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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| ClinicalTrials.gov Identifier: NCT00000794 |
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Recruitment Status
:
Completed
First Posted
: August 31, 2001
Last Update Posted
: April 3, 2012
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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 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Enrollment : | 100 participants |
| 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 : | April 1998 |
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| Ages Eligible for Study: | 13 Years and older (Child, Adult, Senior) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00000794
| 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 | |
| Indiana Univ. School of Medicine, Infectious Disease Research Clinic | |
| Indianapolis, Indiana, United States, 462025250 | |
| Methodist Hosp. of Indiana | |
| Indianapolis, Indiana, United States, 46202 | |
| 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 | |
| Beth Israel Med. Ctr. (Mt. Sinai) | |
| New York, New York, United States, 10003 | |
| NY Univ. HIV/AIDS CRS | |
| New York, New York, United States | |
| United States, Ohio | |
| Univ. of Cincinnati CRS | |
| Cincinnati, Ohio, United States, 452670405 | |
| The Ohio State Univ. AIDS CRS | |
| Columbus, Ohio, United States, 432101228 | |
| Study Chair: | Luft B | ||
| Study Chair: | Chirgwin K |
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 ( Registry Identifier: DAIDS-ES ) |
| First Posted: | August 31, 2001 Key Record Dates |
| Last Update Posted: | April 3, 2012 |
| Last Verified: | April 2012 |
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
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Pyrimethamine Leucovorin Drug Therapy, Combination Encephalitis Acquired Immunodeficiency Syndrome |
Antiprotozoal Agents Clarithromycin atovaquone Toxoplasmosis, Cerebral Sulfadiazine |
Additional relevant MeSH terms:
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HIV Infections 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 Brain Diseases Central Nervous System Diseases Nervous System Diseases |
Coccidiosis Protozoan Infections Parasitic Diseases Brain Abscess Abscess Suppuration Infection Central Nervous System Protozoal Infections Central Nervous System Parasitic Infections Central Nervous System Infections Clarithromycin Pyrimethamine Atovaquone Sulfadiazine Levoleucovorin |