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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine which dosing regimen of pyrimethamine (Daraprim), combined with sulfadiazine and leucovorin, is most effective for treating congenital toxoplasmosis. This condition, passed from an infected mother to her unborn child, can lead to serious health issues like eye and nervous system damage in the baby. The trial includes infants diagnosed with congenital toxoplasmosis before 2.5 months of age. Researchers will divide the infants into two groups, each receiving different dosing regimens, to identify the most effective one. As a Phase 4 trial, this research focuses on understanding how this FDA-approved treatment can benefit more patients.

Will I have to stop taking my current medications?

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

What is the safety track record for these treatments?

Research has shown that the combination of pyrimethamine, sulfadiazine, and leucovorin effectively treats congenital toxoplasmosis, particularly in infants. Pyrimethamine ranks among the most effective drugs for this condition.

In terms of safety, this treatment is generally well-tolerated. However, like any medication, it can cause side effects. Some individuals might experience mild reactions, but serious side effects are rare. Leucovorin, a form of folic acid, is included to help prevent some potential side effects of pyrimethamine, such as blood-related issues.

For those considering joining a trial, it is reassuring that this combination has been used safely for many years. Consulting a healthcare professional is essential to understand what this means personally. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about using the combination of pyrimethamine, sulfadiazine, and leucovorin for congenital toxoplasmosis because it offers a tailored dosing regimen that could optimize effectiveness while minimizing side effects. Unlike standard treatments, which often have a fixed dosage, this approach uses an initial high dose of pyrimethamine to quickly combat the infection, followed by a lower maintenance dose to sustain the effect over a year. Additionally, the concurrent use of sulfadiazine and leucovorin helps enhance the treatment's potency and protect against potential side effects, setting it apart from other treatments that may not utilize this combination. This regimen's unique dosing strategy and combination therapy could improve outcomes for infants with this condition.

What evidence suggests that this trial's treatments could be effective for congenital toxoplasmosis?

This trial will evaluate two different dosing regimens of a combination of three drugs—pyrimethamine, sulfadiazine, and leucovorin—for treating congenital toxoplasmosis. Research has shown that this combination effectively treats toxoplasmosis. Pyrimethamine is a potent medicine against this infection and works even better with sulfadiazine. This combination has reversed symptoms in people with the disease. Leucovorin is added to help reduce side effects. This treatment is already known to be effective for toxoplasmosis, making it the standard approach for this condition. ^{1 2 3 4 6}

Who Is on the Research Team?

Rima McLeod

Principal Investigator

University of Chicago

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6148195/

Treatment of Toxoplasmosis: Historical Perspective, Animal ... Acute toxoplasmosis. Effective treatment with pyrimethamine, sulfadiazine, leucovorin calcium, and yeast. JAMA 173:1471–1476. [DOI] [PubMed] [Google Scholar] ...

2. cdc.gov cdc.gov/toxoplasmosis/hcp/clinical-care/index.html

Clinical Care of Toxoplasmosis Pyrimethamine, considered the most effective drug against toxoplasmosis, is a standard component of therapy. Pyrimethamine is a folic acid ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9091718/

Sulfadiazine Plus Pyrimethamine Therapy Reversed Multiple ... Sulfadiazine plus pyrimethamine therapy reverses behavioral changes present in the early and long-term chronic T. gondii infection. Chronically infected mice ...

4. sciencedirect.com sciencedirect.com/topics/medicine-and-dentistry/pyrimethamine-sulfadiazine

Pyrimethamine Sulfadiazine - an overview Sulfadiazine is an effective toxoplasmacidal agent that works synergistically with pyrimethamine, and combination therapy is generally used.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT00004317?intr=NSC-55926&aggFilters=studyType:int&viewType=Table&rank=4

Pyrimethamine, Sulfadiazine, and Leucovorin in Treating ... Data collected at the beginning of a clinical study for all participants and for each arm or comparison group. These data include demographics, such as age, sex ...

6. pubs.acs.org pubs.acs.org/doi/10.1021/acs.jmedchem.8b01754

Discovery of Selective Toxoplasma gondii Dihydrofolate ... A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, ...