente Med Ctr	San Francisco	California
United States	Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium	San Jose	California
United States	Univ of Washington	Seattle	Washington
United States	San Mateo AIDS Program / Stanford Univ	Stanford	California
United States	Stanford Univ Med Ctr	Stanford	California
United States	Olive View Med Ctr	Sylmar	California
United States	SUNY / State Univ of New York	Syracuse	New York
United States	Univ of South Florida	Tampa	Florida
United States	Med College of Ohio	Toledo	Ohio
United States	Harbor UCLA Med Ctr	Torrance	California
United States	George Washington Univ / Hershey Med Ctr	Washington	District of Columbia
United States	Georgetown Univ Med Ctr	Washington	District of Columbia
United States	HIV Ctr - District of Columbia Gen Hosp	Washington	District of Columbia
United States	Howard Univ	Washington	District of Columbia
United States	Whitman - Walker Clinic / Georgetown Univ Med Ctr	Washington	District of Columbia
United States	Great Lakes Hemophilia Foundation	Wauwatosa	Wisconsin
United States	Julio Arroyo	West Columbia	South Carolina
United States	Worcester Memorial Hosp / Med Ctr of Cntrl MA-Memorial	Worcester	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Bristol-Myers Squibb, Glaxo Wellcome

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (7)

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)

Henry K, Erice A, Tierney C, Balfour HH Jr, Fischl MA, Kmack A, Liou SH, Kenton A, Hirsch MS, Phair J, Martinez A, Kahn JO. A randomized, controlled, double-blind study comparing the survival benefit of four different reverse transcriptase inhibitor therapies (three-drug, two-drug, and alternating drug) for the treatment of advanced AIDS. AIDS Clinical Trial Group 193A Study Team. J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Dec 1;19(4):339-49. — View Citation

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)

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)

Price RW, Yiannoutsos CT, Clifford DB, Zaborski L, Tselis A, Sidtis JJ, Cohen B, Hall CD, Erice A, Henry K. Neurological outcomes in late HIV infection: adverse impact of neurological impairment on survival and protective effect of antiviral therapy. AIDS Clinical Trial Group and Neurological AIDS Research Consortium study team. AIDS. 1999 Sep 10;13(13):1677-85. — View Citation

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)