Chlorproguanil-Dapsone in Pregnant Women

• Status: Suspended
• Trial end date: 1969-12-31
• Target enrollment: 0
• Participant gender: Female

Summary

Controlling malaria during pregnancy is a vital strategy in decreasing maternal and child mortality in Africa. There are data from clinical trials and program evaluations in stable transmission areas that show that intermittent preventive treatment (IPT) with two doses of sulfadoxine-pyrimethamine (SP) is safe, efficacious, and effective in preventing maternal anemia, placental parasitemia, and low birth weight (LBW). SP is also the first-line drug for the case-management of malaria in pregnancy. Resistance to SP, however, is increasing rapidly in East and Central Africa and compliance to the rescue treatment, 7-days of oral quinine, is low. There is an urgent need to find effective, safe and practical alternative drugs for the treatment of malaria in pregnancy. The synergistic antifolate combination chlorproguanil-dapsone (CD), has recently become available. It is inexpensive, well tolerated, is given as single daily treatment doses for 3 days, and is effective in the treatment of drug-resistant falciparum malaria.

The investigators propose a small pharmacokinetic study of CD to determine if current fixed combination CD tablets provide an adequate dosage in pregnancy. Such a study is a necessary precursor to any large Phase II trials to further evaluate the safety and efficacy of CD for use in pregnant women. To accomplish this, a group of 66 parasitemic pregnant women in this open label trial will receive CD and be sampled by venipuncture at two of the seven follow-up visits scheduled for pharmacokinetic analyses, such that 11 patients are sampled at each of 12 time points. To serve as a reference, 66 non-pregnant women with symptomatic malaria will also be treated with CD and will have identical pharmacokinetic (PK) analyses performed.

Pregnant women greater than or equal to 20 weeks gestation with P. falciparum parasitemia on peripheral blood film will be given an insecticide-treated net (ITN) and will receive CD (1.5 or 2 tablets daily for 3 days, depending on weight). All study drug dosing will be observed. Women will be examined, adverse events recorded, and blood samples collected at days 0, 1, 2, 3, 7, 14, 21, and 28 after treatment, and thereafter every 14 days until delivery. Women will be further randomized to receive additional blood draws for pharmacokinetic analyses using a modified rich PK schedule. Each woman will only have 2 additional blood draws. Women at delivery will have peripheral and placental blood films prepared. Newborns will be weighed, examined, and gestational age determined. Women requiring antimalarial treatment for parasitemia at any point between enrollment and delivery will be treated with quinine. Adverse effects will be assessed at each scheduled visit, any sick visits during the study, and at delivery.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Centers for Disease Control and Prevention
• Collaborators: Liverpool School of Tropical Medicine; Malaria Research and Training Center, Bamako, Mali
• Treatments: Chlorproguanil; Dapsone; Proguanil

Criteria

Inclusion Criteria:

For the pregnancy part of the study, a subject will be considered eligible for inclusion in this study only if all of the following criteria apply: She

• Is pregnant and presents at the antenatal clinic (ANC) facilities of the study hospital.

• Has uncomplicated malaria (either symptomatic or not) with pure (on microscopic grounds) P falciparum parasitemia.

• Has a gestational age of >= 20 and < 36 weeks (defined by fundal height).

• Is willing and able to participate and comply with the study protocol, attend the ANCs regularly and agrees to supervised drug delivery.

• Has no history of antimalarial intake in the previous 4 weeks, with the exception of chloroquine or quinine.

• Has given written or witnessed verbal consent.

For the 66 non-pregnant women, the following inclusion criteria will apply:

• Has uncomplicated malaria (either symptomatic or not) with pure (on microscopic grounds) P falciparum parasitemia.

• Negative urine pregnancy test.

• Is willing and able to participate and comply with the study protocol, attend the ANCs regularly and agrees to supervised drug delivery.

• Has no history of antimalarial intake in the previous 4 weeks, with the exception of chloroquine or quinine.

• Has given written or witnessed verbal consent.

Exclusion Criteria:

• Any feature of severe malaria.

• A history of convulsions during the present illness.

• Known history of G6PD deficiency or sickle cell disease.

• Other conditions requiring hospitalization or evidence of severe concomitant infection at time of presentation.

• Women on daily cotrimoxazole prophylaxis

• Use of any antimalarial (other than chloroquine or quinine) in the past 4 weeks.

• Known chronic disease (cardiac, renal, hepatic, hemoglobinopathy), or known hepatic or renal impairment.

• Inability to follow the ANC consultation.

• Hemoglobin < 7 g/dL (will be measured before enrollment)

• Inability to tolerate oral treatment reflected by persistent vomiting of the study drugs.

• Known allergy to either the study drugs, or to any sulfa-containing medications.

• Age <15 years.

• Age >49 years.