Pyrimethamine, Sulfadiazine, and Leucovorin in Treating Patients With Congenital Toxoplasmosis

Study Overview
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Brief Summary
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RATIONALE: Congenital toxoplasmosis is an infection caused by the parasitic organism Toxoplasma gondii, and it may be passed from an infected mother to her unborn child. The mother may have mild symptoms or no symptoms; the fetus, however, may experience damage to the eyes, nervous system, skin, and ears. The newborn may have a low birth weight, enlarged liver and spleen, jaundice, anemia, petechiae, and eye damage. Giving the antiparasitic drugs pyrimethamine and sulfadiazine is standard treatment for congenital toxoplasmosis, but it is not yet known which regimen of pyrimethamine is most effective for the disease. PURPOSE: Randomized phase IV trial to determine which regimen of pyrimethamine is most effective when combined with sulfadiazine and leucovorin in treating patients who have congenital toxoplasmosis.

Detailed Description
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PROTOCOL OUTLINE: Infants are randomly assigned to 1 of 2 treatment groups. Patients are stratified by disease severity, chorioretinitis, prenatal treatment, and certainty of diagnosis at birth. One group of infants is treated with a loading dose of oral pyrimethamine followed by a higher dose for the first two months then a lower dose for the remainder of the 12 months. Sulfadiazine and leucovorin calcium are also given orally for 12 months. The pyrimethamine loading dose is omitted if prior prenatal therapy was given. Another group of infants is treated with a higher dose of oral pyrimethamine for the first 6 months and then the lower dose for the remainder of the 12 months. Sulfadiazine and leucovorin calcium are administered concurrently. Infected fetuses of pregnant women are nonrandomly assigned to treatment with pyrimethamine, sulfadiazine, and leucovorin calcium after the first trimester. Spiramycin is administered before the fetal diagnosis is made. Concurrent prednisone for active retinal inflammation or elevated cerebrospinal fluid protein is allowed. Collaborating physicians will also refer historical controls, who have not been treated in the first year of life or who received one month or less therapy, and are older than one year. Absence of treatment in the first year of life will be due to parental preference, prior inadequate follow-up by the family physicians, or lack of detection or treatment of eye disease before the age of one year in otherwise asymptomatic children. These historical, untreated patients (who enter the study when they are older than one year) will be compared with treated children in the randomized study. These historical patients will not be randomized. Any abnormality requiring treatment (e.g., active chorioretinitis) in any child (including historical patients) will be treated. All infants are followed at birth, then at age 1, 3.5, 5, 7.5, 10, 15, and 20.

Official Title
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Phase IV Randomized Study of Pyrimethamine, Sulfadiazine, and Leucovorin Calcium for Congenital Toxoplasmosis

Conditions
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Toxoplasmosis

Intervention / Treatment
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* Drug: Leucovorin calcium
* Drug: Pyrimethamine
* Drug: Spiramycin
* Drug: Sulfadiazine


Participation Criteria
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Eligibility Criteria
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PROTOCOL ENTRY CRITERIA: Infants with congenital toxoplasmosis Toxoplasma gondii confirmed prior to age 2.5 months Pregnant women with evidence of toxoplasma infection by clinical observation and amniotic fluid sampling Acute infection acquired during gestation with evidence of fetal infection Untreated older children entered as controls Asymptomatic congenital toxoplasmosis Age more than 1 year No treatment within the first year of life No more than 1 month of prior therapy
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>This group of infants is treated with a loading dose of oral pyrimethamine followed by a higher dose for the first two months then a lower dose for the remainder of the 12 months. Sulfadiazine and leucovorin calcium are also given orally for 12 months. The pyrimethamine loading dose is omitted if prior prenatal therapy was given. | Drug: Leucovorin calcium<br>* See arm descriptions<br>Drug: Pyrimethamine<br>* See arm descriptions<br>Drug: Spiramycin<br>* Spiramycin is administered before the fetal diagnosis is made.<br>Drug: Sulfadiazine<br>* See arm descriptions<br>|
| Experimental: 2<br>This group of infants is treated with a higher dose of oral pyrimethamine for the first 6 months and then the lower dose for the remainder of the 12 months. Sulfadiazine and leucovorin calcium are administered concurrently. | Drug: Leucovorin calcium<br>* See arm descriptions<br>Drug: Pyrimethamine<br>* See arm descriptions<br>Drug: Spiramycin<br>* Spiramycin is administered before the fetal diagnosis is made.<br>Drug: Sulfadiazine<br>* See arm descriptions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Persistent motor abnormality |  | At pre-specified time points | 
| Vision |  | At pre-specified time points | 
| Hearing |  | At pre-specified time points | 
| New chorioretinal lesion |  | At pre-specified time points | 
| IQ less than 70 |  | At pre-specified time points | 
| Decrease in IQ of greater than or equal to 15 points |  | At pre-specified time points | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunologic disorders and infectious disorders, rare disease, toxoplasmosis