Chlorproguanil-Dapsone in Pregnant Women - Full Text View

Sponsors and Collaborators:	Centers for Disease Control and Prevention Malaria Research and Training Center, Bamako Liverpool School of Tropical Medicine
Information provided by:	Centers for Disease Control and Prevention
ClinicalTrials.gov Identifier:	NCT00126971

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 I

MedlinePlus related topics: Malaria

Drug Information available for: Dapsone Chlorproguanil

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Pharmacokinetics Study
Official Title:	Pharmacokinetics of Chlorproguanil-Dapsone in Pregnant Women With Plasmodium Falciparum Infection, and Reinfection With P. Falciparum During Pregnancy Following Treatment

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

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

Locations

Mali
Faladje Missionary Dispensary
Faladje, Mali

Sponsors and Collaborators

Centers for Disease Control and Prevention

Malaria Research and Training Center, Bamako

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:

Mutabingwa T, Nzila A, Mberu E, Nduati E, Winstanley P, Hills E, Watkins W. Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania. Lancet. 2001 Oct 13;358(9289):1218-23. Erratum in: Lancet 2001 Nov 3;358(9292):1556.

Keuter M, van Eijk A, Hoogstrate M, Raasveld M, van de Ree M, Ngwawe WA, Watkins WM, Were JB, Brandling-Bennett AD. Comparison of chloroquine, pyrimethamine and sulfadoxine, and chlorproguanil and dapsone as treatment for falciparum malaria in pregnant and non-pregnant women, Kakamega District, Kenya. BMJ. 1990 Sep 8;301(6750):466-70.

Winstanley P, Watkins W, Muhia D, Szwandt S, Amukoye E, Marsh K. Chlorproguanil/dapsone for uncomplicated Plasmodium falciparum malaria in young children: pharmacokinetics and therapeutic range. Trans R Soc Trop Med Hyg. 1997 May-Jun;91(3):322-7.

Study ID Numbers:	CDC-NCID-4341
Study First Received:	August 3, 2005
Last Updated:	August 14, 2006
ClinicalTrials.gov Identifier:	NCT00126971
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

Study placed in the following topic categories:

Folic Acid
Protozoan Infections
Chloroguanide
Dapsone

Parasitic Diseases
Malaria
Chlorproguanil

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Antiprotozoal Agents
Molecular Mechanisms of Pharmacological Action
Coccidiosis
Enzyme Inhibitors
Folic Acid Antagonists

Pharmacologic Actions
Antimalarials
Anti-Bacterial Agents
Antiparasitic Agents
Therapeutic Uses
Leprostatic Agents

ClinicalTrials.gov processed this record on January 16, 2009