Pharmacokinetics of Mefloquine-Artesunate in Pregnant Women With Uncomplicated Plasmodium Falciparum Infection

April 12, 2012 updated by: Centers for Disease Control and Prevention

Artemisinin-based combination therapies (ACTs) are now the treatment of choice for malaria in non-pregnant individuals living in areas with established chloroquine resistance; they have been shown to be both safe and highly efficacious. There is rapidly increasing experience with artemisinin derivatives in the 2nd and 3rd trimesters of pregnancy, with over 1,000 well documented cases with no reported serious adverse effects to mother or fetus (WHO Malaria Treatment Guidelines, 2006). Many countries in Latin America have abandoned the previous 1st line regimen of Quinine-Clindamycin for treatment of malaria in pregnancy, a complex and poorly tolerated regimen with low adherence, in favor of ACTs, despite limited safety and pharmacokinetic data on the use of these compounds in pregnant women. Lack of pharmacokinetic data may lead to underdosing of pregnant women, with subsequent reduced efficacy and increased potential for development of resistance.

One ACT regimen, Artesunate-Mefloquine, has been developed as a fixed-dose combination (Farmanguinhos Artesunato + Mefloquina), as part of an international collaborative research effort led by Drugs for Neglected Diseases Initiative (DNDi), and manufactured by Farmanguinhos, laboratory of the Brazilian Ministry of Health. Initial clinical trials suggest that it is very well tolerated and efficacious in both pregnant and non-pregnant individuals. The convenient dosing afforded by a fixed drug combination make this a very promising candidate for treatment of pregnant women with malaria. Preliminary pharmacokinetic data from mefloquine monotherapy and prophylaxis suggest that the peak concentration of mefloquine is lowered in pregnant women. Prior to wide-spread adoption of the Artesunate-Mefloquine combination, further studies on safety, efficacy, and dose optimization are imperative. We propose to compare the pharmacokinetics of the fixed combination of mefloquine-artesunate (MA) for treatment of P.falciparum in 28 pregnant women in the second and third trimesters to the pharmacokinetics of this regimen in 28 matched non-pregnant P.falciparum infected women. This will allow us to determine whether the standard adult dose is sufficient for pregnant women.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Study Type

Interventional

Phase

  • Phase 2
  • Phase 3

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  1. Cases: Pregnant women, age ≥18 years, in 2nd or 3rd trimester (gestational age ≥12 weeks determined by LMP and confirmed by fundal height measurement) Controls: Non-pregnant women ≥18 years old (negative urine pregnancy test)
  2. Presence of P. falciparum ≤ 50,000 parasites/microliter
  3. Fever (≥37.5C) or history of fever in preceding 48 hours
  4. Willing to sign or thumb print informed consent
  5. Willing to be hospitalized for 3 days and to return for scheduled follow up visits for treatment and observation until delivery
  6. Willing to deliver in health facility

Exclusion Criteria:

  1. Pregnancy < 12 weeks
  2. Presence of malaria species other than P. falciparum on the slide (P. vivax, P. malariae, or P. ovale, or mixed infection (P. falciparum in combination with any other malaria species)
  3. History of allergy or hypersensitivity to interventional drugs
  4. Exposure to antimalarial drugs and other drugs with antimalarial activity within the past 2 months, as determined by history from the woman.
  5. Patients taking drugs with possible interaction with study drugs (ie, digoxin or warfarin)
  6. History or family history of epilepsy or psychiatric disorder
  7. Presence of signs and symptoms of severe malaria
  8. Inability to tolerate oral medication (repeated vomiting, impairment of consciousness). Vomiting of any of the treatment doses will lead to exclusion from the pharmacokinetic sampling, but not the follow-up for drug efficacy.
  9. History of chronic disease including diabetes, renal failure, hepatic failure, heart disease requiring anti-arrhythmic drugs or warfarin, AIDS (HIV itself will not be an exclusion, but anyone with AIDS or HIV requiring HAART will be excluded), hemoglobinopathy,
  10. Participant's inability to return for follow up visits
  11. Age <18 years
  12. Hb<8g/dl

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pregnant women
Pregnant women with P. falciparum malaria
Drug: Mefloquine Artesunate
Mefloquine-artesunate fixed dose combination (Farmanguinhos): Artesuanto 100 mg and Mefloquine 220mg per tablet, dosed once daily for 3 days such that mefloquine dose is approximately 8mg/kg/day.
Other Names:
  • Artesunato- mefloquina
Active Comparator: Non pregnant women
Non pregnant women with P. falciparum malaria
Drug: Mefloquine Artesunate
Mefloquine-artesunate fixed dose combination (Farmanguinhos): Artesuanto 100 mg and Mefloquine 220mg per tablet, dosed once daily for 3 days such that mefloquine dose is approximately 8mg/kg/day.
Other Names:
  • Artesunato- mefloquina

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Area under the curve of Mefloquine - artesunate in pregnant versus matched non-pregnant women with P. falciparum malaria
Time Frame: Multiple measures up to 63 days
Multiple measures up to 63 days

Secondary Outcome Measures

Outcome Measure
Time Frame
PCR correct cure rate on Day 63
Time Frame: Day 63
Day 63

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centers for Disease Control and Prevention

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2010

Primary Completion (Anticipated)

October 1, 2010

Study Completion (Anticipated)

October 1, 2010

Study Registration Dates

First Submitted

March 8, 2010

First Submitted That Met QC Criteria

March 8, 2010

First Posted (Estimate)

March 9, 2010

Study Record Updates

Last Update Posted (Estimate)

April 13, 2012

Last Update Submitted That Met QC Criteria

April 12, 2012

Last Verified

April 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PAACT PK

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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