San Francisco,
California
94115
Purpose:
To compare the effectiveness of zalcitabine ( dideoxycytidine; ddC ) therapy to zidovudine (
AZT ) in the treatment of AIDS or advanced AIDS related complex ( ARC ) in patients who have
already received at least 1 year of AZT therapy and to define the safety profile.
ddC has been shown to have an antiviral effect, and AZT is known to significantly decrease
mortality and to 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. This may be due to
the emergence of AZT resistant virus isolated from some patients who have been on long-term
AZT therapy. These isolates were still sensitive to ddC. A study of long-term effectiveness
of ddC in patients with AIDS or advanced ARC who have been on long-term AZT therapy is
warranted because (1) ddC has antiviral activity, (2) there is no blood toxicity associated
with taking ddC, and (3) the effectiveness of ddC in test tube studies does not seem to be
diminished by decreased effectiveness of AZT.
Study summary:
ddC has been shown to have an antiviral effect, and AZT is known to significantly decrease
mortality and to 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. This may be due to
the emergence of AZT resistant virus isolated from some patients who have been on long-term
AZT therapy. These isolates were still sensitive to ddC. A study of long-term effectiveness
of ddC in patients with AIDS or advanced ARC who have been on long-term AZT therapy is
warranted because (1) ddC has antiviral activity, (2) there is no blood toxicity associated
with taking ddC, and (3) the effectiveness of ddC in test tube studies does not seem to be
diminished by decreased effectiveness of AZT.
AMENDED: AZT will be administered orally every 4 or 5 hours. Patients in the second arm
discontinue AZT and take ddC as two tablets every 8 hours. Duration of the study is 1 year
with interim analysis done at 6 months after 75 percent enrollment and at end of the study.
Original design: Patients with AIDS or advanced ARC who have been receiving at least 500
mg/day of AZT for at least 48 weeks are randomized to 1 of 2 treatment arms. Patients in the
first treatment arm continue their current dose of AZT.
Criteria:
Inclusion Criteria
Concurrent Medication:
Required:
- Aerosolized pentamidine will be given, as tolerated for all patients, for
Pneumocystis carinii pneumonia prophylaxis at a dose of 300 mg once every 4 weeks.
Allowed maintenance treatment with:
- Pyrimethamine (= or < 75 mg/day).
- Sulfadiazine (< 4 gl/day).
- Amphotericin (1 mg/kg/day up to 5 days).
- Fluconazole (400 mg/day).
- Ketoconazole (400 mg/day).
- Acyclovir (up to 12.4 mg/kg q8h IV for zoster or up to 4000 mg/day will be allowed PO
with precautions - nausea and vomiting possible with doses > 1000 mg/day).
- Ganciclovir (6 mg/kg/day).
- 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.
- Erythropoietin and megace as needed.
- Isoniazid if patient has no peripheral neuropathy at study entry and is taking
pyridoxine at least 50 mg/day concomitantly.
- Phenytoin if patient has no peripheral neuropathy at study entry and has been stable
on the drug for at least 3 months.
Patients must have had Pneumocystis carinii pneumonia (PCP) and no other AIDS defining
opportunistic infection present when zidovudine (AZT) therapy was first initiated.
Patients must have:
- Advanced AIDS related complex (ARC).
- Antibody to HIV by federally licensed ELISA and confirmed by Western blot analysis.
- Ability to give conformed consent.
Exclusion Criteria
Co-existing Condition:
Patients are excluded who:
- Have had zidovudine (AZT) therapy interrupted for > 30 consecutive days at any time
during AZT therapy or have been off AZT for > 90 days total.
- Have had AZT therapy interrupted for "recurrent" grade 4 toxicity, defined as > one
episode of the same grade 4 toxicity after dose interruption or attenuation.
- Have visceral or extensive Kaposi's sarcoma requiring therapy or any other malignancy
requiring therapy.
- Have a history of peripheral neuropathy.
Concurrent Medication:
Excluded:
- Other experimental medications, including foscarnet, ribavirin, and fluconazole
(prior to IND approval).
- Other antiretroviral agents, biologic modifiers or corticosteroids.
- Drugs that can cause peripheral neuropathy including phenytoin (under conditions not
specifically allowed), hydralazine, metronidazole, nitrofurantoin, vincristine,
cisplatinum, dapsone, disulfiram, and diethyldithiocarbamate.
Patients with the following are excluded:
- History of peripheral neuropathy or moderate to severe peripheral neuropathy as
defined by the combination of signs or symptoms of peripheral neuropathy and findings
indicative of peripheral neuropathy on the standardized neurologic exam.
- Active opportunistic infection.
- Participation in another research treatment study.
Prior Medication:
Excluded:
- Dideoxycytidine (ddC).
- Didanosine (ddI).
Active substance or alcohol abuse.