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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00000794
First received: November 2, 1999
Last updated: April 2, 2012
Last verified: April 2012
  Purpose

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 Intervention Phase
Toxoplasmosis, Cerebral
HIV Infections
Drug: Sulfadiazine
Drug: Clarithromycin
Drug: Atovaquone
Drug: Pyrimethamine
Drug: Leucovorin calcium
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Primary Purpose: Treatment
Official Title: Phase II Randomized Open-Label Trial of Atovaquone Plus Pyrimethamine and Atovaquone Plus Sulfadiazine for the Treatment of Acute Toxoplasmic Encephalitis

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Estimated Enrollment: 100
Study Completion Date: April 1998
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

Ages Eligible for Study:   13 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00000794

Locations
United States, California
USC CRS
Los Angeles, California, United States, 900331079
United States, Florida
Univ. of Miami AIDS CRS
Miami, Florida, United States, 331361013
United States, Hawaii
Queens Med. Ctr.
Honolulu, Hawaii, United States, 96816
Univ. of Hawaii at Manoa, Leahi Hosp.
Honolulu, Hawaii, United States, 96816
United States, Illinois
Northwestern University CRS
Chicago, Illinois, United States, 60611
Cook County Hosp. CORE Ctr.
Chicago, Illinois, United States, 60612
United States, Indiana
Methodist Hosp. of Indiana
Indianapolis, Indiana, United States, 46202
Indiana Univ. School of Medicine, Infectious Disease Research Clinic
Indianapolis, Indiana, United States, 462025250
United States, Maryland
Johns Hopkins Adult AIDS CRS
Baltimore, Maryland, United States, 21287
United States, Missouri
Washington U CRS
St. Louis, Missouri, United States, 63110
St. Louis ConnectCare, Infectious Diseases Clinic
St. Louis, Missouri, United States
United States, New York
SUNY - Buffalo, Erie County Medical Ctr.
Buffalo, New York, United States, 13210
NY Univ. HIV/AIDS CRS
New York, New York, United States
Beth Israel Med. Ctr. (Mt. Sinai)
New York, New York, United States, 10003
United States, Ohio
Univ. of Cincinnati CRS
Cincinnati, Ohio, United States, 452670405
The Ohio State Univ. AIDS CRS
Columbus, Ohio, United States, 432101228
Sponsors and Collaborators
Investigators
Study Chair: Luft B
Study Chair: Chirgwin K
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00000794     History of Changes
Other Study ID Numbers: ACTG 237, ANRS 039, 11214
Study First Received: November 2, 1999
Last Updated: April 2, 2012
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Pyrimethamine
Leucovorin
Drug Therapy, Combination
Encephalitis
Acquired Immunodeficiency Syndrome
Antiprotozoal Agents
Clarithromycin
atovaquone
Toxoplasmosis, Cerebral
Sulfadiazine

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Encephalitis
Toxoplasmosis
Toxoplasmosis, Cerebral
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Central Nervous System Viral Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Central Nervous System Infections
Coccidiosis
Protozoan Infections
Parasitic Diseases
Brain Abscess
Abscess
Suppuration
Infection
Central Nervous System Protozoal Infections
Central Nervous System Parasitic Infections
Levoleucovorin
Pyrimethamine

ClinicalTrials.gov processed this record on September 30, 2014