Clinical trial NCT00000651: A Randomized, Double Blind, Comparative Study of Dideoxycytidine (ddC) Alone or ddC/AZT Combination Versus Zidovudine (ZDV) Alone in Patients With HIV Infection Who Have Received Prior ZDV Therapy
Official title: A Randomized, Double Blind, Comparative Study of Dideoxycytidine (ddC) Alone or ddC/AZT Combination Versus Zidovudine (ZDV) Alone in Patients With HIV Infection Who Have Received Prior ZDV Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Zalcitabine
Antiviral Agents
Zidovudine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Hoffmann-La Roche
name: Glaxo Wellcome
First posted: 2001-08-31
Enrollment: 750
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: To evaluate the safety of zalcitabine (dideoxycytidine; ddC) alone and in combination with zidovudine (AZT) versus AZT alone when administered to asymptomatic patients with a CD4 count = or \< 200 cells/mm3 and symptomatic patients with a CD4 count = or \< 300 cells/mm3. To compare the effectiveness of ddC alone and in combination with AZT versus AZT alone.

ddC has been shown to demonstrate an antiviral effect. AZT has been shown to significantly decrease mortality and reduce the frequency of opportunistic infections in patients with AIDS or advanced ARC. After 1 year of AZT therapy, the effectiveness tends to diminish and patients progress with more opportunistic infections and higher mortality rates. Because of the demonstrated antiviral activity, absence of hematologic toxicity, and lack of cross tolerance in laboratory studies of ddC, a study to investigate the long-term effectiveness of ddC in patients with HIV infection who have received AZT therapy is warranted.

Detailed description: ddC has been shown to demonstrate an antiviral effect. AZT has been shown to significantly decrease mortality and reduce the frequency of opportunistic infections in patients with AIDS or advanced ARC. After 1 year of AZT therapy, the effectiveness tends to diminish and patients progress with more opportunistic infections and higher mortality rates. Because of the demonstrated antiviral activity, absence of hematologic toxicity, and lack of cross tolerance in laboratory studies of ddC, a study to investigate the long-term effectiveness of ddC in patients with HIV infection who have received AZT therapy is warranted.

Patients are randomly assigned to 1 of 3 treatment groups. In study arm 1, patients receive AZT plus ddC placebo. In study arm 2, patients receive ddC plus AZT placebo capsules. In study arm 3, patients receive ddC plus AZT. Patients are seen every other week for first 8 weeks and monthly thereafter. Patients are stratified by HIV disease status, length of time receiving AZT, and systemic or local Pneumocystis carinii pneumonia (PCP) prophylaxis. Patients who reach a clinical AIDS-defining endpoint are offered open-label combination therapy.

Eligibility criteria: Inclusion Criteria

Concurrent Medication:

Required:

* Zidovudine (AZT) = or \> 300 mg/day for 6 weeks prior to study entry.

Allowed:

* Chemoprophylaxis for Pneumocystis carinii pneumonia (PCP), candidiasis, and herpes.
* 21 day course of adjuvant systemic corticosteroids for moderate to severe PCP.
* Maintenance treatment with pyrimethamine, sulfadiazine, amphotericin, fluconazole, ketoconazole, acyclovir, ganciclovir, or medications for tuberculosis or Mycobacterium avium for patients who have recovered from toxoplasmosis, cryptococcosis, candidiasis, herpes virus infections, cytomegalovirus infections, tuberculosis or Mycobacterium avium intracellulare.
* 14 day course of metronidazole.
* Erythropoietin and megace if clinically indicated.
* Isoniazid if patient has no peripheral neuropathy at entry and is taking pyridoxine = or \> 50 mg/day concomitantly.
* Phenytoin if patient has \< grade 2 peripheral neuropathy at entry and has been stable on phenytoin = or \> 3 months.

Patients must have:

* Ability and willingness to give informed consent.
* Written informed consent from a parent or guardian if \< 18 years old.
* Been tolerating zidovudine (AZT) therapy.
* Diagnosis of HIV infection.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

* Kaposi's sarcoma or other malignancy requiring therapy.
* Active opportunistic infections.
* Peripheral neuropathy as manifested by complaints of moderate pain, burning, numbness, or tingling in hands/arms or feet/legs; moderate sensory deficit in the upper or lower extremities; or motor weakness in the upper or lower extremities.

Concurrent Medication:

Excluded:

* Other experimental medications.
* Other anti-HIV drugs.
* Biologic response modifiers.
* Cytotoxic chemotherapy.
* Drugs that could cause peripheral neuropathy including phenytoin not specifically allowed, hydralazine, nitrofurantoin, vincristine, cisplatinum, dapsone, disulfiram, and diethyldithiocarbamate.

Concurrent Treatment:

Excluded:

* Radiation therapy.

Patients with the following are excluded:

* Active opportunistic infection. Must have ended acute therapy at least 14 days prior to study entry.
* Peripheral neuropathy = or \> grade 2.
* History of intolerance to 500 to 600 mg/day of zidovudine (AZT) as manifested by the same recurrent grade 3 toxicity requiring dose interruptions and dose reductions to \< 500 mg/day or any prior grade 4 toxicity.
* Prior development of peripheral neuropathy on ddI = or \> grade 2.

Prior Medication:

Excluded:

* Dideoxycytidine (ddC).

Required:

* Zidovudine (AZT) for total of at least 24 weeks; and included within that time period, AZT = or \> 300 mg/day for 6 weeks prior to the study entry.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC CRS
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: San Diego
country: United States
facility: UCSD Maternal, Child, and Adolescent HIV CRS
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Infectious Disease Research Clinic
state: Indiana
city: New Orleans
country: United States
facility: Tulane Hemophilia Treatment Ctr.
state: Louisiana
city: New Orleans
country: United States
facility: Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: HMS - Children's Hosp. Boston, Div. of Infectious Diseases
state: Massachusetts
city: Boston
country: United States
facility: Bmc Actg Crs
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess - East Campus A0102 CRS
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp., Div. of Infectious Disease
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota, ACTU
state: Minnesota
city: Saint Louis
country: United States
facility: St. Louis ConnectCare, Infectious Diseases Clinic
state: Missouri
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Newark
country: United States
facility: NJ Med. School CRS
state: New Jersey
city: Buffalo
country: United States
facility: SUNY - Buffalo, Erie County Medical Ctr.
state: New York
city: New York
country: United States
facility: NYU Med. Ctr., Dept. of Medicine
state: New York
city: New York
country: United States
facility: Cornell University A2201
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Ctr.
state: New York
city: New York
country: United States
facility: Beth Israel Med. Ctr. (Mt. Sinai)
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas HealthCare System, Carolinas Med. Ctr.
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS
state: North Carolina
city: Greensboro
country: United States
facility: Regional Center for Infectious Disease, Wendover Medical Center CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS
state: Ohio
city: Pittsburgh
country: United States
facility: Pitt CRS
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
Study officials:
name: M Fischl
role: STUDY_CHAIR
name: A Collier
role: STUDY_CHAIR
References:
citation: Blum AS, Dal Pan GJ, Feinberg J, Raines C, Mayjo K, Cornblath DR, McArthur JC. Low-dose zalcitabine-related toxic neuropathy: frequency, natural history, and risk factors. Neurology. 1996 Apr;46(4):999-1003. doi: 10.1212/wnl.46.4.999.
citation: Fichtenbaum CJ, Clifford DB, Powderly WG. Risk factors for dideoxynucleoside-induced toxic neuropathy in patients with the human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Oct 1;10(2):169-74. doi: 10.1097/00042560-199510020-00009.
citation: Fischl M, Collier A, Stanley K, Ardunio JM, Kazial K, Stein D. The safety and efficacy of zidovudine (ZDV) and zalcitabine (ddC) or ddC alone versus ZDV. ACTG 155 Team of the NIAID. Int Conf AIDS. 1993 Jun 6-11;9(1):68 (abstract no WS-B25-1)
citation: Keruly J, Kendig N, Feinberg J, Cotton S, Biggs M, Benjamin Y, Francis H, Wade W, Coplin M, Bartlett J. A model for conducting AIDS clinical trials in a state correctional system. Int Conf AIDS. 1992 Jul 19-24;8(2):B236 (abstract no PoB 3873)
citation: Johnson VA. Combination therapy: more effective control of HIV type 1? AIDS Res Hum Retroviruses. 1994 Aug;10(8):907-12. doi: 10.1089/aid.1994.10.907.
citation: Fischl MA, Stanley K, Collier AC, Arduino JM, Stein DS, Feinberg JE, Allan JD, Goldsmith JC, Powderly WG. Combination and monotherapy with zidovudine and zalcitabine in patients with advanced HIV disease. The NIAID AIDS Clinical Trials Group. Ann Intern Med. 1995 Jan 1;122(1):24-32. doi: 10.7326/0003-4819-122-1-199501010-00004.
citation: Spino C, Kahn JO, Dolin R, Phair JP. Predictors of survival in HIV-infected persons with 50 or fewer CD4 cells/mm3. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Aug 15;15(5):346-55. doi: 10.1097/00042560-199708150-00004.
citation: Zackin RA, Clark RA, Currier JS, Mildvan D. Predictive markers of HIV-related weight loss and determination of differences between populations with weight loss stratified by opportunistic processes. J Acquir Immune Defic Syndr. 1999 Oct 1;22(2):189-93. doi: 10.1097/00126334-199910010-00012.