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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00000794

Collaborator

(none)

100

Enrollment

Locations

6.3

Patients Per Site

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Toxoplasmosis, Cerebral HIV Infections	Drug: Sulfadiazine Drug: Clarithromycin Drug: Atovaquone Drug: Pyrimethamine Drug: Leucovorin calcium	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

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

Actual Study Completion Date :

Apr 1, 1998

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

13 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	USC CRS	Los Angeles	California	United States	900331079
2	Univ. of Miami AIDS CRS	Miami	Florida	United States	331361013
3	Queens Med. Ctr.	Honolulu	Hawaii	United States	96816
4	Univ. of Hawaii at Manoa, Leahi Hosp.	Honolulu	Hawaii	United States	96816
5	Northwestern University CRS	Chicago	Illinois	United States	60611
6	Cook County Hosp. CORE Ctr.	Chicago	Illinois	United States	60612
7	Indiana Univ. School of Medicine, Infectious Disease Research Clinic	Indianapolis	Indiana	United States	462025250
8	Methodist Hosp. of Indiana	Indianapolis	Indiana	United States	46202
9	Johns Hopkins Adult AIDS CRS	Baltimore	Maryland	United States	21287
10	Washington U CRS	Saint Louis	Missouri	United States	63110
11	St. Louis ConnectCare, Infectious Diseases Clinic	Saint Louis	Missouri	United States
12	SUNY - Buffalo, Erie County Medical Ctr.	Buffalo	New York	United States	13210
13	Beth Israel Med. Ctr. (Mt. Sinai)	New York	New York	United States	10003
14	NY Univ. HIV/AIDS CRS	New York	New York	United States
15	Univ. of Cincinnati CRS	Cincinnati	Ohio	United States	452670405
16	The Ohio State Univ. AIDS CRS	Columbus	Ohio	United States	432101228