(Ro 24-2027) A Randomized, Double-Blind, Comparative Study of Dideoxycytidine (ddC) Versus Zidovudine (AZT) in Patients With AIDS or Advanced ARC

Condition(s) targeted: HIV Infections

Intervention: Zidovudine (Drug); Zalcitabine (Drug)

Phase: Phase 2

Status: Completed

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

To show that zalcitabine (dideoxycytidine; ddC) is at least as effective as zidovudine (AZT) in the treatment of AIDS or advanced AIDS related complex (ARC), and also that ddC shows a different safety profile than AZT.

In clinical studies, ddC shows antiviral activity. Because of the antiviral activity, and because of the low incidence of mild, reversible neurotoxicity and absence of blood-related toxicity with low dose ddC therapy, a long-term Phase II/III study comparing ddC to AZT in patients with AIDS or advanced ARC is now warranted.

Official title: (Ro 24-2027) A Randomized, Double-Blind, Comparative Study of Dideoxycytidine (ddC) Versus Zidovudine (AZT) in Patients With AIDS or Advanced ARC

Study design: Treatment, Double-Blind

Detailed description: In clinical studies, ddC shows antiviral activity. Because of the antiviral activity, and because of the low incidence of mild, reversible neurotoxicity and absence of blood-related toxicity with low dose ddC therapy, a long-term Phase II/III study comparing ddC to AZT in patients with AIDS or advanced ARC is now warranted.

After screening, physical examination and laboratory tests (within 14 days of entry) patients are randomized to one of two treatment groups. They receive either ddC plus an AZT placebo or AZT plus a ddC placebo. Because it is a blinded study, patients do not know which group they are in. Patients are evaluated weekly for the first 10 weeks and then biweekly thereafter.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria

Concurrent Medication:

Allowed:

- Aerosolized pentamidine (300 mg once every 4 weeks) for Pneumocystis carinii pneumonia

(PCP) prophylaxis.

- Neuroleptics, benzodiazepines, or antidepressants if patient has been stable with

chronic treatment > 1 month.

- Low dose benzodiazepines or low dose antidepressants.

- Drugs that are unlikely to cause increased toxicity with either study drug and are

unlikely to cause peripheral neuropathy.

- Drugs with little nephrotoxicity, hepatotoxicity, or cytotoxicity that the patient has

been taking and tolerating well.

- Acyclovir (up to 600 mg/kg/day) for up to 21 days.

- Ketoconazole (up to 400 mg/day) Nystatin.

- Low-dose acetaminophen or nonsteroidal anti-inflammatory agents.

- Isoniazid if patient has no evidence of peripheral neuropathy at entry and if patient

takes 50 mg/day pyridoxine concomitantly with isoniazid.

- Allowed with interruption of study medication for up to 21 days per episode and for a

total of 42 days for the study:

- Drugs that could cause serious additive toxicity when coadministered with either study

medication for treatment of an acute intercurrent illness or opportunistic infection, including:

- Acyclovir (< 600 mg/day), fluconazole, systemic pentamidine, foscarnet, pyrimethamine,

triple sulfa, ansamycin, ganciclovir, trimethoprim / sulfamethoxazole.

Patients must have a diagnosis of AIDS or advanced AIDS related complex (ARC). At least 20 percent of the patients must have a consistently positive serum HIV p24 antigen (= or > 70 pg/ml) as defined by the Abbott HIV antigen test, on two separate occasions at least 72 hours apart.

- Patients found at screening to have a temperature > 38. 5 degrees C should be evaluated

for the possibility of an occult opportunistic or bacterial infection or neoplasm. If this complete evaluation reveals an infection, they can be entered. If this evaluation is unrevealing, they may be entered after evaluation is completed but while mycobacterial cultures are still pending. Patients with a history of unexplained temperatures > 38. 5 degrees C should be evaluated as above and/or be afebrile (temperature < 38. 0 degrees C) for 2 weeks prior to study entry.

- Allowed: Kaposi's sarcoma not specifically excluded, basal cell carcinoma of the skin

or in situ carcinoma of the cervix.

- Current positive venereal disease research label (VDRL) and fluorescent treponemal

antibody (FTA) if treated as for asymptomatic neurosyphilis.

Prior Medication:

Allowed:

- Drugs that cause peripheral neuropathy and drugs that could cause significant

increased toxicity with zidovudine (AZT) or dideoxycytidine (ddC) including experimental drugs if therapy with these drugs is completed and patient is stable for 14 days.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

- Active AIDS defining opportunistic infection or other active intercurrent illness is

excluded if ongoing treatment requires the use of excluded concomitant medication.

- Patients with symptomatic visceral Kaposi's sarcoma (KS), progression of KS within the

month prior to entry into the study, or with current neoplasms not specifically allowed.

- Severe AIDS dementia complex defined by a score of < 23 on the Mini-Mental State

Exam.

- Signs, symptoms, or history of peripheral neuropathy.

- Significant cardiac disease, defined as history of ventricular arrhythmias requiring

medication, prior myocardial infarct, or history of angina or ischemia changes on ECG (electrocardiography).

- Requiring > 2 weeks of acyclovir therapy at > 600 mg/day.

- Current positive venereal disease research label (VDRL) and fluorescent treponemal

antibody (FTA) not specifically allowed.

- Significant liver disease.

Concurrent Medication:

Excluded:

- Drugs that cause peripheral neuropathy:

- chloramphenicol, cisplatinum, iodoquinol, dapsone, phenytoin, disulfiram, ethionamide,

glutethimide, gold, hydralazine, ribavirin, metronidazole, vincristine, nitrofurantoin.

- Drugs that could cause significant increased toxicity with zidovudine (AZT) or

dideoxycytidine (ddC), including experimental drugs not specifically allowed.

- Drugs that could cause seizures or changes in mental status or neurological

examination.

Concurrent Treatment:

Excluded:

- Transfusion dependency.

Patients with the following are excluded:

- Active AIDS defining opportunistic infection or other active intercurrent illness if

ongoing treatment requires use of excluded concomitant medication.

- Symptomatic visceral Kaposi's sarcoma (KS), progression of KS within the month prior

to study entry, or current neoplasms not specifically allowed.

- Severe AIDS dementia complex defined by a score of < 23 on the Mini-Mental State

Exam.

- Signs, symptoms, or history of peripheral neuropathy.

- Unwilling or unable to sign informed consent.

Prior Medication:

Excluded:

- Zidovudine (AZT), dideoxycytidine (ddC), or any other antiretroviral nucleoside

analog.

- Excluded within 90 days of study entry:

- Any experimental drug including fluconazole, ganciclovir, foscarnet, erythropoietin,

or ribavirin.

Excluded within 90 days of study entry:

- Drugs that have caused significant nephrotoxicity or significant hepatotoxicity.

- Drugs that could cause peripheral neuropathy including phenytoin, hydralazine,

metronidazole, and nitrofurantoin.

- Systemic corticosteroids or immunomodulators including interferon and interleukin.

Prior Treatment:

Excluded within 30 days of study entry:

- Radiation therapy.

Active substance or alcohol abuse.

Mount Zion Med Ctr, San Francisco, California 94115, United States

Davies Med Ctr, San Francisco, California 94114, United States

San Francisco Veterans Administration Med Ctr, San Francisco, California 94121, United States

UCD Med Ctr, Sacramento, California 95817, United States

Kaiser Permanente Med Ctr, Los Angeles, California 90027, United States

Santa Clara Valley Med Ctr, San Jose, California 95128, United States

Kaiser Foundation Hosp, Harbor City, California 90710, United States

Georgetown Univ Med Ctr, Washington, District of Columbia 20007, United States

Comprehensive Clinic / Dr Robert Schwartz, Fort Myers, Florida 33901, United States

Med Service, Miami, Florida 33125, United States

Ctr for Special Immunology, Fort Lauderdale, Florida 33308, United States

AIDS Research Consortium of Atlanta, Atlanta, Georgia 30308, United States

Northwestern Univ Med School, Chicago, Illinois 60611, United States

Rush Presbyterian - Saint Luke's Med Ctr, Chicago, Illinois 60612, United States

New England Med Ctr, Boston, Massachusetts 02111, United States

Henry Ford Hosp, Detroit, Michigan 48202, United States

Saint Michael's Med Ctr, Newark, New Jersey 07102, United States

Sunset Park Health Ctr - Lutheran Med Ctr, Brooklyn, New York 11220, United States

Albany Med College / AIDS Treatment Ctr, Albany, New York 12203, United States

Bowman Gray School of Medicine / North Carolina Baptist Hosp, Winston Salem, North Carolina 27103, United States

Univ Hosp of Cleveland / Case Western Reserve Univ, Cleveland, Ohio 44106, United States

Graduate Hosp, Philadelphia, Pennsylvania 19146, United States

N Texas Ctr for AIDS & Clin Rsch, Dallas, Texas 75219, United States

Baylor College of Medicine, Houston, Texas 77030, United States

Univ TX Galveston Med Branch, Galveston, Texas 77550, United States

Click here for more information about Zidovudine

Click here for more information about Zalcitabine

Related publications:

Bozzette SA, Hays RD, Berry SH, Kanouse DE. A Perceived Health Index for use in persons with advanced HIV disease: derivation, reliability, and validity. Med Care. 1994 Jul;32(7):716-31.

Bozzette SA, Hays RD, Berry SH, Kanouse DE, Wu AW. Derivation and properties of a brief health status assessment instrument for use in HIV disease. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Mar 1;8(3):253-65.

Bozzette SA, Kanouse DE, Berry S, Duan N. Health status and function with zidovudine or zalcitabine as initial therapy for AIDS. A randomized controlled trial. Roche 3300/ACTG 114 Study Group. JAMA. 1995 Jan 25;273(4):295-301.

Bozzette SA, Kanouse D, Berry S, Duan N, Downes-LeGuin T, Hays R, Petinnelli C, Richman DD, Gocke D, Kahn J. Relative effects of ddC or ddI versus ZDV on health status, function and disability in N3300 (ACTG 114) and ACTG 116b/117. Int Conf AIDS. 1992 Jul 19-24;8(1):Mo21 (abstract no MoB 0077)

Remick S, Follansbee S, Olson R, Pollard R, Reiter W, Salgo M. Safety and tolerance of zalcitabine (ddC, HIVID) in a double-blind, comparative trial (ACTG 114; N3300). Int Conf AIDS. 1993 Jun 6-11;9(1):488 (abstract no PO-B26-2115)

Follansbee S, Drew L, Olson R, Pollard R, Relter W, Salgo M. The efficacy of zalcitabine (ddC, HIVID) versus zidovudine (ZDV) as monotherapy in ZDV naive patients with advanced HIV disease: a randomized, double-blind, comparative trial (ACTG 114; N3300). Int Conf AIDS. 1993 Jun 6-11;9(1):487 (abstract no PO-B26-2113)

Gries JM, Troconiz IF, Verotta D, Jacobson M, Sheiner LB. A pooled analysis of CD4 response to zidovudine and zalcitabine treatment in patients with AIDS and AIDS-related complex. Clin Pharmacol Ther. 1997 Jan;61(1):70-82.

Last updated: June 23, 2005