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

NCT ID: NCT01916954

Last Updated: 2014-03-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 96 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-07-31

Brief 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.

Detailed 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.

Conditions

Malaria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

3-day artemether-lumefantrine

Standard artemether-lumefantrine regimen (3-day treatment)

Group Type: ACTIVE_COMPARATOR

3-day artemether-lumefantrine

Intervention Type: DRUG

5-day artemether-lumefantrine

Artemether-lumefantrine extended regimen (5-day treatment)

Group Type: EXPERIMENTAL

5-day artemether-lumefantrine

Intervention Type: DRUG

Interventions

3-day artemether-lumefantrine

Intervention Type: DRUG

5-day artemether-lumefantrine

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

• Gestational Age ≥ 14 weeks confirmed by ultrasound
• Singleton viable fetus

Exclusion Criteria

• 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

• Signs of labour
• Fetal abnormalities identified by ultrasound

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

University of Kinshasa

OTHER

Sponsor Role: collaborator

University of Oxford

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nicholas P Day, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University of Oxford

Locations

University of Kinshasa, Democratic Republic of Congo

Kinshasa, , Republic of the Congo

Countries

Republic of the Congo

References

Onyamboko MA, Hoglund RM, Lee SJ, Kabedi C, Kayembe D, Badjanga BB, Turner GDH, Jackson NV, Tarning J, McGready R, Nosten F, White NJ, Day NPJ, Fanello C. A Randomized Controlled Trial of Three- versus Five-Day Artemether-Lumefantrine Regimens for Treatment of Uncomplicated Plasmodium falciparum Malaria in Pregnancy in Africa. Antimicrob Agents Chemother. 2020 Feb 21;64(3):e01140-19. doi: 10.1128/AAC.01140-19. Print 2020 Feb 21.

Reference Type: DERIVED

PMID: 31818818 (View on PubMed)

Other Identifiers

ALN5P

Identifier Type: -

Identifier Source: org_study_id