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

This study has been completed.
Sponsor:
Collaborator:
University of Kinshasa
Information provided by (Responsible Party):
University of Oxford
ClinicalTrials.gov Identifier:
NCT01916954
First received: August 1, 2013
Last updated: March 24, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Malaria
Drug: 3-day artemether-lumefantrine
Drug: 5-day artemether-lumefantrine
Phase 3

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

Resource links provided by NLM:


Further study details as provided by University of Oxford:

Primary Outcome Measures:
  • Pharmacokinetics measures [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Tolerability and safety measures [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Detection and assessment of adverse events during the therapy and in the follow-up period.


Other Outcome Measures:
  • Efficacy measures [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    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.


Enrollment: 96
Study Start Date: July 2013
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 3-day artemether-lumefantrine
Standard artemether-lumefantrine regimen (3-day treatment)
Drug: 3-day artemether-lumefantrine
Experimental: 5-day artemether-lumefantrine
Artemether-lumefantrine extended regimen (5-day treatment)
Drug: 5-day artemether-lumefantrine

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.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01916954

Locations
Congo
University of Kinshasa, Democratic Republic of Congo
Kinshasa, Congo
Sponsors and Collaborators
University of Oxford
University of Kinshasa
Investigators
Principal Investigator: Nicholas P Day, MD PhD University of Oxford
  More Information

No publications provided

Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT01916954     History of Changes
Other Study ID Numbers: ALN5P
Study First Received: August 1, 2013
Last Updated: March 24, 2014
Health Authority: United Kingdom: Research Ethics Committee
Democratic Republic of Congo: Research Ethics Committee

Keywords provided by University of Oxford:
Malaria
Pregnancy
Plasmodium falciparum

Additional relevant MeSH terms:
Malaria
Malaria, Falciparum
Protozoan Infections
Parasitic Diseases
Artemether
Artemisinins
Lumefantrine
Artemether-lumefantrine combination
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Coccidiostats
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics

ClinicalTrials.gov processed this record on August 26, 2014