Phase II Randomized Open-Label Trial of Atovaquone Plus Pyrimethamine and Atovaquone Plus Sulfadiazine for the Treatment of Acute Toxoplasmic Encephalitis
Information source: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
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
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.
Clinical Details
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: Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Primary Purpose: Treatment
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.
Eligibility
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.
Locations and Contacts
USC CRS, Los Angeles, California 900331079, United States
Univ. of Miami AIDS CRS, Miami, Florida 331361013, United States
Queens Med. Ctr., Honolulu, Hawaii 96816, United States
Univ. of Hawaii at Manoa, Leahi Hosp., Honolulu, Hawaii 96816, United States
Cook County Hosp. CORE Ctr., Chicago, Illinois 60612, United States
Northwestern University CRS, Chicago, Illinois 60611, United States
Indiana Univ. School of Medicine, Infectious Disease Research Clinic, Indianapolis, Indiana 462025250, United States
Methodist Hosp. of Indiana, Indianapolis, Indiana 46202, United States
Johns Hopkins Adult AIDS CRS, Baltimore, Maryland 21287, United States
St. Louis ConnectCare, Infectious Diseases Clinic, St. Louis, Missouri, United States
Washington U CRS, St. Louis, Missouri 63110, United States
SUNY - Buffalo, Erie County Medical Ctr., Buffalo, New York 13210, United States
Beth Israel Med. Ctr. (Mt. Sinai), New York, New York 10003, United States
NY Univ. HIV/AIDS CRS, New York, New York, United States
Univ. of Cincinnati CRS, Cincinnati, Ohio 452670405, United States
The Ohio State Univ. AIDS CRS, Columbus, Ohio 432101228, United States
Additional Information
Click here for more information about Clarithromycin
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: April 2, 2012
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