Severe MalariaCaramal DRMNCT04037332
Monitoring of Molecular Markers of Artemisinin Resistance Through Repeated Cross-sectional Assessments in DR Congo, Nigeria and Uganda
An observational study of Severe Malaria, run by Swiss Tropical & Public Health Institute at 7 sites in 3 countries.
Trial summary
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… Read more about this study
- Who is it for?
- Ages Up to 5 years
- Conditions the study is for
- Severe Malaria
- What is being tested?
- Blood sample (combined with malaria RDT) followed by gentoyping analysis
- Type of treatment
- Injection or infusion
- How many people
- 916 participants
- Where
- 7 sitesin 3 countries
- Study dates
- 27 Jul 2018to 31 Jul 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 5 years
- All sexes
- Child
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
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
7 sites in 3 countries.
7 sites in 3 countries
Democratic Republic of the Congo3 sites
Health Zone of Ipamu
Ipamu, Kwilu
Health Zone of Kenge
Kenge, Kwango
Health Zone of Kingandu
Kingandu, Kwilu
Uganda3 sites
Apac District
Lira, Apac
Kole District
Lira, Kole
Oyam District
Lira, Oyam
About this study
Official title: 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.
Read the 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).
- Conditions
- Severe Malaria
- Being tested
- Blood sample (combined with malaria RDT) followed by gentoyping analysis
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Blood sample (combined with malaria RDT) followed by gentoyping analysisOther
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
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Other: Blood sample (combined with malaria RDT) followed by gentoyping analysis | |
| 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. Receives: Other: Blood sample (combined with malaria RDT) followed by gentoyping analysis | |
| 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). Receives: Other: Blood sample (combined with malaria RDT) followed by gentoyping analysis | |
| 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. Receives: Other: Blood sample (combined with malaria RDT) followed by gentoyping analysis |
What is being measured
The primary outcome is the main question the study is designed to answer.
K13-propeller sequence polymorphisms in P. falciparum
Prevalence of molecular markers of artemisinin resistance in P. falciparum, namely K13-propeller sequence polymorphisms - before, after introduction of RAS in respective study area
Measured: Through study completion, up to one year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jul 2019
- Study start27 Jul 2018
- Primary completion31 Jul 2020
- Study completion31 Jul 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Severe MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Enrolment
- 916 participants (actual)
Sponsor and investigators
- Lead sponsor
- Swiss Tropical & Public Health Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Clinton Health Access Initiative, Nigeria, Akena Associates Ltd., Kinshasa School of Public Health, Makerere University
- Responsible party
- Sponsor
- Investigators
- Christian Burri, Principal investigator, Swiss TPH, Department of MedicineChristian Lengeler, PhD, Principal investigator, Swiss TPH, Department of Epidemiology and Public Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04037332
- Sponsor's protocol ID
- P 001-18-2.0
- Acronym
- Caramal DRM
- Status last verified
- Jul 2019
- First submitted
- 25 Jul 2019
- Last updated
- 29 Jan 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Monitoring of Molecular Markers of Artemisinin Resistance in Plasmodium Falciparum Malaria: Repeated Cross-sectional Assessments in DR Congo, Nigeria and Uganda
- ClinicalTrials.gov ID
- NCT04037332
- Acronym / sponsor ID
- Caramal DRM / P 001-18-2.0
- Conditions
- Severe Malaria
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 916 participants (actual)
- Lead sponsor
- Swiss Tropical & Public Health InstituteUniversity, hospital or other
- Collaborators
- Clinton Health Access Initiative, Nigeria, Akena Associates Ltd., Kinshasa School of Public Health, Makerere University
- Study start
- 27 Jul 2018 (actual)
- Primary completion
- 31 Jul 2020 (actual)
- Study completion
- 31 Jul 2020 (actual)
- First posted
- 30 Jul 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Pre-RAS roll-out . Group I | – | Other: Blood sample (combined with malaria RDT) followed by gentoyping analysisI. 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 |
| Post-RAS roll-out - Group II | – | Other: Blood sample (combined with malaria RDT) followed by gentoyping analysisII. 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. |
| Post-RAS roll-out - Group III | – | Other: Blood sample (combined with malaria RDT) followed by gentoyping analysisIII. Children receiving pre-referral RAS from community-based provider and successfully referred to a referral health facility: group receiving pre-referral RAS (monotherapy). |
| Post-RAS roll-out - Group IV | – | Other: Blood sample (combined with malaria RDT) followed by gentoyping analysisIV. 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. |
Who may qualify
- Ages
- Up to 5 years
- Sex
- All
- Age groups
- Child
- 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
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (3 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Blood sample (combined with malaria RDT) followed by gentoyping analysisFinger-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 | Other | Post-RAS roll-out - Group II, Post-RAS roll-out - Group III, Post-RAS roll-out - Group IV, Pre-RAS roll-out . Group I |
Primary outcome
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jan 2021.
- Registration info on major study into which drug resistance monitoring is nestedLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Christian Burri principal investigator
Swiss TPH, Department of Medicine
Christian Lengeler, PhD principal investigator
Swiss TPH, Department of Epidemiology and Public Health
7 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Severe Malaria, run by Swiss Tropical & Public Health Institute at 7 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in Democratic Republic of the Congo, Uganda, Nigeria. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
K13-propeller sequence polymorphisms in P. falciparum (time frame: Through study completion, up to one year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jan 2021.