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

Plasmodium Falciparum Malaria Clinical Trial

Official title:

The Pharmacokinetic of the Fixed-dose Combination of Mefloquine-Artesunate in Plasmodium Falciparum Malaria Infection in Pregnant Women

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00701961
• Other study ID #: ITMP0208
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: June 18, 2008
• Last updated: September 12, 2010
• Start date: October 2008
• Est. completion date: July 2009

Study information

• Verified date: September 2010
• Source: Institute of Tropical Medicine, Belgium
• Contact: n/a
• Is FDA regulated: No
• Health authority: Burkina Faso: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: July 2009
• Est. primary completion date: July 2009
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 49 Years

Eligibility

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.

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum
• 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).

Locations

Country	Name	City	State
Burkina Faso	Centre Muraz	Nanoro

Sponsors (3)

Lead Sponsor	Collaborator
Institute of Tropical Medicine, Belgium	Centre Muraz, Liverpool School of Tropical Medicine

Country where clinical trial is conducted

Burkina Faso, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To estimate the pharmacokinetic of MQ-AS for treatment of P. falciparum or mixed infection in pregnant compared to non-pregnant women.		6 months	No
Secondary	The proportion of women in each treatment group with parasitological cure at 63 days, corrected by PCR for re-infection.		6 months	Yes