Prevention of Congenital Toxoplasmosis With Pyrimethamine + Sulfadiazine Versus Spiramycine During Pregnancy (TOXOGEST)

Multicenter, Randomized Clinical Trial to Compare the Efficacy and Tolerance of Prenatal Therapy With Pyrimethamine + Sulfadiazine vs Spiramycine to Reduce Vertical Transmission of Toxoplasma Gondii Following Primary Infection in Pregnancy

Background : When a mother contracts toxoplasmosis during pregnancy, the parasite may be transmitted from to her unborn child. This results in congenital toxoplasmosis, which may cause damage to the eyes and nervous system of the child. To date, no method has been proved effective to prevent this transmission. In France, spiramycin is usually prescribed to women who have toxoplasma seroconversion in pregnancy, however its efficacy has not been determined. The standard treatment for toxoplasmosis is the combination of the antiparasitic drugs pyrimethamine and sulfadiazine, but this strategy has not been evaluated for the prevention of mother-to-child transmission.

Purpose : Randomized phase 3 trial to determine whether pyrimethamine + sulfadiazine is more effective than spiramycin to prevent congenital toxoplasmosis.

Study Overview

• Status: Completed
• Conditions: Congenital Toxoplasmosis
• Intervention / Treatment: Drug: Pyrimethamine/Sulfadiazine; Drug: Spiramycine

Detailed Description

The protocol is a comparison of 2 strategies to prevent mother-to-child transmission of T. gondii following maternal seroconversion.

Screening for toxoplasmosis is mandatory in France. Patients with confirmed seroconversion will be eligible for the trial, after 14 weeks gestational age.

Participants will be randomly allocated to one of the treatment groups, and will receive open-label pyrimethamine + sulfadiazine or spiramycin.

The protocol will not change the usual procedures for prenatal diagnosis, nor will it change the management of infected fetuses and neonates.

• Study Type: Interventional
• Enrollment (Actual): 149
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Hauts-de-Saine
    • Colombes, Hauts-de-Saine, France, 92700
      • Hopital Louis Mourier

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• > 18 years old
• Toxoplasmosis infection acquired during the pregnancy documented by at least one negative serology in the first trimester and seroconversion with presence of specific IgG antibodies
• Gestational age > 14 weeks from last menstrual period
• Signature of informed consent

Exclusion Criteria:

• Lack of a documented negative serology during the pregnancy
• Antiparasitic therapy with spiramycin, pyrimethamine or sulfa drugs for more than 10 days after seroconversion and before randomization,
• Known allergy to any of the study drugs, serious allergic conditions or G6PD deficiency,
• Known hepatic or renal insufficiency,
• Other ongoing severe conditions in mother or fetus
• Lack of public health insurance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pyrimethamine/Sulfadiazine; Women who are enrolled and randomised in Pyrimethamine + sulfadiazine group : Pyrimethamine 50 mg once daily orally and sulfadiazine 1g tid. orally, with supplemental folinic acid 50 mg once a week.	Drug: Pyrimethamine/Sulfadiazine; Pyrimethamine + sulfadiazine group : Pyrimethamine 50 mg once daily orally and sulfadiazine 1g tid. orally, with supplemental folinic acid 50 mg once a week. Follow-up includes clinical and biological tolerance, according to usual recommendations. Monthly fetal ultrasound is performed. Prenatal diagnosis with amniocentesis is offered after 18 weeks gestation, usually 4 weeks after the maternal infection. Treatment is be stopped or changed in case of toxicity. If prenatal diagnosis shows fetal infection with T. gondii, management is to be determined by the clinicians with the patient. If the prenatal diagnosis is negative the treatment can be stopped in order to reduce the risk of intolerance, providing that the mother receives at least 4 weeks of therapy.; Other Names: Pyrimethamine = Malocide®; Sulfadiazine = Adiazine®
Active Comparator: Spiramycine; Spiramycin group : spiramycin 1g tid orally	Drug: Spiramycine; Spiramycin group : spiramycin 1g tid orally Follow-up includes clinical and biological tolerance, according to usual recommendations. Monthly fetal ultrasound is performed. Prenatal diagnosis with amniocentesis is offered after 18 weeks gestation, usually 4 weeks after the maternal infection. Treatment is be stopped or changed in case of toxicity. If prenatal diagnosis shows fetal infection with T. gondii, management is to be determined by the clinicians with the patient. If the prenatal diagnosis is negative the treatment is continued according to usual procedures; Other Names: Spiramycine = Rovamycine®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of mother-to-child transmission	Rate of mother-to-child transmission of toxoplasma gondii, determined by PCR on amniocentesis and/or synthesis of specific antibodies by the neonate	Up to six months after birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary Outcome Measure	Mother-to-child transmission rate according to the time between primary infection and start of therapy; Tolerance in mothers and neonates (grade 3-4 toxicities); Severity of infection at birth in case of congenital toxoplasmosis (parasite load in amniotic fluid, clinical and biological signs)	Up to six months after birth

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Laurent Mandelbrot, MD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: August 25, 2010
• First Submitted That Met QC Criteria: August 25, 2010
• First Posted (Estimate): August 26, 2010

Study Record Updates

• Last Update Posted (Estimate): September 29, 2016
• Last Update Submitted That Met QC Criteria: September 28, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Pregnancy,; Congenital Toxoplasmosis,; prenatal diagnosis,; mother-to-child transmission,; prevention,; spiramycine,; pyrimethamine-sulfadiazine
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Infant, Newborn, Diseases; Central Nervous System Infections; Parasitic Diseases; Coccidiosis; Protozoan Infections; Central Nervous System Parasitic Infections; Central Nervous System Protozoal Infections; Toxoplasmosis; Toxoplasmosis, Congenital; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Coccidiostats; Pyrimethamine; Sulfadiazine; Spiramycin
• Other Study ID Numbers: P081234; 2010-019972-65 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided