Clinical trial NCT00000781: 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)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Zalcitabine
Didanosine
Drug Therapy, Combination
Acquired Immunodeficiency Syndrome
Zidovudine
Nevirapine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Bristol-Myers Squibb
name: Glaxo Wellcome
First posted: 2001-08-31
Enrollment: 1292
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief 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.

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 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.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Univ of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: Children's Hosp of Los Angeles
state: California
city: Los Angeles
country: United States
facility: Univ of Southern California / LA County USC Med Ctr
state: California
city: Pasadena
country: United States
facility: Huntington Memorial Hosp / Children's Hosp of Los Angeles
state: California
city: San Diego
country: United States
facility: Univ of California / San Diego Treatment Ctr
state: California
city: San Francisco
country: United States
facility: San Francisco AIDS Clinic / San Francisco Gen Hosp
state: California
city: San Francisco
country: United States
facility: San Francisco Gen Hosp
state: California
city: San Francisco
country: United States
facility: Stanford at Kaiser / Kaiser Permanente Med Ctr
state: California
city: San Jose
country: United States
facility: Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium
state: California
city: Stanford
country: United States
facility: San Mateo AIDS Program / Stanford Univ
state: California
city: Stanford
country: United States
facility: Stanford Univ Med Ctr
state: California
city: Sylmar
country: United States
facility: Olive View Med Ctr
state: California
city: Torrance
country: United States
facility: Harbor UCLA Med Ctr
state: California
city: Denver
country: United States
facility: Denver Dept of Health and Hosps
state: Colorado
city: Denver
country: United States
facility: Mountain States Reg Hemo Ctr / Univ of Colorado
state: Colorado
city: Denver
country: United States
facility: Rose Med Ctr
state: Colorado
city: Denver
country: United States
facility: Univ of Colorado Health Sciences Ctr
state: Colorado
city: New Haven
country: United States
facility: Yale Univ / New Haven
state: Connecticut
city: Washington
country: United States
facility: HIV Ctr - District of Columbia Gen Hosp
state: District of Columbia
city: Washington
country: United States
facility: Whitman - Walker Clinic / Georgetown Univ Med Ctr
state: District of Columbia
city: Washington
country: United States
facility: Georgetown Univ Med Ctr
state: District of Columbia
city: Washington
country: United States
facility: George Washington Univ / Hershey Med Ctr
state: District of Columbia
city: Washington
country: United States
facility: Howard Univ
state: District of Columbia
city: Miami
country: United States
facility: Univ of Miami School of Medicine
state: Florida
city: Tampa
country: United States
facility: Univ of South Florida
state: Florida
city: Honolulu
country: United States
facility: Univ of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: Northwestern Univ Med School
state: Illinois
city: Chicago
country: United States
facility: Cook County Hosp
state: Illinois
city: Chicago
country: United States
facility: Rush Presbyterian - Saint Luke's Med Ctr
state: Illinois
city: Chicago
country: United States
facility: Louis A Weiss Memorial Hosp
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ Hosp
state: Indiana
city: Indianapolis
country: United States
facility: Methodist Hosp of Indiana / Life Care Clinic
state: Indiana
city: Louisville
country: United States
facility: Univ of Louisville / East Tennesee Comprehensive Hem Ctr
state: Kentucky
city: Boston
country: United States
facility: Harvard (Massachusetts Gen Hosp)
state: Massachusetts
city: Boston
country: United States
facility: Boston Med Ctr
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess - West Campus
state: Massachusetts
city: Worcester
country: United States
facility: Worcester Memorial Hosp / Med Ctr of Cntrl MA-Memorial
state: Massachusetts
city: Minneapolis
country: United States
facility: Hennepin County Med Clinic
state: Minnesota
city: Minneapolis
country: United States
facility: Univ of Minnesota
state: Minnesota
city: Saint Paul
country: United States
facility: St Paul Ramsey Med Ctr
state: Minnesota
city: Saint Louis
country: United States
facility: St Louis Regional Hosp / St Louis Regional Med Ctr
state: Missouri
city: Omaha
country: United States
facility: Univ of Nebraska Med Ctr
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth - Hitchcock Med Ctr / Med Ctr Cntrl Massachusetts
state: New Hampshire
city: New Brunswick
country: United States
facility: Robert Wood Johnson Med School / Hershey Med Ctr
state: New Jersey
city: Newark
country: United States
facility: Univ of Medicine & Dentistry of New Jersey / Univ Hosp
state: New Jersey
city: Albany
country: United States
facility: Adirondack Med Ctr at Saranac Lake
state: New York
city: Albany
country: United States
facility: Albany Med College / Division of HIV Medicine A158
state: New York
city: Albany
country: United States
facility: Mid - Hudson Care Ctr
state: New York
city: Bronx
country: United States
facility: Bronx Municipal Hosp Ctr/Jacobi Med Ctr
state: New York
city: Bronx
country: United States
facility: Comprehensive Health Care Ctr / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Montefiore Drug Treatment Ctr / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Montefiore Family Health Ctr / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Samaritan Village Inc / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Jack Weiler Hosp / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Montefiore Med Ctr / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Montefiore Med Ctr Adolescent AIDS Program
state: New York
city: Bronx
country: United States
facility: North Central Bronx Hosp / Bronx Municipal Hosp
state: New York
city: Bronx
country: United States
facility: Bronx Veterans Administration / Mount Sinai Hosp
state: New York
city: Brooklyn
country: United States
facility: SUNY / Health Sciences Ctr at Brooklyn
state: New York
city: Buffalo
country: United States
facility: SUNY / Erie County Med Ctr at Buffalo
state: New York
city: Elmhurst
country: United States
facility: City Hosp Ctr at Elmhurst / Mount Sinai Hosp
state: New York
city: Manhasset
country: United States
facility: North Shore Univ Hosp
state: New York
city: New York
country: United States
facility: Beth Israel Med Ctr
state: New York
city: New York
country: United States
facility: Bellevue Hosp / New York Univ Med Ctr
state: New York
city: New York
country: United States
facility: Saint Clare's Hosp and Health Ctr
state: New York
city: New York
country: United States
facility: Cornell Univ Med Ctr
state: New York
city: New York
country: United States
facility: Mem Sloan - Kettering Cancer Ctr
state: New York
city: New York
country: United States
facility: Mount Sinai Med Ctr / Hemophilia Treatment Ctr
state: New York
city: New York
country: United States
facility: Mount Sinai Med Ctr
state: New York
city: New York
country: United States
facility: Columbia Presbyterian Med Ctr
state: New York
city: New York
country: United States
facility: Harlem Hosp Ctr
state: New York
city: Rochester
country: United States
facility: Univ of Rochester Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY / State Univ of New York
state: New York
city: Chapel Hill
country: United States
facility: Univ of North Carolina
state: North Carolina
city: Greensboro
country: United States
facility: Moses H Cone Memorial Hosp
state: North Carolina
city: Cincinnati
country: United States
facility: Univ of Cincinnati
state: Ohio
city: Cincinnati
country: United States
facility: Univ of Kentucky Lexington
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve Univ
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Med Ctr
state: Ohio
city: Columbus
country: United States
facility: Columbus Children's Hosp
state: Ohio
city: Toledo
country: United States
facility: Med College of Ohio
state: Ohio
city: Hershey
country: United States
facility: Milton S Hershey Med Ctr
state: Pennsylvania
city: Hershey
country: United States
facility: Saint Michael's Med Ctr / Milton S Hershey Med Ctr
state: Pennsylvania
city: Philadelphia
country: United States
facility: Girard Med Ctr
state: Pennsylvania
city: Philadelphia
country: United States
facility: Univ of Pennsylvania at Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson Univ Hosp
state: Pennsylvania
city: Charleston
country: United States
facility: Med Univ of South Carolina / UNC
state: South Carolina
city: West Columbia
country: United States
facility: Julio Arroyo
state: South Carolina
city: Knoxville
country: United States
facility: Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr
state: Tennessee
city: Nashville
country: United States
facility: Meharry Med College
state: Tennessee
city: Galveston
country: United States
facility: Univ of Texas Galveston
state: Texas
city: Houston
country: United States
facility: Univ Texas Health Science Ctr / Univ Texas Med School
state: Texas
city: Seattle
country: United States
facility: Univ of Washington
state: Washington
city: Green Bay
country: United States
facility: Northern Wisconsin Hemophilia Ctr / Saint Vincent's Hosp
state: Wisconsin
city: Wauwatosa
country: United States
facility: Great Lakes Hemophilia Foundation
state: Wisconsin
city: San Juan
country: Puerto Rico
facility: Univ of Puerto Rico
Study officials:
name: Henry WK
role: STUDY_CHAIR
name: Kahn JO
role: STUDY_CHAIR
name: Balfour HH
role: STUDY_CHAIR
References:
citation: 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. doi: 10.1097/00042560-199812010-00004.
citation: 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)
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)
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)
citation: 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)
citation: 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)
citation: 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. doi: 10.1097/00002030-199909100-00011.