Official Title: “The Pharmacokinetic of the Fixed-Dose Combination of Mefloquine-Artesunate in Plasmodium Falciparum Malaria Infection in Pregnant Women”

Malaria in pregnancy is a major public health problem in Sub-Saharan Africa. Over the past decades, P. falciparum has shown increasing resistance to chloroquine and Sulphadoxine-Pyrimethamine, which has prompted a change in treatment approach; artemisinin containing combination therapies (ACTs) are now the standard treatment of P. falciparum malaria in areas with established resistance to traditional therapies. However, a standard approach for using ACT in pregnancy does not exist in Africa, where some countries keep on using quinine, while others allow the use of ACTs. Thus, there is need of establishing the safety and efficacy of ACTs in malaria-infected pregnant women. Since the pharmacokinetic of antimalarials may be altered during pregnancy and since available pharmacokinetic data are still somewhat limited, we propose to carry out a study confirming or disproving existing pharmacokinetic data (collected in South-East Asia), before starting any larger African efficacy and safety trials. The fixed-dose combination mefloquine-artesunate (MQ-AS), developed by the Drugs for Neglected Diseases Initiative, will be used in the study, which will compare the pharmacokinetics of MQ-AS for treatment of P.falciparum in 24 pregnant women in the second and third trimesters, to the pharmacokinetics of this regimen in 24 matched non-pregnant P.falciparum infected women. The study will be carried out in Burkina Faso.

Study Type: Interventional

Study Design: Treatment, Open Label, Active Control, Single Group Assignment, Pharmacokinetics Study

Study Primary Completion Date: April 2009

Malaria during pregnancy constitutes a major public health problem in Sub-Saharan Africa, where it increases the risk of low birth weight (<2500g), infant mortality, infant morbidity during the first year of life, prematurity and infant anemia. Over the past decades, P.

falciparum has shown increasing resistance to standard antimalarial therapy (chloroquine CQ and Sulphadoxine-Pyrimethamine). The inexorable development and spread of P. falciparum resistance to antimalarials has prompted a change in treatment approach; artemisinin containing combination therapies (ACTs) are now the standard treatment of P. falciparum malaria in areas with established resistance to the traditional therapies. The use of combinations reduces the theoretical likelihood of selecting resistant mutants; it is hoped that this strategy will delay the development of new resistances.

A standard approach for using ACT in pregnancy does not exist in Africa. Even if the World Health Organization endorses the use of ACTs for treatment of uncomplicated malaria in 2nd and 3rd trimesters of pregnancy, some countries keep on using quinine, while others allow the use of ACTs. These different approaches point out to the necessity of establishing the safety and efficacy of ACTs in malaria-infected pregnant women. Nevertheless, considering that the pharmacokinetic of antimalarials may be altered during pregnancy (potentially leading to under-dosing) and that the available safety and pharmacokinetic data are still somewhat limited, it is important to carry out a preliminary pharmacokinetic study confirming or disproving available data (collected in South-East Asia), before starting any larger African efficacy and safety trials.

The ACT regimen mefloquine-artesunate (MQ-AS) has recently been developed as a fixed-dose combination by the Drugs for Neglected Diseases Initiative (DNDi) and has been registered in Brazil (the country of manufacture) in 2008. Artesunate is an artemisinin derivative with a rapidly increasing positive experience in pregnancy, while Mefloquine (Lariam®) has been used for many years for both prevention and treatment of malaria, and has been shown to be safe in pregnant women. The convenient dosing afforded by a fixed drug combination makes MQ-AS a very promising candidate for use in treating pregnant women in Africa, as rescue treatment alternative to quinine. Since preliminary data suggest that the peak concentration of mefloquine is lowered in pregnant women, further studies on safety, efficacy, and dose optimization are imperative, prior to wide-spread adoption of this medicine.

Therefore, we propose to compare the pharmacokinetics of the fixed combination of MQ-AS for treatment of P.falciparum in 24 pregnant women in the second and third trimesters to the pharmacokinetics of this regimen in 24 matched non-pregnant P.falciparum infected women, in an African setting. This will allow for dose optimization in pregnant women.

Intervention(s) in this Clinical Trial

• Drug: Mefloquine-artesunate
  • Mefloquine-artesunate fixed dose combination comprised of 100 mg of artesunate and 220mg of mefloquine per tablet, developed by DNDi and manufactured by farmanguinhos (Brazil).

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Pregnat women receiving MQ-AS fixed dose combination comprised of 100 mg of artesunate and 220mg of mefloquine per tablet, dosed once daily such that mefloquine dose is approximately 8mg/kg/day for 3 days.
• Active Comparator: 2
  • Non-pregnant women receiving MQ-AS fixed dose combination comprised of 100 mg of artesunate and 220mg of mefloquine per tablet, dosed once daily such that mefloquine dose is approximately 8mg/kg/day for 3 days.

Primary Measures

• To estimate the pharmacokinetic of MQ-AS for treatment of P. falciparum or mixed infection in pregnant compared to non-pregnant women.
  • Time Frame: 6 months
    Safety Issue?: No

Secondary Measures

• The proportion of women in each treatment group with parasitological cure at 63 days, corrected by PCR for re-infection.
  • Time Frame: 6 months
    Safety Issue?: Yes

Inclusion Criteria:

• 1. Plasmodium falciparum monoinfection (any density)
• 2. At least 18 years old;
• 3. Haemoglobin at leats 7 g/dL;
• 4. Residence within the health facility catchment's area;
• 5. Willing to adhere to the study requirements
• 6. Willing to deliver in health facility
• 7. Ability to provide written informed consent
• 8. EITHER pregnant women in the 2nd or 3rd trimester (cases)or non-pregnant women between the ages of 18 and 49 years (controls).

Exclusion Criteria:

• 1. Pregnancy 1st trimester
• 2. History of known pregnancy complications or bad obstetric history such as repeated stillbirths or eclampsia;
• 3. Known major illnesses likely to influence pregnancy outcome including diabetes mellitus, severe renal or heart disease, or active tuberculosis;
• 4. Current cotrimoxazole prophylaxis or ARV treatment;
• 5. Any significant presenting illness that requires hospitalization, including severe malaria;
• 6. Intent to move out of the study catchment area before delivery or deliver at relative's home out of the catchment area.
• 7. Prior enrollment in the study or concurrent enrollment in another study.
• 8. Unable to take oral medication
• 9. Clear evidence of treatment with antimicrobials with antimalarial activity (erythromycin or other macrolides, co-trimoxazole or other sulfonamides, any tetracycline including doxycycline, quinolones and clindamycin) or exposure to antimalarial drugs within the week prior enrollment.
• 10. History of allergy or hypersensivity to interventional drugs
• 11. Patients taking drugs with possible interaction with study drugs (i.e. digoxin or warfarin)
• 12. History or family history of epilepsy or psychiatric disorder
• 13. Presence of signs and symptoms of severe malaria
• 14. Inability to tolerate oral medication (repeated vomiting, impairment of consciousness). Vomiting of any of the treatment doses will lead to exclusion from the pharmacokinetic sampling.

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 49 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Institute of Tropical Medicine, Belgium

Overall Clinical Trial Officials and Contacts

Tinto Halidou, PhD Principal Investigator Centre Muraz, Bobo Dioulasso, Burkina Faso.  

Overall Contact: Tinto Halidou, PhD  tintohalidou@yahoo.fr

Information obtained from ClinicalTrials.gov on August 27, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00701961

Study ID Number: ITMP0208

ClinicalTrials.gov Identifier: NCT00701961

Health Authority: Burkina Faso: Ministry of Health