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

Primary Purpose

Toxoplasmosis, Cerebral, HIV Infections

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sulfadiazine
Clarithromycin
Atovaquone
Pyrimethamine
Leucovorin calcium
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Toxoplasmosis, Cerebral focused on measuring Pyrimethamine, Leucovorin, Drug Therapy, Combination, Encephalitis, Acquired Immunodeficiency Syndrome, Antiprotozoal Agents, Clarithromycin, atovaquone, Toxoplasmosis, Cerebral, Sulfadiazine

Eligibility Criteria

13 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • USC CRS
  • Univ. of Miami AIDS CRS
  • Queens Med. Ctr.
  • Univ. of Hawaii at Manoa, Leahi Hosp.
  • Northwestern University CRS
  • Cook County Hosp. CORE Ctr.
  • Indiana Univ. School of Medicine, Infectious Disease Research Clinic
  • Methodist Hosp. of Indiana
  • Johns Hopkins Adult AIDS CRS
  • Washington U CRS
  • St. Louis ConnectCare, Infectious Diseases Clinic
  • SUNY - Buffalo, Erie County Medical Ctr.
  • Beth Israel Med. Ctr. (Mt. Sinai)
  • NY Univ. HIV/AIDS CRS
  • Univ. of Cincinnati CRS
  • The Ohio State Univ. AIDS CRS

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

First Posted
November 2, 1999
Last Updated
October 27, 2021
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00000794
Brief Title
Phase II Randomized Open-Label Trial of Atovaquone Plus Pyrimethamine and Atovaquone Plus Sulfadiazine for the Treatment of Acute Toxoplasmic Encephalitis
Official Title
Phase II Randomized Open-Label Trial of Atovaquone Plus Pyrimethamine and Atovaquone Plus Sulfadiazine for the Treatment of Acute Toxoplasmic Encephalitis
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
undefined (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
April 1998 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Toxoplasmosis, Cerebral, HIV Infections
Keywords
Pyrimethamine, Leucovorin, Drug Therapy, Combination, Encephalitis, Acquired Immunodeficiency Syndrome, Antiprotozoal Agents, Clarithromycin, atovaquone, Toxoplasmosis, Cerebral, Sulfadiazine

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Enrollment
100 (false)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Sulfadiazine
Intervention Type
Drug
Intervention Name(s)
Clarithromycin
Intervention Type
Drug
Intervention Name(s)
Atovaquone
Intervention Type
Drug
Intervention Name(s)
Pyrimethamine
Intervention Type
Drug
Intervention Name(s)
Leucovorin calcium

10. Eligibility

Sex
All
Minimum Age & Unit of Time
13 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Luft B
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Chirgwin K
Official's Role
Study Chair
Facility Information:
Facility Name
USC CRS
City
Los Angeles
State/Province
California
ZIP/Postal Code
900331079
Country
United States
Facility Name
Univ. of Miami AIDS CRS
City
Miami
State/Province
Florida
ZIP/Postal Code
331361013
Country
United States
Facility Name
Queens Med. Ctr.
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96816
Country
United States
Facility Name
Univ. of Hawaii at Manoa, Leahi Hosp.
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96816
Country
United States
Facility Name
Northwestern University CRS
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Cook County Hosp. CORE Ctr.
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Indiana Univ. School of Medicine, Infectious Disease Research Clinic
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
462025250
Country
United States
Facility Name
Methodist Hosp. of Indiana
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Johns Hopkins Adult AIDS CRS
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Washington U CRS
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
St. Louis ConnectCare, Infectious Diseases Clinic
City
Saint Louis
State/Province
Missouri
Country
United States
Facility Name
SUNY - Buffalo, Erie County Medical Ctr.
City
Buffalo
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
Beth Israel Med. Ctr. (Mt. Sinai)
City
New York
State/Province
New York
ZIP/Postal Code
10003
Country
United States
Facility Name
NY Univ. HIV/AIDS CRS
City
New York
State/Province
New York
Country
United States
Facility Name
Univ. of Cincinnati CRS
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
452670405
Country
United States
Facility Name
The Ohio State Univ. AIDS CRS
City
Columbus
State/Province
Ohio
ZIP/Postal Code
432101228
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
11941551
Citation
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. doi: 10.1086/339551.
Results Reference
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Phase II Randomized Open-Label Trial of Atovaquone Plus Pyrimethamine and Atovaquone Plus Sulfadiazine for the Treatment of Acute Toxoplasmic Encephalitis

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