Efficacy and Bio-availability of Artemether-Lumefantrine in Severely Malnourished Children (MAL-NUT)

December 17, 2015 updated by: Epicentre

Efficacy and Bio-availability of Artemether-Lumefantrine Fixed Combination in Severely Malnourished Children Compared to Non-severely Malnourished Children

The general objective of the study is to answer to the question: "Is the current dose of AL less efficacious in the severely malnourished compared to the non-severely malnourished children, and is PK in cause?" We aim to assess whether the current treatment dose is adequate for children with severe acute malnutrition, and we hope results will guide further recommendations for malaria treatment in this specific population.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Study hypothesis:

We hypothesize that AL efficacy might be impaired in severely malnourished children, due to impaired bio-availability of antimalarial drugs in this population.

Objectives:

The general objective of the study is to answer to the question: "Is the current dose of Artemether-Lumefantrine (AL) less efficacious in the severely malnourished compared to the non-severely malnourished children, because of impaired bio-availability?" We aim to assess whether the current treatment dose should be adjusted for this specific population.

The primary objective of the study is to compare the rates of treatment failure (after PCR correction) between severely malnourished and non-severely malnourished children.

The secondary objectives are:

  • To compare the bio-availability of lumefantrine between severely malnourished and non-severely malnourished children (AUC, concentration at day 7…)
  • To compare other efficacy parameters (such as the rates of early parasitological failure, early clinical failure, late therapeutic failure, reinfection and recrudescence) and safety parameters between severely malnourished and non-severely malnourished children.
  • Additionally, If the rate of early parasitological failure appears high in severely malnourished children, we will measure the bio-availability of the artemisinin derivative and will compare it between severely malnourished and non-severely malnourished children.

Settings:

This study will be conducted in two sites in Mali and Niger, two country most affected by malaria and malnutrition, with a high malaria transmission roughly from July to December, corresponding to the malnutrition peak.

Study population:

This study will enrol children with uncomplicated P. falciparum malaria aged between 6 and 59 months, according to the WHO standardized protocol for the surveillance of antimalarial drug efficacy .

The definition of severe acute malnutrition will be weight-for-height <-3 z-scores to the reference WHO 2006 growth standards or middle upper arm circumference (MUAC) <115 mm.

The definition of non-severe acute malnutrition will be a weight-for-height z-score ≥-3 and MUAC ≥115 mm.

Severely stunted children (height-for-age z -score <-3) will be excluded from this study, which is primarily focused on wasted children.

The following modifications of the inclusion criteria will be applied, compared to the standardised WHO protocol:

  • Decreased lower level of parasite density (PD) from 2000 to 1000 parasites per micro litre, as previous studies showed frequent low parasitemias in these patients.
  • In the malnourished children arms, malnutrition <-3 z-score will be an inclusion criterion rather than an exclusion criterion.
  • Children with complications of acute malnutrition needing intensive treatment will be excluded.

Study procedures:

Children will be screened at the renutrition center and pediatric ward of each site.

Two non-malnourished children will be enrolled soon after the enrolment of each malnourished child (ideally, during the same week), to allow carrying out inclusions in parallel for the two study groups, with benefit in terms of representativeness of the study population throughout the malaria season. The ratio of 2 non-severely malnourished children for 1 severely malnourished has been chosen to lower the total number of severely malnourished children to be recruited.

Treatment intake will be supervised and children will be followed-up for 42 days, according to the WHO standardized protocol4. PCR will be used to distinguish recrudescence and re-infection.

In malnourished children, the standardized nutritional rehabilitation program will also be conducted in parallel, and weekly follow-up will include the assessment of nutritional rehabilitation.

Treatment adverse events will be monitored and a Data Safety Monitory Board (DSMB) will be instituted.

To assess the bio-availability of the study drugs, a population pharmacokinetics approach will be used to reduce the number of blood sampling. Capillary blood will be collected on filter paper for measurement of lumefantrine concentrations, 5 times between Day 0 and day 7. Assays will use a liquid chromatography technique with tandem mass spectrometry.

Statistical considerations:

Efficacy analysis:

The primary analysis will compare the efficacy of AL in malnourished children versus non-malnourished children.

It will be designed to detect a minimum crude difference of 8% in Adequate Clinical and Parasitological Response (ACPR) rate in the population of malnourished children (87% versus 95% in non-malnourished children for both treatment combinations), with a statistical power of 80% and a 2-sided significance level of 5%. 160 severely malnourished children and 320 non-severely malnourished children will be enrolled. An additional 10% will be added to account for losses to follow-up and exclusions, yielding to 180 malnourished children and 360 non-malnourished children for each treatment evaluated. To summarize, a total of 540 children will be recruited as a whole.

To answer to the primary objective of the study, we will use multivariate models in which ACPR will be explained by malnutrition status after adjustment for baseline parasitemia, age, and other baseline characteristics that differ between the two populations of children. Cox proportional hazards models and logistic regression models will be used.

Pharmacokinetics (PK) analysis:

A population pharmacokinetics approach will be used, according to the WHO guidelines recommending 5 sampling windows for lumefantrine. Ideally, each sampling window should contain an equal number of samples randomly distributed over the duration of the window. Alternatively, we will use fixed, pre-determined sampling times within the suggested windows, which will fit other samplings required by the protocol. The 5 blood samples will be collected in the 180 severely malnourished children enrolled, and in 180 non-severely malnourished children (randomly chosen), which will allow us to obtain data representative of the studied populations5.

To limit blood sampling in severely malnourished children, we choose to initially restrict the PK assessment to lumefantrine, which exposure is the most correlated to overall treatment response5.

We will have the possibility to add the dosage of artemisinin derivatives in a second phase, in case of "relatively high" observed rate of early parasitological failures or impaired parasite clearance. Indeed, the main pharmacodynamics effect initially (during the first 3 days of treatment) is that of the artemisinin component5. If parasites are still present at day 3, it could be due to under-exposure to the artemisinin component. Otherwise, there is no reason to suspect such under-exposure.

The DSMB will have the responsibility to monitor closely all cases of early parasitological failure, and to recommend adding artemether PK assessment if they reckon that the rate is "unexpectedly high".

PK data will be analysed using nonlinear mixed-effects modelling (with external partnership).

Benefits and risks:

Benefit for the participants will be to receive free of charge treatment for a confirmed diagnosis of malaria. Participants will also benefit from regular visits that will ensure that the treatment cleared the malaria infection and any recurrent malaria episode or emergence of new diseases will be treated quickly. Malnourished patients will benefit from the standardized nutritional rehabilitation program.

The child will be asked to come to the study site for regular check and will be exposed to a series of blood sampling that would not happen if he was not enrolled in the study.

Ethical and regulatory considerations:

The study has been funded by the MSF innovative fund. The protocol is submitted to the approval of MSF Ethics Review Board and the Malian Institutional Ethics Committee.

A DSMB will closely monitor early parasitological failures, and follow serious adverse events.

An external monitoring will be performed during the study.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
399

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Mali
      • Ouelessebougou, Mali
        • District Hospital
  • Niger
      • Maradi city, Niger
        • CSI Andoumè

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

6 months to 5 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age between 6 and 59 months
  • Weight ≥ 5 kg
  • P. falciparum monoinfection confirmed on a thick blood film
  • Parasitic density between 1,000 and 200,000 asexual forms/µL of blood.
  • Measured axillary temperature ≥ 37.5 ° C or history of fever during the previous 24 hours
  • High probability of compliance with follow-up visits (no near-term travel plans)
  • Consent of a parent or guardian who is at least 18 years of age.
  • According to the group: in severely malnourished, weight-for-height z-score <-3 SD or MUAC <115 mm, and in non-severely malnourished, weight-for-height z-score ≥- 3 standard deviations (SD), and MUAC≥ 115 mm.

Exclusion Criteria:

  • General danger signs or signs of complicated malaria as defined by the WHO (Appendix 1)
  • Mixed or mono-infection with another Plasmodium species detected by microscopy
  • Severe anemia (hemoglobin <5 g / dL)
  • Known underlying chronic or severe disease (e.g. cardiac, renal or hepatic disease, tuberculosis, sickle cell)
  • Known HIV/AIDS infection
  • Known history of hypersensitivity or contra-indication to any of the study medications: artemether, lumefantrine (first-line medications), or artesunate, amodiaquine (rescue medications)
  • Presence of febrile conditions due to diseases other than malaria which could alter the outcome of the study
  • History of a full treatment course with AL in the past 14 days.
  • Height-for-age <-3 Z scores
  • Severe complications of malnutrition requiring hospitalization in intensive care or stabilization: Severe signs of kwashiorkor, Anorexia (failure to the appetite test), Hyperemesis, Severe acute infection, Hypothermia <35 ˚ C (axillary) or hypoglycemia, Diarrhea with dehydration, Lethargy, coma, Clinical signs of vitamin A deficiency (xerophthalmia)

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: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Artemether-Lumefantrine
All patients will receive Artemether-Lumefantrine and the endpoints will be compared between the two populations of severely malnourished and non-severely malnourished children
Drug: Artemether-lumefantrine fixed combination
Other Names:
  • Coartem Novartis

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Proportion of adequate clinical and parasitological response after PCR correction
Time Frame: 28 days
Standard primary outcome as defined wy the WHO guidelines for assessing antimalarial efficacy
28 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Percentage of adequate clinical and parasitological response corrected by PCR
Time Frame: 42 days
same as primary outcome but after 42 days of follow-up
42 days
Proportion of treatment failures by types (Early Treatment Failure, Late Clinical Failure, Late Parasitological Failure)
Time Frame: 28 and 42 days
Endpoints defined by the standardised WHO protocol
28 and 42 days
Proportion of reinfection and recrudescence
Time Frame: 28 and 42 days
28 and 42 days
Bio-availability of lumefantrine
Time Frame: 21 days
Area under curve, Cmax, Tmax of lumefantrine (estimated through population based approach, 5 samples collected per subject)
21 days
Type and frequency of adverse events
Time Frame: 42 days
42 days

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Time Frame
Level of antimalarial antibodies at enrolment
Time Frame: Enrolment
Enrolment

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Epicentre

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
University of Cape Town
Malaria Research and Training Center, Bamako, Mali

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Jean-François Etard, MD, PhD, Epicentre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 1, 2013

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 1, 2015

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
May 1, 2015

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 7, 2013

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 7, 2013

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 9, 2013

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 18, 2015

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 17, 2015

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2015

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 824338

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.

Clinical Trials on Malaria

Clinical Trials on Artemether-lumefantrine fixed combination

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings