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.

Condition	Treatment or Intervention	Phase
Toxoplasmosis, Cerebral HIV Infections	Drug: Sulfadiazine  Drug: Clarithromycin  Drug: Atovaquone  Drug: Pyrimethamine  Drug: Leucovorin calcium	Phase II

Further Study Details: 

Expected Total Enrollment:  100

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.

Ages Eligible for Study:  13 Years and above,  Genders Eligible for Study:  Both

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.

California
      Univ of Southern California / LA County USC Med Ctr, Los Angeles,  California,  900331079,  United States
Florida
      Univ of Miami School of Medicine, Miami,  Florida,  331361013,  United States
Hawaii
      Queens Med Ctr, Honolulu,  Hawaii,  96816,  United States
      Univ of Hawaii, Honolulu,  Hawaii,  96816,  United States
Illinois
      Northwestern Univ Med School, Chicago,  Illinois,  60611,  United States
      Cook County Hosp, Chicago,  Illinois,  60612,  United States
Indiana
      Indiana Univ Hosp, Indianapolis,  Indiana,  462025250,  United States
      Methodist Hosp of Indiana / Life Care Clinic, Indianapolis,  Indiana,  46202,  United States
Maryland
      Johns Hopkins Hosp, Baltimore,  Maryland,  21287,  United States
Missouri
      St Louis Regional Hosp / St Louis Regional Med Ctr, St. Louis,  Missouri,  63112,  United States
New York
      SUNY / State Univ of New York, Syracuse,  New York,  13210,  United States
      Bellevue Hosp / New York Univ Med Ctr, New York,  New York,  10016,  United States
      Jack Weiler Hosp / Bronx Municipal Hosp, Bronx,  New York,  10465,  United States
      Bronx Municipal Hosp Ctr/Jacobi Med Ctr, Bronx,  New York,  10461,  United States
      Bronx Veterans Administration / Mount Sinai Hosp, Bronx,  New York,  10468,  United States
      SUNY / Erie County Med Ctr at Buffalo, Buffalo,  New York,  14215,  United States
      Beth Israel Med Ctr, New York,  New York,  10003,  United States
      SUNY / Health Sciences Ctr at Brooklyn, Brooklyn,  New York,  112032098,  United States
      Harlem Hosp Ctr, New York,  New York,  10037,  United States
Ohio
      Univ of Cincinnati, Cincinnati,  Ohio,  452670405,  United States
      Ohio State Univ Hosp Clinic, Columbus,  Ohio,  432101228,  United States
South Carolina
      Julio Arroyo, West Columbia,  South Carolina,  29169,  United States
France
      Hopital Cochin - Port Royal, Paris,  France
      Hopital Bichat - Claude Bernard, Paris,  France
      Hopital Hotel Dieu de Lyon, Lyon,  France
      Hosp Jean Verdier A Bondy, Bondy,  France
      Hopital Pasteur, Paris,  France
      Hopital Saint Andre, Bordeaux,  France

Study chairs or principal investigators

Luft B,  Study Chair
Chirgwin K,  Study Chair

Study ID Numbers:  ACTG 237; ANRS 039
Record last reviewed:  January 1997
Last Updated:  April 7, 2005
Record first received:  November 2, 1999
ClinicalTrials.gov Identifier:  NCT00000794
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08