A Double-Blind, Randomized, Dose Response Study of Three Doses of Delavirdine Mesylate (U-90152S) in Combination With Zidovudine (ZDV) Versus ZDV Alone in HIV-1 Infected Individuals With CD4 Counts of 200-500mm3

A Double-Blind, Randomized, Dose Response Study of Three Doses of Delavirdine Mesylate (U-90152S) in Combination With Zidovudine (ZDV) Versus ZDV Alone in HIV-1 Infected Individuals With CD4 Counts of 200-500mm3

PART I: To evaluate the safety, tolerance, efficacy, and pharmacokinetics of three fixed doses of delavirdine mesylate (DLV) in combination with zidovudine (AZT) versus AZT alone in HIV-positive patients.

PART II: To evaluate the safety, tolerance, efficacy, and pharmacokinetics of ZDV plus 3TC with or without DLV versus ZDV plus DLV in HIV-positive patients.

PART I: Patients are originally randomized to receive ZDV plus DLV (DLV at 1 of 3 doses) or ZDV plus placebo.

AS PER AMENDMENT 3/7/96:

PART II: Patients are rerandomized from PART I. Arm I: ZDV plus 3TC plus placebo. Arm II: ZDV plus 3TC plus DLV. Arm III: ZDV plus DLV (DLV at a higher dose than in the original protocol). Arm IV: ZDV plus DLV (no change from original; same treatment as Arm III).

AS PER AMENDMENT 1/24/97: Approximately 450 more patients will be enrolled in one of these 3 revised arms on PART II. Half of these new patients will be anti-retroviral naive and half will be anti-retroviral experienced.

Inclusion Criteria

Patients must have:

• HIV-1 seropositivity.
• CD4 count 200-500 cells/mm3.
• No active or acute (onset within the past month) opportunistic infections such as active cryptococcosis, pneumocystis carinii, herpes zoster, histoplasmosis, or cytomegalovirus (CMV).
• Consent of parent or guardian if less than 18 years of age.
• Understanding of potential risk to fetus related to study participation.
• Acceptable medical history, physical exam, EKG, and chest x-ray during screening.

NOTE:

• Patients with cutaneous Kaposi's sarcoma requiring no systemic therapy are permitted.

PER AMENDMENT 3/7/96:

• ZDV therapy for 0-6 months prior to study entry. (Part II)

Prior Medication:

Allowed:

• Prior AZT (no more than 6 months total).

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Active tuberculosis that is sensitive to rifampin.
• Inability to swallow numerous tablets.
• Clinically significant active or acute medical problems, including progressive multifocal leukoencephalopathy, lymphoma, or malignancy requiring systemic therapy.
• Clinically significant hypersensitivity to piperazine-type drugs (e.g., Antepar and Stelazine).
• Grade 2 or worse baseline organ function. NOTE:
• Hemophiliacs with grade 2 bilirubin, alkaline phosphatase, SGOT, or SGPT will be considered if these values have been stable over the past year. NOTE:
• Patients with suspected Gilbert's syndrome will be considered if bilirubin is grade 2 or better.

Patients with the following prior conditions are excluded:

• History of pancreatitis within the past 2 years.
• History of clinically significant nervous system or muscle disease, seizure disorder, AIDS dementia, or psychiatric disorder that would preclude study compliance.
• History of grade 2 or worse peripheral neuropathy.
• Intolerance to AZT in previously treated patients.

Prior Medication:

Excluded:

• More than 6 months total of prior AZT.
• Any prior ddC, d4T, 3TC, or ddI.
• Prior non-nucleoside reverse transcriptase inhibitors, including L-drugs, nevirapine, TIBO, HEPT, delavirdine, atevirdine, and alpha-APA.
• Other investigational antiretroviral medications (including foscarnet) or immunomodulators (including all interferons) within 21 days prior to initial study drug dose.
• Prior prophylactic or therapeutic HIV-1 gp120 or 160 vaccines.
• Rifampin, rifabutin, astemizole, loratadine, or terfenadine within 21 days prior to initial study drug dose.
• Any unapproved investigational medication for any indication within 21 days prior to initial study drug dose.
• Any enzyme-inducing drugs known to affect cytochrome P450 3A, (e.g., ketoconazole, fluconazole, isoniazid, itraconazole, etc.) within 21 days prior to initial study drug dose.

Active substance abuse.