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

Condition(s) targeted: Toxoplasmosis, Cerebral; HIV Infections

Intervention: Sulfadiazine (Drug); Clarithromycin (Drug); Atovaquone (Drug); Pyrimethamine (Drug); Leucovorin calcium (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Luft B, Study Chair
Chirgwin K, Study Chair

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.

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

Study design: Treatment, Parallel Assignment, Safety Study

Detailed description: 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.

Minimum age: 13 Years. Maximum age: N/A. Gender(s): 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.

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

Univ of Southern California / LA County USC Med Ctr, Los Angeles, California 900331079, United States

Univ of Miami School of Medicine, Miami, Florida 331361013, United States

Queens Med Ctr, Honolulu, Hawaii 96816, United States

Univ of Hawaii, Honolulu, Hawaii 96816, United States

Northwestern Univ Med School, Chicago, Illinois 60611, United States

Cook County Hosp, Chicago, Illinois 60612, United States

Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States

Methodist Hosp of Indiana / Life Care Clinic, Indianapolis, Indiana 46202, United States

Johns Hopkins Hosp, Baltimore, Maryland 21287, United States

St Louis Regional Hosp / St Louis Regional Med Ctr, St. Louis, Missouri 63112, United States

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

Univ of Cincinnati, Cincinnati, Ohio 452670405, United States

Ohio State Univ Hosp Clinic, Columbus, Ohio 432101228, United States

Julio Arroyo, West Columbia, South Carolina 29169, United States

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Related publications:

Chirgwin K, Hafner R, Leport C, Remington J, Andersen J, Bosler EM, Roque C, Rajicic N, McAuliffe V, Morlat P, Jayaweera DT, Vilde JL, Luft BJ. Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039. Clin Infect Dis. 2002 May 1;34(9):1243-50.

Last updated: June 23, 2005