Official Title: “Phase II Randomized Open-Label Trial of Atovaquone Plus Pyrimethamine and Atovaquone Plus Sulfadiazine for the Treatment of Acute Toxoplasmic Encephalitis”

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.

Study Type: Interventional

Study Design: Treatment, Parallel Assignment, Safety Study

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.

Seventy patients are randomized to receive atovaquone with either pyrimethamine or sulfonamides for up to 48 weeks. Additionally, three cohorts of 10 patients each who have a history of treatment-limiting toxicity to pyrimethamine, sulfadiazine, or both drugs receive atovaquone plus the alternate drug or atovaquone plus clarithromycin. All patients receiving pyrimethamine also receive leucovorin protection.

PER AMENDMENT 4/3/96:

The open treatment groups are: Atovaquone plus pyrimethamine for patients with acute toxoplasmic encephalitis who have no treatment limiting toxicity to pyrimethamine, and Atovaquone plus clarithromycin for patients with acute toxoplasmic encephalitis who have treatment limiting toxicity to both pyrimethamine and sulfadiazine. The following arms closed on 12/22/95: Randomization to the atovaquone plus sulfadiazine arm for patients with acute toxoplasmic encephalitis who had no treatment limiting toxicity to pyrimethamine or sulfonamides, and Atovaquone plus sulfadiazine for patients with acute toxoplasmic encephalitis who had treatment limiting toxicity to pyrimethamine. The following arm closed on 9/26/95: Atovaquone plus pyrimethamine for patients with acute toxoplasmic encephalitis who had treatment limiting toxicity to sulfonamides. NOTE: Any patients enrolled in previous versions will continue to be treated with that same drug treatment and followed under their previous version guidelines.

Intervention(s) in this Clinical Trial

• Drug: Sulfadiazine
• Drug: Clarithromycin
• Drug: Atovaquone
• Drug: Pyrimethamine
• Drug: Leucovorin calcium

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 13 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Overall Clinical Trial Officials and Contacts

Luft B Study Chair   

Information obtained from ClinicalTrials.gov on November 18, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00000794

Study ID Number: ACTG 237

ClinicalTrials.gov Identifier: NCT00000794

Health Authority: United States: Federal Government

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