A Study of Indinavir Sulfate Plus Zidovudine (AZT) Plus Lamivudine in HIV-Infected Patients Who Have Taken AZT for Six or More Months

A Randomized, Double-Blind, Phase III Study of Indinavir Sulfate With Open-Label Zidovudine (AZT) and Lamivudine (3TC) in Subjects With HIV Infection With CD4 Cell Counts <= 200 Cells/mm3 and >= 6 Months of Prior AZT Experience

To determine the clinical efficacy of indinavir sulfate or placebo in combination with zidovudine ( AZT ) and lamivudine ( 3TC ) in AIDS patients.

Protease inhibitors such as indinavir sulfate may be effective in patients with advanced HIV disease who have received prior AZT therapy. Since studies suggest that triple drug therapy may have an advantage over both monotherapy and two drug therapy, the combination of indinavir sulfate with AZT and 3TC should be evaluated.

Protease inhibitors such as indinavir sulfate may be effective in patients with advanced HIV disease who have received prior AZT therapy. Since studies suggest that triple drug therapy may have an advantage over both monotherapy and two drug therapy, the combination of indinavir sulfate with AZT and 3TC should be evaluated.

Patients are randomized to receive open-label AZT and 3TC with or without indinavir sulfate for at least 48 weeks. Patients who develop intolerance to AZT or have progressive disease after 24 weeks on study may substitute stavudine ( d4T ) for AZT. Patients are followed at weeks 4, 8, 16, 24, 32, 40, and 48 and every 8 weeks thereafter up to week 96. [AS PER 02/25/97 AMENDMENT: Accrual has been halted because interim analysis has shown triple therapy superior to double-agent therapy. An open label extension phase has been added for the period through 06/30/97. Patients who had been randomized to AZT/3TC are given the option of continuing on assigned ACTG 320 study drugs, crossing over to open-label indinavir, or permanently discontinuing all study therapies and going off study. Patients who were randomized to AZT/3TC plus indinavir or who were crossed to such therapy are given the option of continuing their currently assigned therapies. It is strongly suggested that patients who were on AZT/3TC who wish to receive open-label indinavir consider changing the nucleoside analog component of their regimen if at all possible.] [ AS PER 06/06/97 AMENDMENT: The availability of the current ACTG 320 treatment has been further extended for approximately 12 additional weeks (but not beyond 09/30/97). This extension will allow patients to continue receiving study medications until ACTG 372 is open to accrual (the rollover protocol for subjects originally randomized to the triple drug component of ACTG 320 or who are crossed over due to a confirmed study endpoint is finalized).] [ AS PER 09/15/97 AMENDMENT: Open-label therapy will be provided for no more than 90 days beyond the enrollment of the first subject on ACTG 372.]

Inclusion Criteria

Concurrent Medication:

Required:

• PCP prophylaxis.

Allowed:

• Topical or oral antifungal agents (other than oral ketoconazole).
• Approved agents for opportunistic infections.
• Antibiotics unless specifically excluded.
• Systemic corticosteroids for no more than 21 days.
• Vitamins.
• Recombinant erythropoietin.
• G-CSF.
• Regularly prescribed medications such as allergy medications, antidepressants, antipyretics, analgesics, oral contraceptives, megestrol, and testosterone.

Concurrent Treatment:

Allowed:

• Acupuncture.
• Visualization techniques.

Patients must have:

• HIV infection.
• CD4 count <= 200 cells/mm3.
• At least 6 months total prior AZT therapy.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Malignancy requiring systemic therapy other than minimal Kaposi's sarcoma.

Concurrent Medication:

Excluded:

• Antiretrovirals other than study drugs.
• Rifabutin and rifampin.
• Investigational drugs other than indinavir sulfate.
• Systemic cytotoxic chemotherapy.
• Oral ketoconazole.
• Chronic systemic corticosteroids.
• Herbal therapies.

Patients with the following prior conditions are excluded:

• Unexplained temperature > 38.5 C for any 7 days within 30 days prior to study entry.
• Chronic diarrhea persisting for 15 days within 30 days prior to study entry.
• History of acute or chronic pancreatitis.
• Acute hepatitis within 30 days prior to study entry.
• Grade 2 or worse bilateral peripheral neuropathy within 60 days prior to study entry.
• Dose-limiting intolerance to prior AZT at 600 mg/day.

Prior Medication:

Excluded:

• More than 1 week of prior 3TC.
• Any prior protease inhibitors.
• Rifampin or rifabutin within 14 days prior to study entry.

Excluded within 30 days prior to study entry:

• Erythropoietin.
• G-CSF or GM-CSF.
• Non-nucleoside reverse transcriptase inhibitors.
• Interferons.
• Interleukins.
• HIV vaccines.
• Any experimental therapy.