Clinical trial NCT00001022: A Comparison of Zidovudine (AZT) Used Alone or in Combination With Didanosine (ddI) or Dideoxycytidine (ddC) in HIV-Infected Patients
Official title: A Randomized, Comparative Trial of Zidovudine (AZT) Versus AZT Plus Didanosine (ddI) Versus AZT Plus Dideoxycytidine (ddC) in HIV-Infected Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Zalcitabine
Didanosine
Drug Therapy, Combination
Acquired Immunodeficiency Syndrome
AIDS-Related Complex
Zidovudine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 1200
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: Primary: To compare the efficacy of zidovudine ( AZT ) given alone versus AZT plus didanosine ( ddI ) versus AZT plus zalcitabine ( dideoxycytidine; ddC ) in delaying the occurrence of AIDS-related conditions in HIV-infected patients.

Secondary: To compare the frequency and severity of adverse experiences in the three regimens. To compare the mortality rates in the three regimens. To compare the effects of antiretroviral regimens on CD4+ cell levels.

Studies have indicated that maintenance therapy with AZT over extended periods may be limited by dose-dependent toxicity, primarily myelosuppression, and by the emergence of drug-resistant HIV strains. It is anticipated that the combination of AZT with either ddI or ddC may promote higher antiviral efficacy, with acceptable toxicity and less likelihood of development of drug-resistant strains, than AZT alone.

Detailed description: Studies have indicated that maintenance therapy with AZT over extended periods may be limited by dose-dependent toxicity, primarily myelosuppression, and by the emergence of drug-resistant HIV strains. It is anticipated that the combination of AZT with either ddI or ddC may promote higher antiviral efficacy, with acceptable toxicity and less likelihood of development of drug-resistant strains, than AZT alone.

Approximately 1200 patients are randomized in a 2:1:1:2 ratio to one of the following four treatment arms: AZT plus ddI, AZT plus ddI placebo, AZT plus ddC placebo, and AZT plus ddC. Average follow-up is 2 years.

Eligibility criteria: Inclusion Criteria

Required:

* Documented HIV infection OR working diagnosis of HIV OR evidence of idiopathic suppression with an AIDS-defining opportunistic infection or malignancy (except Kaposi's sarcoma).
* CD4+ cell count = or \< 200/mm3 or = or \< 15 percent of total lymphocyte count within previous 90 days OR history of AIDS-defining opportunistic infection.
* Current PCP prophylaxis.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms and conditions are excluded:

* Symptoms of pancreatitis or peripheral neuropathy of grade 2 or worse.
* Requirement for acute therapy for any active AIDS-defining opportunistic infection or systemic chemotherapy for malignancy.
* Stage 2 or worse (moderate) AIDS Dementia Complex.
* Other disorders or conditions for which the study drugs are contraindicated or that may prevent adequate compliance with study therapy.

Concurrent Medication:

Excluded:

* Acute therapy for active AIDS-defining opportunistic infection.
* Systemic chemotherapy for malignancy.
* Antiretroviral therapy other than that provided by this study.

Patients with the following prior conditions are excluded:

* History of pancreatitis or peripheral neuropathy of grade 2 or worse.
* History of intolerance to the study drugs at entry doses and/or frequencies.
* History of phenylketonuria.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: Community Consortium of San Francisco
state: California
city: Denver
country: United States
facility: Denver CPCRA / Denver Public Hlth
state: Colorado
city: New Haven
country: United States
facility: Hill Health Corp
state: Connecticut
city: Wilmington
country: United States
facility: Wilmington Hosp / Med Ctr of Delaware
state: Delaware
city: Washington
country: United States
facility: Veterans Administration Med Ctr / Regional AIDS Program
state: District of Columbia
city: Atlanta
country: United States
facility: AIDS Research Consortium of Atlanta
state: Georgia
city: Chicago
country: United States
facility: AIDS Research Alliance - Chicago
state: Illinois
city: New Orleans
country: United States
facility: Louisiana Comm AIDS Rsch Prog / Tulane Univ Med
state: Louisiana
city: Detroit
country: United States
facility: Comprehensive AIDS Alliance of Detroit
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hosp
state: Michigan
city: Newark
country: United States
facility: North Jersey Community Research Initiative
state: New Jersey
city: Brooklyn
country: United States
facility: Addiction Research and Treatment Corp
state: New York
city: New York
country: United States
facility: Clinical Directors Network of Region II
state: New York
city: New York
country: United States
facility: Harlem AIDS Treatment Group / Harlem Hosp Ctr
state: New York
city: Portland
country: United States
facility: Portland Veterans Adm Med Ctr / Rsch & Education Grp
state: Oregon
city: Richmond
country: United States
facility: Richmond AIDS Consortium
state: Virginia
Study officials:
name: L Saravolatz
role: STUDY_CHAIR
name: D Winslow
role: STUDY_CHAIR
References:
citation: New trials reach same conclusion: two drugs are better than AZT alone. AIDS Alert. 1995 Nov;10(11):133-6.
citation: Saravolatz LD, Collins G, Hodges D, Winslow D, Pettinelli C. A randomized, comparative trial of ZDV versus ZDV plus ddI versus ZDV plus ddC in persons with CD4 cell counts of less than 200/mm3. Int Conf AIDS. 1996 Jul 7-12;11(1):21 (abstract no MoB291)
citation: Ethnicity and treatment. Proj Inf Perspect. 1997 Jul;(22):15-6.
citation: Besch CL, Morse E, Simon P, Hodges J, Franchino B. Preliminary results of a compliance study within CPCRA 007 combination nucleoside study (NuCombo). Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:111 (abstract no 254)
citation: Mayers D, Saravolatz L, Winslow D, Jagodzinski L, Collins G, Hodges D, Pettinelli C, Weislow O, Stein D. Viral burden measurements in CPCRA 007. Int Conf AIDS. 1996 Jul 7-12;11(Program Supplement):16 (abstract no ThB911)
citation: Kumi J, Collins G, Saravolatz L. Does ethnicity influence the efficacy and toxicity of combination versus monotherapy with nucleosides in AIDS patients? Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:166 (abstract no 547)
citation: James JS. AZT, ddI, and ddC combinations at FDA advisory hearing. Food and Drug Administration. AIDS Treat News. 1996 Apr 5;(no 244):6.
citation: Researchers are rethinking role of AZT in drug therapy. AIDS Policy Law. 1995 Oct 6;10(18):11.
citation: Saravolatz LD, Winslow DL, Collins G, Hodges JS, Pettinelli C, Stein DS, Markowitz N, Reves R, Loveless MO, Crane L, Thompson M, Abrams D. Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. Investigators for the Terry Beirn Community Programs for Clinical Research on AIDS. N Engl J Med. 1996 Oct 10;335(15):1099-106. doi: 10.1056/NEJM199610103351503.
citation: Randall P. CPCRA 007: preliminary results of combination antiretroviral study. NIAID AIDS Agenda. 1996 Mar:2.