A Phase I Safety, Efficacy, and Pharmacokinetic Study of 2',3'-Dideoxyinosine (ddI) Administered Twice Daily to Patients With AIDS or AIDS Related Complex

Zidovudine (AZT) has produced the best clinical results in the drug therapy of AIDS to date, but it produces toxicity in approximately 50 percent of patients. Early data show that ddI possesses high antiviral activity and less toxicity than AZT. The most effective route and dose of ddI has yet to be determined.

Patients are given intravenous drug for 14 days with a 1 day washout period, then 76 weeks of oral medication. To expedite this safety study and still be able to maintain close monitoring of the patient's health, an overlapping dosing regimen is used. After 6 patients have been enrolled and at least 4 have completed 4 weeks of dosing without significant toxic effects, a second group of patients is started at the next dose level.

AMENDED: An alternative oral dosing formulation of ddI will be provided as a buffer powder blend packaged in sealed foil sachets in several strengths.

Inclusion criteria

Concurrent Medication:

Recommended:

• Allopurinol for consistent occurrence of hyperuricemia observed with 2',3'-dideoxyinosine (ddI) administration.

Allowed:

• Aerosolized pentamidine for Pneumocystis carinii pneumonia (PCP) prophylaxis.
• Oral acyclovir for herpes simplex infections provided ddI dosing is suspended during this time.
• Ketoconazole for patients not responding to any other therapy and after consultation with the sponsor.
• Symptomatic therapy such as analgesics, antihistamines, antiemetics, antidiarrheal agents, or other supportive therapy may be administered as deemed necessary by the principal investigator.
• Aspirin rather than acetaminophen for fever.

Patients with the following will be included:

• An absence of life-threatening opportunistic infection on enrollment.
• A life expectancy less than 6 months.
• Available for follow-up for at least 6 months.
• Able to provide informed consent. Exclusion Criteria

Co-existing Condition:

Patients with the following are excluded:

• Intractable diarrhea.
• No venous access.
• A history of or propensity for seizure disorders.
• A history of past or current heart disease or other significant abnormality on routine EKG.

Concurrent Medication:

Excluded:

• Adenine deaminase inhibitors.
• Trimethoprim / sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) infections.
• Antibiotics.
• Acetaminophen for therapy of fever.

Patients with the following are excluded:

• Intractable diarrhea.
• A life expectancy less than 6 months.
• No venous access.
• A history of or propensity for seizure disorders.
• A history of past or current heart disease or other significant abnormality on routine EKG.

Prior Medication:

Excluded:

• Any agent known as a potent inducer or inhibitor of drug-metabolizing enzymes.
• Excluded within 2 weeks of study entry:
• Trimethoprim / sulfamethoxazole.
• Excluded within 1 month of study entry:
• Any antiretroviral drug.
• Investigational agents.
• 2',3'-didanosine.
• AL721.
• Interferons.
• Immunomodulating drugs.
• Excluded within 3 months of study entry:
• Ribavirin.
• Cytotoxic agents.

Risk Behavior:

Excluded:

Active alcohol or drug abuse sufficient in the investigator's opinion to prevent adequate compliance.