Pyrimethamine + Sulfadiazine + Leucovorin for Congenital Toxoplasmosis

Age: Any Age

Sex: Any

Trial Phase: Phase 4

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Antiparasitics

Disqualifiers: Age more than 1 year, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

600 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications.

Is the combination of Pyrimethamine, Sulfadiazine, and Leucovorin safe for treating congenital toxoplasmosis?

The combination of Pyrimethamine, Sulfadiazine, and Leucovorin is generally well tolerated in humans, though some may experience minor side effects like hypersensitivity reactions (such as fever and rash) or changes in blood cell counts. In studies, most patients completed treatment without significant issues, but close monitoring is recommended. ^{1 2 3 4 5}

How is the drug Pyrimethamine + Sulfadiazine + Leucovorin unique for treating congenital toxoplasmosis?

This drug combination is unique because it simplifies the treatment of congenital toxoplasmosis by combining pyrimethamine and sulfadiazine with leucovorin (a form of folic acid) to reduce side effects, and it effectively reduces the number of parasites in the fetus to undetectable levels when administered early. ^{2 3 4 5 6}

Research Team

Rima McLeod

Principal Investigator

University of Chicago

Eligibility Criteria

This trial is for pregnant women with toxoplasma infection confirmed by clinical observation and amniotic fluid tests, infants diagnosed with congenital toxoplasmosis before 2.5 months old, and untreated older children as controls. It excludes those who've had over a month of prior therapy, are older than a year or weren't treated in their first year.

Inclusion Criteria

Acute infection acquired during gestation with evidence of fetal infection

I have toxoplasmosis from birth but no symptoms.

I am older than 1 year.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Infants receive 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.

12 months

Follow-up

Participants are monitored at birth, then at age 1, 3.5, 5, 7.5, 10, 15, and 20 for safety and effectiveness after treatment

20 years

Treatment Details

Interventions

• Leucovorin calcium
• Pyrimethamine
• Sulfadiazine

Trial Overview The study aims to find the most effective regimen of pyrimethamine when combined with sulfadiazine and leucovorin for treating congenital toxoplasmosis. Participants will be randomly assigned different dosages to determine which works best.

Participant Groups

Group I: 2 Experimental Treatment 4 Interventions

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.

Group II: 1 Experimental Treatment 4 Interventions

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.

Pyrimethamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Daraprim for:

• Malaria
• Toxoplasmosis

Approved in European Union as Pyrimethamine for:

• Malaria
• Toxoplasmosis

Approved in Canada as Pyrimethamine for:

• Malaria
• Toxoplasmosis

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

University of Chicago

Collaborator

Trials

1,086

Recruited

844,000+

Findings from Research

In a study of 48 infants treated for congenital toxoplasmosis, 86% tolerated the combination of pyrimethamine and sulfadiazine well, with no significant impact on weight gain or severe side effects, although some had low neutrophil counts.

The plasma concentrations of pyrimethamine and sulfadiazine were within expected therapeutic limits, but concerns about treatment efficacy arose due to observed progression of eye lesions in some children during follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of infants with congenital toxoplasmosis: tolerability and plasma concentrations of sulfadiazine and pyrimethamine. Schmidt, DR., Hogh, B., Andersen, O., et al.[2018]

The combination of pyrimethamine and sulfadiazine effectively treated congenital Toxoplasma gondii infection in rhesus monkeys, with no toxic side effects observed, leading to undetectable levels of the parasite in the fetus when administered early after infection.

Both drugs crossed the placenta efficiently, with pyrimethamine accumulating in brain tissue, suggesting a strong potential for this treatment regimen to be effective in similar cases in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study of treatment of congenital Toxoplasma gondii infection in rhesus monkeys with pyrimethamine and sulfadiazine. Schoondermark-van de Ven, E., Galama, J., Vree, T., et al.[2021]

In a study involving two patients with congenital toxoplasmosis (CTox) who were hypersensitive to sulfadiazine, desensitization to the drug was successfully achieved in one patient.

This suggests that desensitization may be a potential strategy for safely administering sulfadiazine in patients with hypersensitivity, allowing for effective treatment of CTox.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sulfadiazine Hypersensitivity and Desensitization in Children With Congenital Toxoplasmosis: A Report on Two Cases. Yamamoto, K., Kutsuna, S., Kato, Y., et al.[2021]

The pyrimethamine-sulfadoxine combination was administered to 24 children with congenital toxoplasmosis and was found to be effective, similar to other treatments, with a dosage of 500 mg sulfadoxine and 25 mg pyrimethamine per 20 kg body weight every two weeks.

This treatment was generally well tolerated, with only 3 patients experiencing minor side effects, and it is considered a simpler alternative to traditional therapies when combined with folinic acid.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Congenital toxoplasmosis. Tolerability of the sulfadoxine-pyrimethamine combination. 24 cases]. Maisonneuve, H., Faber, C., Piens, MA., et al.[2016]

The combination treatment of pyrimethamine and sulfadiazine/sulfadoxine for congenital toxoplasmosis can lead to severe side effects, such as pancytopenia, which is a reduction in red and white blood cells and platelets.

In this case, a pregnant woman developed pancytopenia during treatment, but her condition improved with high doses of folinic acid, platelet transfusion, and antibiotics, highlighting the need for careful monitoring of blood cell levels during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Maternal pancytopenia during antenatal treatment of congenital toxoplasmosis]. Mubiayi, N., Coutty, N., Detourmignies, L., et al.[2019]

A study of 78 children with congenital toxoplasmosis showed that a 24-month treatment with pyrimethamine-sulfadoxine, combined with folinic acid, resulted in the lowest rates of complications, such as chorioretinitis and other severe outcomes.

The treatment was well tolerated, and while immunological rebounds occurred in 90% of cases, they generally did not lead to clinical issues, indicating the safety and efficacy of this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pyrimethamine-sulfadoxine treatment of congenital toxoplasmosis: follow-up of 78 cases between 1980 and 1997. Reims Toxoplasmosis Group. Villena, I., Aubert, D., Leroux, B., et al.[2019]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Treatment of infants with congenital toxoplasmosis: tolerability and plasma concentrations of sulfadiazine and pyrimethamine. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Study of treatment of congenital Toxoplasma gondii infection in rhesus monkeys with pyrimethamine and sulfadiazine. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Sulfadiazine Hypersensitivity and Desensitization in Children With Congenital Toxoplasmosis: A Report on Two Cases. [2021]

4. France pubmed.ncbi.nlm.nih.gov

[Congenital toxoplasmosis. Tolerability of the sulfadoxine-pyrimethamine combination. 24 cases]. [2016]

5. France pubmed.ncbi.nlm.nih.gov

[Maternal pancytopenia during antenatal treatment of congenital toxoplasmosis]. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Pyrimethamine-sulfadoxine treatment of congenital toxoplasmosis: follow-up of 78 cases between 1980 and 1997. Reims Toxoplasmosis Group. [2019]