Comparison of Two Regimens of Artemether-lumefantrine for the Treatment of Malaria in Pregnancy

Study Overview
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Brief Summary
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Malaria in pregnancy is a major cause of maternal and newborn morbidity and mortality in sub-Saharan Africa]. Effective antimalarial preventive and treatment regimens can significantly reduce malaria-related morbidity and mortality in the mother and baby. However, therapeutic choices are limited by concerns about possible toxicity to the fetus and because of these concerns pregnant women are normally excluded from clinical trials. This, combined with the lack of adverse events reporting system, results in a scarcity of data on drug safety and efficacy in pregnancy. Moreover, changes in the maternal physiology in pregnancy often alter the pharmacokinetic of drugs. Artemether-lumefantrine (ALN) is a highly efficacious artemisinin-based combination therapy approved by the World Health Organisation for use in the 2nd and 3rd trimesters, although it is still infrequently used in pregnancy and there is uncertainty as to the optimum dose. The pharmacokinetics of ALN are altered in pregnancy, resulting in reduced plasma concentrations and while the standard adult dose is still effective in high transmission settings, where pregnant women have higher levels of immunity, efficacy is reduced significantly in low transmission settings where women have lower levels of immunity. Inadequate antimalarial treatment dosing in pregnancy risks treatment failure or breakthrough infection and exposure of malaria parasites to sub-therapeutic drug concentrations thus selecting for drug resistance.

Detailed Description
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The aim of the current trial is to compare the standard 3-day regimen of artemether-lumefantrine to a 5-day regimen of artemether-lumefantrine in a group of pregnant women and a control of non-pregnant women with uncomplicated P. falciparum malaria. The pharmacokinetics of lumefantrine is modified in pregnancy and the standard regimen used for treatment of adults might not be sufficient to cure malaria, therefore exposing pregnant women to sub-therapeutic drug levels and increased risk of clinical failure. Previous pharmacokinetic studies have shown that the standard 3-day treatment during pregnancy results in reduced plasma concentrations of artemether, dihydroartemisinin and lumefantrine and a faster elimination of lumefantrine. Low lumefantrine plasma concentrations at day 7 are associated with therapeutic failure. Population-based simulations suggest that increased dose and treatment duration are needed for adequate drug exposure in these patients. We propose to assess the pharmacokinetics of a longer regimen of artemether-lumefantrine, (10 doses of artemether-lumefantrine over five days) compared to the standard regimen, (6 doses of artemether-lumefantrine over three days) in a small group of pregnant African women with uncomplicated P. falciparum malaria. The longer regimen should ensure that curative plasma concentration of lumefantrine is reached, and is unlikely to result in any increased frequency of adverse events.

Official Title
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Comparison of Two Regimens of Artemether-lumefantrine for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Pregnant Women in the Democratic Republic of Congo

Conditions
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Malaria

Intervention / Treatment
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* Drug: 3-day artemether-lumefantrine
* Drug: 5-day artemether-lumefantrine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria for non pregnant women: Age ≥18 and ≤ 45 years P. falciparum parasitemia ≥ 100 parasites/μL and less than 200.000 parasites/μL Hematocrit ≥21% Negative HIV test Negative pregnancy test* Written informed consent provided Willing to stay for 3 or 5 days at the hospital and to comply with the follow-up schedule Inclusion criteria for pregnant women (in addition to the above criteria except*): Gestational Age ≥ 14 weeks confirmed by ultrasound Singleton viable fetus Exclusion criteria for non-pregnant women: Severe malaria or signs of severe malaria Medical conditions requiring concomitant drug treatment or transfer to a different hospital Intake of artemether-lumefantrine within the two previous 2 weeks Known allergy to the study drugs Previous participation in this study or current participation in other studies Exclusion criteria for pregnant women (in addition to the above criteria): Signs of labour Fetal abnormalities identified by ultrasound

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 3-day artemether-lumefantrine<br>Standard artemether-lumefantrine regimen (3-day treatment) | Drug: 3-day artemether-lumefantrine<br> <br> |
| Experimental: 5-day artemether-lumefantrine<br>Artemether-lumefantrine extended regimen (5-day treatment) | Drug: 5-day artemether-lumefantrine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics measures | Drug plasma concentration profiles for lumefantrine, artemether and dihydroartemisinin will be characterized for each patient. Ten samples per patient will be taken at fixed and random times. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability and safety measures | Detection and assessment of adverse events during the therapy and in the follow-up period. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Pregnancy, Plasmodium falciparum