Chlorproguanil-Dapsone in Pregnant Women

This study has suspended participant recruitment.
Sponsor:
Collaborators:
Malaria Research and Training Center, Bamako, Mali
Liverpool School of Tropical Medicine
Information provided by:
Centers for Disease Control and Prevention
ClinicalTrials.gov Identifier:
NCT00126971
First received: August 3, 2005
Last updated: August 14, 2006
Last verified: August 2006
  Purpose

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.


Condition Intervention Phase
Malaria
Drug: chlorproguanil-dapsone
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pharmacokinetics of Chlorproguanil-Dapsone in Pregnant Women With Plasmodium Falciparum Infection, and Reinfection With P. Falciparum During Pregnancy Following Treatment

Resource links provided by NLM:


Further study details as provided by Centers for Disease Control and Prevention:

Primary Outcome Measures:
  • Pharmacokinetic analyses of pregnant women taking CD

Secondary Outcome Measures:
  • Proportion of pregnant women sleeping under ITNs who become re-infected with malaria before delivery following administration of a single dose of CD for P. falciparum parasitemia
  • Proportion of treatment failures by day 28 following initial treatment
  • Treatment failure will be defined according to standard WHO criteria for low to moderate transmission areas to account for fact that some pregnant women are asymptomatic
  • Early treatment failure: development of danger signs or severe malaria on Day 1, Day 2 or Day 3 in the presence of parasitemia (severe malaria defined by altered sensorium convulsions
  • persistent vomiting
  • renal impairment
  • respiratory distress)
  • a fall in Hb below 5g/dl anytime
  • parasitemia on Day 2 higher than Day 0 count irrespective of axillary temperature
  • parasitemia on Day 3 with axillary temperature >= 37.5 °C
  • parasitemia on Day 3 >= 25% of count on Day 0
  • Late clinical failure: development of danger signs of severe malaria after Day 3 in the presence of parasitemia, without previously meeting any of the criteria of early treatment failure
  • presence of parasitemia and axillary temperature >= 37.5 °C on any day from Day 4 (inclusive) to Day 28 (inclusive), without previously meeting any of the criteria of early treatment failure
  • Late parasitological failure: parasitemia on any day between Day 7 (inclusive) and Day 28 (inclusive)
  • axillary temperature <37.5 °C without previously meeting any of the criteria of early treatment failure or late clinical failure, after exclusion of re-infection by PCR (days
  • adequate clinical and parasitological response [ACPR] will be defined as: absence of parasitemia on Day 28 irrespective of axillary temperature without previously meeting any of the criteria of early treatment failure
  • or late clinical failure
  • or late parasitologic failure)
  • Parasite clearance by Day 3
  • Mean Hb concentrations by Day 28, and hematological recovery by day 28 (Hb > 11 g/dL)
  • Gametocytemia
  • Maternal parasitemia at delivery
  • Placental malaria parasitemia
  • Mean birth weight and gestational age of newborn
  • Presence of congenital abnormalities
  • Incidence of fetal loss
  • Incidence of perinatal and neonatal mortality, assessed 4-6 weeks after due date of delivery
  • Incidence of fetal death, defined as absence of fetal heartbeat
  • Hypoglycemia requiring treatment
  • Other adverse events during treatment period (up to 28 days)

Estimated Enrollment: 132
Study Start Date: July 2005
  Show Detailed Description

  Eligibility

Ages Eligible for Study:   15 Years to 49 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00126971

Locations
Mali
Faladje Missionary Dispensary
Faladje, Mali
Sponsors and Collaborators
Malaria Research and Training Center, Bamako, Mali
Liverpool School of Tropical Medicine
Investigators
Principal Investigator: Robert D Newman, MD, MPH Centers for Disease Control and Prevention
Principal Investigator: Kassoum Kayentao, MD, MSPH Malaria Research and Training Center
Principal Investigator: Feiko ter Kuile, MD, PhD Liverpool School of Tropical Medicine
Principal Investigator: Ogobara Doumbo, MD, PhD Malaria Research and Training Center
Principal Investigator: Monica E Parise, MD Centers for Disease Control and Prevention
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00126971     History of Changes
Other Study ID Numbers: CDC-NCID-4341
Study First Received: August 3, 2005
Last Updated: August 14, 2006
Health Authority: United States: Federal Government
Mali: Ministry of Health

Keywords provided by Centers for Disease Control and Prevention:
malaria
pregnancy
Plasmodium falciparum
antimalarials
pharmacokinetics
treatment outcome
safety

Additional relevant MeSH terms:
Malaria
Parasitic Diseases
Protozoan Infections
Chlorproguanil
Dapsone
Proguanil
Anti-Bacterial Agents
Anti-Infective Agents
Antimalarials
Antimetabolites
Antiparasitic Agents
Antiprotozoal Agents
Enzyme Inhibitors
Folic Acid Antagonists
Leprostatic Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014