An Efficacy Study of 2',3'-Dideoxyinosine (ddI) (BMY-40900) Administered Orally Twice Daily to Zidovudine Intolerant Patients With AIDS or AIDS-Related Complex

Inclusion Criteria

Concurrent Medication:

Required:

• Aerosolized pentamidine (300 mg every 4 weeks). In the event of physiological intolerance, alternative PCP prophylaxis may be trimethoprim/sulfamethoxazole 1 DS tab per day or dapsone 50 - 100 mg per day.

Allowed:

• Chronic suppressive treatment for toxoplasmosis, Pneumocystis carinii pneumonia (PCP), cryptococcal meningitis, herpes simplex virus, cytomegalovirus, coccidioidomycosis, and histoplasmosis (absorption of ketoconazole or dapsone may be inhibited if given at the same time as the buffered solution of ddI, and should be taken 2 hours before or 2 hours after taking ddI; oral acidifying agents are not allowed). Isoniazid is permitted only if no acceptable alternative therapy is available. Metronidazole may be used for single courses not to exceed 14 days within consecutive 90 day intervals, the first of which begins at the initiation of the study. Erythropoietin for patients under the relevant treatment IND. Intravenous acyclovir for short courses of therapy.

Patients must:

• Have documented hematologic intolerance to zidovudine (AZT).
• Have the diagnosis of AIDS or advanced AIDS related complex (ARC).
• Have ended treatment for acute Pneumocystis carinii pneumonia (PCP) at least 2 weeks before study entry.

Have previous intolerance on at least two courses of AZT therapy (one of which must have been at daily doses of 500 mg of AZT or less).

• Be able to provide informed consent (and/or guardian as appropriate).
• Be available for follow-up for at least 6 months.
• Have baseline laboratory values as measured within 7 days before initial drug dosing.
• Allowed:
• Development of new opportunistic infections during the study - patients remain in the protocol.

Prior Medication:

Required:

• Prior use and intolerance to zidovudine (AZT).
• Allowed:
• Intralesional agents.

Exclusion Criteria

Co-existing Condition:

Patients with the following are excluded:

• Presence of Kaposi's sarcoma (KS) with known or suspected visceral disease or where KS requires chemotherapy.
• Active AIDS defining opportunistic infections not specifically allowed.
• Intractable diarrhea.
• Stage 2 AIDS-dementia complex.
• History of intolerance to aerosolized pentamidine.
• Grade 2 neuropathy, based on the Neuropathy Targeted Symptom Questionnaire, or any moderate abnormality indicative of peripheral neuropathy, particularly impaired sensation of sharp pain, light touch, or vibration in the lower extremities, distal extremity weakness, or distal extremity hyporeflexia.
• Prior history of acute or chronic pancreatitis.
• History of seizures within past 2 years or currently requiring anticonvulsants for control.
• Any other clinical conditions or prior therapy which, in the opinion of the investigator, would make the patient unsuitable for study or unable to comply with the dosing requirements.

Concurrent Medication:

Excluded:

• Isoniazid (INH).

Patients with the following are excluded:

• Active AIDS-defining opportunistic infections not specifically allowed.
• Intractable diarrhea.
• AIDS-dementia complex = or > stage 2.
• History of intolerance to aerosolized pentamidine. Grade 2 neuropathy, based on the Neuropathy Targeted Symptom Questionnaire, or any moderate abnormality indicative of peripheral neuropathy, particularly impaired sensation of sharp pain, light touch, or vibration in the lower extremities, distal extremity weakness, or distal extremity hyporeflexia.
• Prior history of acute or chronic pancreatitis.
• History of seizures within past 2 years or currently requiring anticonvulsants for control.
• Any other clinical conditions or prior therapy which, in the opinion of the investigator, would make the patient unsuitable for study or unable to comply with the dosing requirements.
• Previous participation in any Phase I ddI study.
• Life expectancy < 6 months.

Prior Medication:

Excluded:

• Chronic therapy for cytomegalovirus infection with ganciclovir.
• ddI.
• d4T.
• ddC.

Excluded within 2 weeks of study entry:

• Zidovudine (AZT).

Excluded within 1 month of study entry:

• Therapy with any other antiretroviral drug or investigational agent not specifically allowed, including interferon and immunomodulating drugs.
• Ganciclovir.
• Neurotoxic drugs.

Excluded within 3 months of study entry:

• Ribavirin.
• Cytotoxic anticancer therapy.

Prior Treatment:

Excluded within 2 weeks of study randomization:

• Transfusion.

Active alcohol or drug abuse that is sufficient, in investigator's opinion, to prevent adequate compliance with study therapy.

History of severe allergic reactions to study medication Currently pregnant or breastfeeding Recent participation in another clinical trial within the last 30 days Presence of uncontrolled medical conditions that could affect safety