Pharmacokinetic of Mefloquine-Artesunate in Plasmodium Falciparum Malaria Infection in Pregnancy

• ClinicalTrials.gov Identifier: NCT00701961
• Recruitment Status: Completed
• First Posted: June 19, 2008
• Last Update Posted: September 14, 2010
• Sponsor: Institute of Tropical Medicine, Belgium
• Collaborators: Centre Muraz; Liverpool School of Tropical Medicine
• Information provided by: Institute of Tropical Medicine, Belgium

Tracking Information

• First Submitted Date: June 18, 2008
• First Posted Date: June 19, 2008
• Last Update Posted Date: September 14, 2010
• Study Start Date: October 2008
• Actual Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 18, 2008): 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 ]
• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures (submitted: June 18, 2008): The proportion of women in each treatment group with parasitological cure at 63 days, corrected by PCR for re-infection. [ Time Frame: 6 months ]
• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pharmacokinetic of Mefloquine-Artesunate in Plasmodium Falciparum Malaria Infection in Pregnancy
• Official Title: The Pharmacokinetic of the Fixed-dose Combination of Mefloquine-Artesunate in Plasmodium Falciparum Malaria Infection in Pregnant Women
• Brief Summary: 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.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Plasmodium Falciparum Malaria

Intervention

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).

Other Name: MQ-AS

Study Arms

• 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.
  Intervention: Drug: Mefloquine-artesunate
• 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.
  Intervention: Drug: Mefloquine-artesunate

Publications *

• Birgersson S, Valea I, Tinto H, Traore-Coulibaly M, Toe LC, Hoglund RM, Van Geertruyden JP, Ward SA, D'Alessandro U, Abelo A, Tarning J. Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Burkina Faso: an open label trial. Wellcome Open Res. 2019 Mar 7;4:45. doi: 10.12688/wellcomeopenres.14849.2. eCollection 2019.
• Valea I, Tinto H, Traore-Coulibaly M, Toe LC, Lindegardh N, Tarning J, Van Geertruyden JP, D'Alessandro U, Davies GR, Ward SA. Pharmacokinetics of co-formulated mefloquine and artesunate in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum infection in Burkina Faso. J Antimicrob Chemother. 2014 Sep;69(9):2499-507. doi: 10.1093/jac/dku154. Epub 2014 Jun 2.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 18, 2008): 48
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: July 2009
• Actual Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 49 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Burkina Faso

Administrative Information

• NCT Number: NCT00701961
• Other Study ID Numbers: ITMP0208
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Prof. Umberto D'Alessandro, Parasitology Department, Institute Tropical Medicine, Antwerp, Belgium
• Original Responsible Party: Same as current
• Current Study Sponsor: Institute of Tropical Medicine, Belgium
• Original Study Sponsor: Same as current

Collaborators

• Centre Muraz
• Liverpool School of Tropical Medicine

Investigators

• Principal Investigator: Tinto Halidou, PhD; Centre Muraz
• Study Chair: Umberto D'Alessandro, MD; ITM Belgium

• PRS Account: Institute of Tropical Medicine, Belgium
• Verification Date: September 2010