Phase II Randomized Open-Label Trial of Atovaquone Plus Pyrimethamine and Atovaquone Plus Sulfadiazine for the Treatment of Acute Toxoplasmic Encephalitis

• Status: Completed
• Trial end date: 1998-04-01
• Target enrollment: 0
• Participant gender: All

Summary

To evaluate the efficacy, safety, and tolerance of atovaquone with either pyrimethamine or sulfadiazine in AIDS patients with toxoplasmic encephalitis.

AIDS patients with toxoplasmic encephalitis who receive the standard therapy combination of sulfadiazine and pyrimethamine experience a high frequency of severe toxicity. Atovaquone, an antibiotic that has demonstrated efficacy against toxoplasmosis in animal models and in preclinical testing has been well tolerated, is now available as a suspension, which is more readily absorbed than the tablet form of the drug. The efficacy and safety of atovaquone in combination with sulfadiazine or pyrimethamine will be studied.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Treatments: Atovaquone; Calcium; Clarithromycin; Leucovorin; Levoleucovorin; Pyrimethamine; Sulfadiazine

Criteria

Inclusion Criteria

Concurrent Medication:

Allowed:

• Aerosolized pentamidine for PCP prophylaxis.

PER AMENDMENT 4/3/96:

• History of treatment limiting toxicity to pyrimethamine. Patients with a history of treatment limiting toxicity to both pyrimethamine and sulfonamides will be assigned to receive atovaquone plus clarithromycin.

Patients must have:

• Documented HIV infection or diagnosis of AIDS (except for CD4 count < 200 cells/mm3).

• Toxoplasmic encephalitis.

• Ability to give informed consent or legal designee who could give consent.

PER AMENDMENT 4/3/96:

• NOTE - A history of treatment limiting toxicity to both pyrimethamine and sulfonamides will result in the patient being enrolled in the atovaquone plus clarithromycin arm.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Coma.

• Opportunistic infection that requires either acute or maintenance treatment with disallowed medications.

• Any infections or neoplasms of the central nervous system other than Toxoplasma, HIV encephalopathy, or syphilis.

• Unable to take oral study drugs.

• Malabsorption (i.e., three or more episodes of diarrhea per day that has caused >= 10 percent loss of body weight over the past 4 weeks).

• Positive CSF or serum for Cryptococcus antigen or culture (a positive serum antigen only is acceptable, provided patient received prior antifungal therapy and is on maintenance, and the likelihood of recurrence is low).

• Malignancy requiring use of cytotoxic chemotherapy.

• Medical or social condition that would adversely affect study participation or compliance.

Concurrent Medication:

Excluded:

• Trimethoprim-sulfamethoxazole.

• Primaquine.

• Sulfonamides.

• Antifolates.

• Dapsone.

• Clarithromycin (except for patients in the cohort to receive this drug).

• Azithromycin.

• Clindamycin.

• Other macrolides.

• Gamma interferon.

• Metoclopramide.

• G-CSF or GM-CSF.

Excluded in patients receiving clarithromycin as study drug:

• Terfenadine, astemizole, or any other long-acting, non-sedating antihistamines.

PER AMENDMENT 4/3/96:

• Cisapride - may increase GI motility and may increase drug absorption.

Patients with the following prior conditions are excluded:

• History of treatment-limiting toxicity to atovaquone.

• Receipt of > 96 hours (per amendment) of treatment prior to study entry for the current episode of toxoplasmic encephalitis.