Comparison of Two Regimens of Artemether-lumefantrine for the Treatment of Malaria in Pregnancy (ALN5P)

University of Oxford

Status and phase: Completed; Phase 3

Conditions: Malaria

Treatments: Drug: 5-day artemether-lumefantrine; Drug: 3-day artemether-lumefantrine

Study type: Interventional

Funder types: Other

Identifiers

NCT01916954

ALN5P

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 96 patients

Sex: Female

Ages: 18 to 45 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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96 participants in 2 patient groups

3-day artemether-lumefantrine

Active Comparator group

Description:

Standard artemether-lumefantrine regimen (3-day treatment)

Treatment:

Drug: 3-day artemether-lumefantrine

5-day artemether-lumefantrine

Experimental group

Description:

Artemether-lumefantrine extended regimen (5-day treatment)

Treatment:

Drug: 5-day artemether-lumefantrine