Monitoring of Molecular Markers of Artemisinin Resistance Through Repeated Cross-sectional Assessments in DR Congo, Nigeria and Uganda (Caramal DRM)

January 28, 2021 updated by: Swiss Tropical & Public Health Institute

Monitoring of Molecular Markers of Artemisinin Resistance in Plasmodium Falciparum Malaria: Repeated Cross-sectional Assessments in DR Congo, Nigeria and Uganda

Currently, 16 African countries include the use of pre-referral rectal artesunate (RAS) in their treatment policies. However, guidelines for RAS use vary widely across countries and inappropriate use of RAS as a monotherapy and consequential development of resistances against artemisinin based treatments is of particular concern.

In the frame of the Unitaid-funded "Community Access to Rectal Artesunate for Malaria" (CARAMAL) Project, quality-assured RAS will be rolled in selected areas of the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Approximately 3,000 treatments of RAS will be dispensed by trained community health workers to children <5 years of age in each project country per year.

Linked to the tracking of (severe) malaria patients in the frame of the CARAMAL project, this study will assess the frequency of artemisinin resistance markers in the study settings and tentatively assess whether the introduction of RAS could increase the selection of resistant P. falciparum strains. The study will be conducted in close collaboration with the Global Malaria Programme of the WHO. Finger-prick blood samples will be collected from children < 5 years of age with signs of severe febrile illness and a positive mRDT presenting to community-based providers and referral facilities before and after the pilot roll-out of pre-referral RAS at community level.

Study Overview

Detailed Description

Currently, 16 African countries include the use of pre-referral rectal artesunate (RAS) in their treatment policies and a number of countries have begun to implement RAS. However, guidelines for RAS use vary widely across countries and often do not align with WHO recommendations. Of particular concern in this context is the inappropriate use of RAS as a monotherapy (i.e. without subsequent ACT treatment).

In the frame of the Unitaid-funded "Community Access to Rectal Artesunate for Malaria" (CARAMAL) Project, quality-assured (QA) RAS will be rolled out through integrated Community Case Management (iCCM) schemes in selected areas of the Democratic Republic of the Congo (DRC), Nigeria and Uganda. The goal of the CARAMAL Project is to contribute to reducing malaria mortality in children by improving the community management of suspected severe malaria cases. The project will contribute to this goal by advancing the development of operational guidance to catalyse effective and appropriate scale-up of quality-assured rectal artesunate (RAS) as pre-referral treatment of severe malaria.

In the frame of the CARAMAL project, approximately 3,000 treatments of RAS will be dispensed by trained community health workers to children <5 years of age in each project country per year. Children treated with pre-referral RAS will be referred to a higher-level health facility for comprehensive clinical management, including the administration of a full course of an artemisinin-based combination therapy, as per WHO guidelines.

While phenotypic resistance of the Plasmodium parasites against artemisinin has not yet been document in the study settings, this potential threat is a major concern. The administration of artemisinin monotherapies increases drug pressure, which may lead to the selection of drug resistance conferring mutations. Mutations in portions of a P. falciparum gene encoding kelch (K13)-propeller domains are the currently known major determinant of partial resistance against artemisinin. Data on artemisinin resistance of Plasmodium parasites in the CARAMAL Project countries are patchy. K13-propeller polymorphisms previously reported from Cambodia have been found e.g. in parasites from northern Uganda, but the mutations linked to artemisinin resistance were uncommon and did not seem to increase over time. The general notion is that numerous K13 polymorphisms circulate in Africa but their distribution does not currently support the spread of artemisinin resistance.

Linked to the tracking of (severe) malaria patients in the frame of the CARAMAL project, this study will assess the frequency of artemisinin resistance markers in the study settings and tentatively assess whether the introduction of RAS could increase the selection of resistant P. falciparum strains. The study will be conducted in close collaboration with the Global Malaria Programme of the WHO. Finger-prick blood samples will be collected from children < 5 years of age with signs of severe febrile illness and a positive mRDT presenting to community-based providers and referral facilities before and after the pilot roll-out of pre-referral RAS at community level.

Dried blood spots on filter papers will be sent to a WHO-chosen laboratory (Malaria Molecular Epidemiology Unit at the Pasteur Institute in Cambodia) for molecular analyses to assess the presence of markers of artemisinin resistance (K13-propeller sequence polymorphisms).

Study Type

Observational

Enrollment (Actual)

916

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

    • Kwango
      • Kenge, Kwango, Congo, The Democratic Republic of the
        • Health Zone of Kenge
    • Kwilu
      • Ipamu, Kwilu, Congo, The Democratic Republic of the
        • Health Zone of Ipamu
      • Kingandu, Kwilu, Congo, The Democratic Republic of the
        • Health Zone of Kingandu
    • Adamawa
      • Yola, Adamawa, Nigeria
        • Adamawa State, selected LGAs
    • Apac
      • Lira, Apac, Uganda
        • Apac District
    • Kole
      • Lira, Kole, Uganda
        • Kole District
    • Oyam
      • Lira, Oyam, Uganda
        • Oyam District

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

No older than 5 years (CHILD)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

All children <5 years in the Health Districts / Health Zones included into the "Community Access to Rectal Artesunate for Malaria" (CARAMAL) Project in the Democratic Republic of the Congo (DRC), Nigeria and Uganda and matching the eligibility criteria will be included

Description

Inclusion Criteria:

  • age below 5 years
  • enrolled in CARAMAL Project
  • history of fever plus danger signs indicative of severe febrile illness / suspected severe malaria, according to local iCCM guidelines
  • positive malaria test result by RDT or microscopy
  • written informed consent from a parent or guardian

Exclusion Criteria:

  • no current malaria infection
  • mixed or mono-infection with a non-P. falciparum species known prior to sample collection
  • no permanent residence in project area

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

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Pre-RAS roll-out . Group I
I. Children presenting directly to a referral health facility without prior administration of RAS (pre-RAS): provides a baseline assessment of artemisinin resistance marker prevalence before the introduction of RAS
Finger-prick blood samples collected from children with signs of severe febrile illness and a positive mRDT presenting to community-based providers and referral facilities ; analysis for mutations in portions of a P. falciparum gene encoding kelch (K13)-propeller domain
Post-RAS roll-out - Group II
II. Children presenting directly to a referral health facility without prior administration of RAS (post-RAS): group not receiving pre-referral RAS and hence having baseline pressure for K13 resistance markers.
Finger-prick blood samples collected from children with signs of severe febrile illness and a positive mRDT presenting to community-based providers and referral facilities ; analysis for mutations in portions of a P. falciparum gene encoding kelch (K13)-propeller domain
Post-RAS roll-out - Group III
III. Children receiving pre-referral RAS from community-based provider and successfully referred to a referral health facility: group receiving pre-referral RAS (monotherapy).
Finger-prick blood samples collected from children with signs of severe febrile illness and a positive mRDT presenting to community-based providers and referral facilities ; analysis for mutations in portions of a P. falciparum gene encoding kelch (K13)-propeller domain
Post-RAS roll-out - Group IV
IV. Children receiving pre-referral RAS from community-based provider but not completing referral to a referral health facility, followed-up at their home on day 28: children malaria-positive on Day 28 may have an increased chance of harboring a resistant infection.
Finger-prick blood samples collected from children with signs of severe febrile illness and a positive mRDT presenting to community-based providers and referral facilities ; analysis for mutations in portions of a P. falciparum gene encoding kelch (K13)-propeller domain

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
K13-propeller sequence polymorphisms in P. falciparum
Time Frame: Through study completion, up to one year
Prevalence of molecular markers of artemisinin resistance in P. falciparum, namely K13-propeller sequence polymorphisms - before, after introduction of RAS in respective study area
Through study completion, up to one year

Collaborators and Investigators

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

Investigators

  • Principal Investigator: Christian Burri, Swiss TPH, Department of Medicine
  • Principal Investigator: Christian Lengeler, PhD, Swiss TPH, Department of Epidemiology and Public Health

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.

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 (ACTUAL)

July 27, 2018

Primary Completion (ACTUAL)

July 31, 2020

Study Completion (ACTUAL)

July 31, 2020

Study Registration Dates

First Submitted

July 25, 2019

First Submitted That Met QC Criteria

July 29, 2019

First Posted (ACTUAL)

July 30, 2019

Study Record Updates

Last Update Posted (ACTUAL)

January 29, 2021

Last Update Submitted That Met QC Criteria

January 28, 2021

Last Verified

July 1, 2019

More Information

Terms related to this study

Other Study ID Numbers

  • P 001-18-2.0

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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 Severe Malaria

3
Subscribe