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

Malaria Clinical Trial

— ALN5P  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01916954
• Other study ID #: ALN5P
• Status: Completed
• Phase: Phase 3
• First received: August 1, 2013
• Last updated: March 24, 2014
• Start date: July 2013

Study information

• Verified date: March 2014
• Source: University of Oxford
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Research Ethics CommitteeDemocratic Republic of Congo: Research Ethics Committee
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 96
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Malaria

Intervention

Drug:
• 3-day artemether-lumefantrine

• 5-day artemether-lumefantrine

Locations

Country	Name	City	State
Congo	University of Kinshasa, Democratic Republic of Congo	Kinshasa

Sponsors (2)

Lead Sponsor	Collaborator
University of Oxford	University of Kinshasa

Country where clinical trial is conducted

Congo, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Efficacy measures	Therapeutic efficacy of the treatment will be assessed in the follow-up period according to WHO protocol for the evaluation of antimalarial efficacy. Therapeutic responses will be correlated with drug concentration profiles.	1 year	No
Primary	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	No
Secondary	Tolerability and safety measures	Detection and assessment of adverse events during the therapy and in the follow-up period.	2 years	Yes