Clinical trial NCT00001011: The Safety and Effectiveness of Zidovudine in the Treatment of Patients With Early AIDS Related Complex
Official title: The Safety and Efficacy of Zidovudine in the Treatment of Patients With Early AIDS Related Complex
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Virus Replication
AIDS-Related Complex
Zidovudine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 538
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To determine the safety and usefulness of zidovudine (AZT) for the treatment of patients with early symptomatic HIV infection or early AIDS related complex (ARC). The ability of AZT to suppress HIV, to improve body defenses, and to prevent the occurrence or development of AIDS or advanced ARC is being evaluated.

In one human study, patients with AIDS or advanced ARC who received AZT had fewer life-threatening infections, improved in weight and performance, and lived longer than patients who received a placebo (inactive medication). Further studies are needed because toxic effects associated with the use of AZT were noted and the long-term effectiveness and toxicity of AZT are still unknown. It is also unknown if AZT will benefit patients with less severe HIV infections such as early ARC or PGL.

Detailed description: In one human study, patients with AIDS or advanced ARC who received AZT had fewer life-threatening infections, improved in weight and performance, and lived longer than patients who received a placebo (inactive medication). Further studies are needed because toxic effects associated with the use of AZT were noted and the long-term effectiveness and toxicity of AZT are still unknown. It is also unknown if AZT will benefit patients with less severe HIV infections such as early ARC or PGL.

Patients accepted into the study are randomly assigned to receive either AZT or placebo. Treatment continues for a minimum of 104 weeks beyond the time the last patient enters the study. If the study medication causes toxic effects, the dose is decreased or temporarily stopped, and if the toxic effects are severe, then the medication will be stopped permanently. Participants visit the clinic every 2 weeks during the first 16 weeks and once a month thereafter. Throughout the study frequent blood samples are taken to monitor the effectiveness and safety of the treatment. AMENDED: The placebo arm has been discontinued as of August 3, 1989 and the AZT dose has been reduced.

Eligibility criteria: Inclusion Criteria

* Patients must have a positive antibody to HIV confirmed by a federally licensed ELISA test kit.
* The CD4 cell count must be 201 - 799 cells/mm3 measured on two separate occasions within 60 days at least 72 hours apart prior to study entry (at least 1 of 2 counts and the mean must be \< 800 cells/mm3, and at least 1 of 2 counts and the mean must be \> 200 cells/mm3). The last count must be within 14 days of study entry.

Concurrent Medication:

Allowed:

* Acetaminophen and acetaminophen products but use should be minimized. Continuous use for \> 72 hours is discouraged.
* Aerosolized pentamidine.

Prior Medication:

Allowed:

* Chemoprophylaxis for Pneumocystis carinii pneumonia with aerosolized pentamidine of 300 mg every 4 weeks through the Respirgard II nebulizer if patient has CD4(+) count \< 200 cells/mm3 measured on 2 determinations at least 48 hours apart.

Exclusion Criteria

Concurrent Medication:

Excluded:

* Other antiretroviral agents, biologic modifiers or corticosteroids.
* Other experimental medications.
* Systemic chemoprophylaxis of Pneumocystic carinii pneumonia (PCP) - aerosolized pentamidine is allowed.

Prior Medication:

Excluded:

* Zidovudine (AZT).
* Other antiretroviral agents.
* Excluded within 30 days of study entry:
* Biologic modifiers or corticosteroids.
* Excluded within 60 days of study entry:
* Ribavirin.

Prior Treatment:

Excluded within 30 days of study entry:

* Blood transfusions.

Patients may not have any of the following diseases or symptoms:

* Active oral candidiasis at entry.
* An opportunistic infection or malignancy fulfilling the definition of AIDS (CDC Surveillance Case Definition for Acquired Immunodeficiency Syndrome).
* Temperature \> 38.5 degrees C persisting for \> 14 consecutive days or \> 15 days in a 30-day interval present at entry.
* Chronic diarrhea defined as = or \> 3 liquid stools per day, persisting for \> 14 days without a definable cause during the past 2 years.
* HIV neurologic disease as manifested by motor abnormalities including impaired rapid eye movements or ataxia; motor weakness in the lower extremities; sensory deficit consistent with a peripheral neuropathy; bladder or bowel incontinence.
* Concurrent neoplasms other than basal cell carcinoma of the skin or in situ carcinoma of the cervix.
* Subjects with hemophilia should be evaluated and treated under the hemophilia protocols, if available at that ACTG.

Patients may not have any of the following diseases or symptoms:

* Active oral candidiasis at entry.
* An opportunistic infection or malignancy fulfilling the definition of AIDS (CDC Surveillance Case Definition for Acquired Immunodeficiency Syndrome).
* Temperature \> 38.5 degrees C persisting for \> 14 consecutive days or \> 15 days in a 30-day interval present at entry.
* Chronic diarrhea defined as = or \> 3 liquid stools per day, persisting for \> 14 days without a definable cause during the past 2 years.
* HIV neurologic disease as manifested by motor abnormalities including impaired rapid eye movements or ataxia; motor weakness in the lower extremities; sensory deficit consistent with a peripheral neuropathy; bladder or bowel incontinence.
* Concurrent neoplasms other than basal cell carcinoma of the skin or in situ carcinoma of the cervix.
* Subjects with hemophilia should be evaluated and treated under the hemophilia protocols, if available at that ACTG.

Active drug or alcohol abuse.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Los Angeles County - USC Med Ctr
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Ctr
state: California
city: Palo Alto
country: United States
facility: Palo Alto Veterans Adm Med Ctr / Stanford Univ
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: Stanford at Kaiser / Kaiser Permanente Med Ctr
state: California
city: Stanford
country: United States
facility: Stanford Univ School of Medicine
state: California
city: Torrance
country: United States
facility: Harbor UCLA Med Ctr
state: California
city: Washington
country: United States
facility: George Washington Univ Med Ctr
state: District of Columbia
city: Miami
country: United States
facility: Univ of Miami School of Medicine
state: Florida
city: Chicago
country: United States
facility: Northwestern Univ Med School
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ Hosp
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins Hosp
state: Maryland
city: Boston
country: United States
facility: Harvard (Massachusetts Gen Hosp)
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess - West Campus
state: Massachusetts
city: Minneapolis
country: United States
facility: Univ of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: St Louis Regional Hosp / St Louis Regional Med Ctr
state: Missouri
city: Bronx
country: United States
facility: Bronx Municipal Hosp Ctr/Jacobi Med Ctr
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: Bronx Veterans Administration / Mount Sinai Hosp
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: New York
country: United States
facility: Beth Israel Med Ctr / Peter Krueger Clinic
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: Cornell Univ Med Ctr
state: New York
city: New York
country: United States
facility: Saint Luke's - Roosevelt Hosp Ctr
state: New York
city: New York
country: United States
facility: Mount Sinai Med Ctr
state: New York
city: Rochester
country: United States
facility: Univ of Rochester Medical Center
state: New York
city: Stony Brook
country: United States
facility: SUNY - Stony Brook
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: Durham
country: United States
facility: Duke Univ Med Ctr
state: North Carolina
city: Cincinnati
country: United States
facility: Holmes Hosp / Univ of Cincinnati Med Ctr
state: Ohio
city: Cleveland
country: United States
facility: Univ Hosp of Cleveland / Case Western Reserve Univ
state: Ohio
city: Columbus
country: United States
facility: Columbus Children's Hosp
state: Ohio
city: Columbus
country: United States
facility: Ohio State Univ Hosp Clinic
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson Univ Hosp
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Univ of Pittsburgh Med School
state: Pennsylvania
city: West Columbia
country: United States
facility: Julio Arroyo
state: South Carolina
city: Seattle
country: United States
facility: Univ of Washington
state: Washington
Study officials:
name: MA Fischl
role: STUDY_CHAIR
name: DD Richman
role: STUDY_CHAIR
References:
citation: Fischl MA, Richman DD, Hansen N, Collier AC, Carey JT, Para MF, Hardy WD, Dolin R, Powderly WG, Allan JD, et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection. A double-blind, placebo-controlled trial. The AIDS Clinical Trials Group. Ann Intern Med. 1990 May 15;112(10):727-37. doi: 10.7326/0003-4819-112-10-727.
citation: Bass HZ, Hardy WD, Mitsuyasu RT, Wang YX, Cumberland W, Fahey JL. Eleven lymphoid phenotypic markers in HIV infection: selective changes induced by zidovudine treatment. J Acquir Immune Defic Syndr (1988). 1992;5(9):890-7.
citation: Bass HZ, Nishanian P, Hardy WD, Mitsuyasu RT, Esmail E, Cumberland W, Fahey JL. Immune changes in HIV-1 infection: significant correlations and differences in serum markers and lymphoid phenotypic antigens. Clin Immunol Immunopathol. 1992 Jul;64(1):63-70. doi: 10.1016/0090-1229(92)90060-2.
citation: Wu AW, Rubin HR, Mathews WC, Brysk LM, Bozzette SA, Hardy WD, Atkinson JH, Grant I, Spector SA, McCutchan JA, et al. Functional status and well-being in a placebo-controlled trial of zidovudine in early symptomatic HIV infection. J Acquir Immune Defic Syndr (1988). 1993 May;6(5):452-8.
citation: Jacobson MA, Gundacker H, Hughes M, Fischl M, Volberding P. Zidovudine side effects as reported by black, Hispanic, and white/non-Hispanic patients with early HIV disease: combined analysis of two multicenter placebo-controlled trials. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Jan 1;11(1):45-52. doi: 10.1097/00042560-199601010-00006.
citation: Kozal MJ, Shafer RW, Winters MA, Katzenstein DA, Merigan TC. A mutation in human immunodeficiency virus reverse transcriptase and decline in CD4 lymphocyte numbers in long-term zidovudine recipients. J Infect Dis. 1993 Mar;167(3):526-32. doi: 10.1093/infdis/167.3.526.
citation: McCorkindale C, Dybevik K, Coulston AM, Sucher KP. Nutritional status of HIV-infected patients during the early disease stages. J Am Diet Assoc. 1990 Sep;90(9):1236-41.
citation: Lin DY, Fischl MA, Schoenfeld DA. Evaluating the role of CD4-lymphocyte counts as surrogate endpoints in human immunodeficiency virus clinical trials. Stat Med. 1993 May 15;12(9):835-42. doi: 10.1002/sim.4780120904.
citation: Lagakos S, Fischl MA, Stein DS, Lim L, Volberding P. Effects of zidovudine therapy in minority and other subpopulations with early HIV infection. JAMA. 1991 Nov 20;266(19):2709-12.
citation: Melnick SL, Hannan P, Decher L, Little JW, Rhame FS, Balfour HH Jr, Volberding P. Increasing CD8+ T lymphocytes predict subsequent development of intraoral lesions among individuals in the early stages of infection by the human immunodeficiency virus. J Acquir Immune Defic Syndr (1988). 1991;4(12):1199-207.