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

HIV Infections Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00000794
• Other study ID #: ACTG 237
• Secondary ID: ANRS 03911214
• Status: Completed
• Phase: Phase 2
• Est. completion date: April 1998

Study information

• Verified date: October 2021
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: April 1998
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Encephalitis
• HIV Infections
• Toxoplasmosis
• Toxoplasmosis, Cerebral

Intervention

Drug:
• Sulfadiazine

• Clarithromycin

• Atovaquone

• Pyrimethamine

• Leucovorin calcium

Locations

Country	Name	City	State
United States	Johns Hopkins Adult AIDS CRS	Baltimore	Maryland
United States	SUNY - Buffalo, Erie County Medical Ctr.	Buffalo	New York
United States	Cook County Hosp. CORE Ctr.	Chicago	Illinois
United States	Northwestern University CRS	Chicago	Illinois
United States	Univ. of Cincinnati CRS	Cincinnati	Ohio
United States	The Ohio State Univ. AIDS CRS	Columbus	Ohio
United States	Queens Med. Ctr.	Honolulu	Hawaii
United States	Univ. of Hawaii at Manoa, Leahi Hosp.	Honolulu	Hawaii
United States	Indiana Univ. School of Medicine, Infectious Disease Research Clinic	Indianapolis	Indiana
United States	Methodist Hosp. of Indiana	Indianapolis	Indiana
United States	USC CRS	Los Angeles	California
United States	Univ. of Miami AIDS CRS	Miami	Florida
United States	Beth Israel Med. Ctr. (Mt. Sinai)	New York	New York
United States	NY Univ. HIV/AIDS CRS	New York	New York
United States	St. Louis ConnectCare, Infectious Diseases Clinic	Saint Louis	Missouri
United States	Washington U CRS	Saint Louis	Missouri

Sponsors (1)

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

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation