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

Condition(s) targeted: HIV Infections

Intervention: Zidovudine (Drug); Zalcitabine (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
M Fischl, Study Chair
A Collier, Study Chair

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.

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 design: Treatment, Double-Blind

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.

Minimum age: 13 Years. Maximum age: N/A. Gender(s): Both.

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.

Univ of California / San Diego Treatment Ctr, San Diego, California 921036325, United States

UCSD Med Ctr / Pediatrics / Clinical Sciences, La Jolla, California 920930672, United States

Sepulveda Veterans Adm Med Ctr / Olive View Med Ctr, Sylmar, California 91342, United States

Stanford at Kaiser / Kaiser Permanente Med Ctr, San Francisco, California 94115, United States

Palo Alto Veterans Adm Med Ctr / Stanford Univ, Palo Alto, California 94304, United States

Stanford Private Practice, Redwood City, California, United States

UCLA CARE Ctr, Los Angeles, California 90095, United States

Univ of Southern California / LA County USC Med Ctr, Los Angeles, California 900331079, United States

Harbor UCLA Med Ctr, Torrance, California 90502, United States

Olive View Med Ctr, Sylmar, California 91342, United States

Univ Hosp / Univ of Colorado Health Sci Ctr, Denver, Colorado 80262, United States

George Washington Univ Med Ctr, Washington, District of Columbia 20037, United States

Univ of Miami School of Medicine, Miami, Florida 331361013, United States

Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States

Johns Hopkins Hosp, Baltimore, Maryland 21287, United States

Harvard (Massachusetts Gen Hosp), Boston, Massachusetts 02114, United States

Beth Israel Deaconess Med Ctr, Boston, Massachusetts 02215, United States

Beth Israel Deaconess - West Campus, Boston, Massachusetts 02215, United States

Boston Med Ctr, Boston, Massachusetts 02118, United States

Children's Hosp of Boston, Boston, Massachusetts 021155724, United States

Baystate Med Ctr of Springfield, Springfield, Massachusetts 01199, United States

Univ of Minnesota, Minneapolis, Minnesota 55455, United States

St Louis Regional Hosp / St Louis Regional Med Ctr, St. Louis, Missouri 63112, United States

Univ of Medicine & Dentistry of New Jersey / Univ Hosp, Newark, New Jersey 071032714, United States

Nassau County Med Ctr, East Meadow, New York 11554, United States

SUNY - Stony Brook, Stony Brook, New York 117948153, United States

Bellevue Hosp / New York Univ Med Ctr, New York, New York 10016, United States

Mem Sloan - Kettering Cancer Ctr, New York, New York 10021, United States

Mount Sinai Med Ctr, New York, New York 10029, United States

Jack Weiler Hosp / Bronx Municipal Hosp, Bronx, New York 10465, United States

Cornell Univ Med Ctr, New York, New York 10021, United States

Saint Luke's - Roosevelt Hosp Ctr, New York, New York 10025, United States

Bronx Municipal Hosp Ctr/Jacobi Med Ctr, Bronx, New York 10461, United States

Montefiore Med Ctr / Bronx Municipal Hosp, Bronx, New York 10467, United States

Bronx Veterans Administration / Mount Sinai Hosp, Bronx, New York 10468, United States

SUNY / Erie County Med Ctr at Buffalo, Buffalo, New York 14215, United States

Beth Israel Med Ctr, New York, New York 10003, United States

City Hosp Ctr at Elmhurst / Mount Sinai Hosp, Elmhurst, New York 11373, United States

North Central Bronx Hosp / Bronx Municipal Hosp, Bronx, New York 10467, United States

Univ of North Carolina, Chapel Hill, North Carolina 275997215, United States

Moses H Cone Memorial Hosp, Greensboro, North Carolina 27401, United States

Duke Univ Med Ctr, Durham, North Carolina 27710, United States

Bowman Gray School of Medicine / Wake Forest Univ, Winston Salem, North Carolina 27103, United States

Case Western Reserve Univ, Cleveland, Ohio 44106, United States

Univ of Cincinnati, Cincinnati, Ohio 452670405, United States

Ohio State Univ Hosp Clinic, Columbus, Ohio 432101228, United States

Columbus Children's Hosp, Columbus, Ohio 432052696, United States

Med College of Ohio, Toledo, Ohio 43699, United States

Univ of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States

Julio Arroyo, West Columbia, South Carolina 29169, United States

Univ of Washington, Seattle, Washington 981224304, United States

Click here for more information about Zidovudine

Click here for more information about Zalcitabine

Related publications:

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.

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.

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)

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)

Johnson VA. Combination therapy: more effective control of HIV type 1? AIDS Res Hum Retroviruses. 1994 Aug;10(8):907-12. Review.

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.

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.

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.

Last updated: June 23, 2005