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

NCT ID: NCT00000679

Last Updated: 2011-03-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 600 participants
• Study Classification: INTERVENTIONAL

Brief Summary

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.

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.

Conditions

HIV Infections

Study Design

• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Interventions

Zidovudine

Intervention Type: DRUG

Zalcitabine

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Locations

Kaiser Foundation Hosp

Harbor City, California, United States

Kaiser Permanente Med Ctr

Los Angeles, California, United States

UCD Med Ctr

Sacramento, California, United States

Davies Med Ctr

San Francisco, California, United States

Mount Zion Med Ctr

San Francisco, California, United States

San Francisco Veterans Administration Med Ctr

San Francisco, California, United States

Santa Clara Valley Med Ctr

San Jose, California, United States

Georgetown Univ Med Ctr

Washington D.C., District of Columbia, United States

Ctr for Special Immunology

Fort Lauderdale, Florida, United States

Comprehensive Clinic / Dr Robert Schwartz

Fort Myers, Florida, United States

Med Service

Miami, Florida, United States

AIDS Research Consortium of Atlanta

Atlanta, Georgia, United States

Northwestern Univ Med School

Chicago, Illinois, United States

Rush Presbyterian - Saint Luke's Med Ctr

Chicago, Illinois, United States

New England Med Ctr

Boston, Massachusetts, United States

Henry Ford Hosp

Detroit, Michigan, United States

Saint Michael's Med Ctr

Newark, New Jersey, United States

Albany Med College / AIDS Treatment Ctr

Albany, New York, United States

Sunset Park Health Ctr - Lutheran Med Ctr

Brooklyn, New York, United States

Bowman Gray School of Medicine / North Carolina Baptist Hosp

Winston-Salem, North Carolina, United States

Univ Hosp of Cleveland / Case Western Reserve Univ

Cleveland, Ohio, United States

Graduate Hosp

Philadelphia, Pennsylvania, United States

N Texas Ctr for AIDS & Clin Rsch

Dallas, Texas, United States

Univ TX Galveston Med Branch

Galveston, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

Countries

United States

References

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. doi: 10.1097/00005650-199407000-00005.

Reference Type: BACKGROUND

PMID: 8028406 (View on PubMed)

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. doi: 10.1097/00042560-199503010-00006.

Reference Type: BACKGROUND

PMID: 7859137 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 7815656 (View on PubMed)

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)

Reference Type: BACKGROUND

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)

Reference Type: BACKGROUND

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)

Reference Type: BACKGROUND

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. doi: 10.1016/S0009-9236(97)90183-1.

Reference Type: BACKGROUND

PMID: 9024175 (View on PubMed)

Other Identifiers

Protocol Number: N3300A

Identifier Type: -

Identifier Source: secondary_id

FDA 31A

Identifier Type: -

Identifier Source: secondary_id

Study Number: 3-27

Identifier Type: -

Identifier Source: secondary_id

ACTG 114

Identifier Type: -

Identifier Source: org_study_id