Severe Malaria in Remote Areas- Closing the Evidence Gap (SEMA ReACT)

Severe Malaria Treatment With Rectal Artesunate and Artemisinin-based Combination Therapy in Remote Settings

The goal of this observational study is to assess whether the giving of rectal artesunate and a three day course of an Artemisinin based Combination Therapy (ACT) to children aged 6 months and ≤ 5 years with severe malaria when referral is not feasible is non inferior to giving of injectable artesunate and three day course of an ACT. The three primary objectives are:

• To evaluate the 28-day PCR corrected cure rate in children aged 6 months to ≤ 5 years treated with RAS+ACT or RAS+injectable artesunate, assessing whether each treatment achieves the clinically acceptable cure rate of 97% ± 5%.
• To evaluate feasibility of provision of rapid treatment of severe malaria with rectal artesunate in children 6 months to ≤ 5 years not able to access a referral health facility, by a community health worker or in health facility where there is no injectable artesunate available.
• To evaluate the impact of reinforcing the integrated Community Case Management (iCCM) on access to the formal health care system

The study is being done in Nchelenge district in Zambia and Kapolowe district in the Democratic Republic of Congo. It will enrol 1008 children with severe malaria and an equal number of children with simple malaria

Study Overview

• Status: Enrolling by invitation
• Conditions: Severe Malaria
• Intervention / Treatment: Drug: Treatment of severe malaria with either RAS + ACT or RAS + injectable artesunate + ACT will each achieve the clinically acceptable cure rate of 97% ± 5% in remote areas

• Study Type: Observational
• Enrollment (Estimated): 2016

Contacts and Locations

Study Locations

• Democratic Republic of the Congo
  • Kinshasa City
    • Kinshasa, Kinshasa City, Democratic Republic of the Congo
      • University of Kinshasa
• Zambia
  • Copperbelt
    • Ndola, Copperbelt, Zambia, 10101
      • Tropical Diseases Research Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population will comprise children 6 months to ≤5 years of age living in Kapolowe, DRC and those living in Nchelenge, Zambia who present with a suspected diagnosis of severe malaria or uncomplicated malaria, confirmed by a rapid diagnostic test; or non-malaria severe disease

Description

Inclusion Criteria:

Inclusion criteria for severe malaria

• From a village without other research interventions

• Children aged from 6 months to ≤5 years that present at the health system and are either; with fever (or history of fever within 2 days) and have a positive mRDT test plus at least one of the following danger signs for malaria (as per standardized national iCCM guidelines):

  • convulsions
  • inability to drink, eat, or suck
  • vomiting all liquids and solids
  • altered consciousness/coma
  • lethargy
  • chest in-drawing Inclusion for uncomplicated malaria
• Children aged from 6 months to ≤5 years; with fever (or history of fever within 2 days) with no danger signs for malaria (as per the standardized national Integrated Management of Childhood Illnesses guidelines) with a positive mRDT for Plasmodium falciparum histidine-rich protein.

Inclusion for severe non-malaria

• From a village without other research interventions

• Children aged from 6 months to ≤5 years that present at the health system and are either; with fever (or history of fever within 2 days) and have a negative mRDT test plus at least one of the following danger signs as per standardized national iCCM guidelines:

  • convulsions
  • inability to drink, eat, or suck
  • vomiting all liquids and solids
  • altered consciousness/coma
  • lethargy
  • chest in-drawing
• For participants in sentinel sites, a written informed consent will be provided by the patient's parent or guardian to take filter paper blood samples and to participate in interviews (questionnaires and IDI) at enrolment, day 14 and day 28 (to assess malaria recurrence and look for markers of resistance). If the parent or guardian is unable to write, thumb print witnessed consent is permitted. The informed consent shall be administered by the CHWs. Willingness and ability of the patient and the parent or guardian to comply with the treatment policy.

Exclusion Criteria:

• Use of any investigational or non-registered product or planned use during the study period.
• Participation in other studies within 30 days before the current study begins and/or during study participation.
• Inability to comprehend and/or unwillingness to follow the study protocol.
• For RAS use: if the child has reacted badly to artesunate in the past (in sites where RAS is administered)

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Two groups i.e rectal artesunate +ACT group while the other is injectable artesunate +ACT group; The group of interest is children aged between 6 months and less than or equal to 5 years with severe malaria. However, we will also enrol children of the same age group with simple malaria and non malaria severe disease to compare their journeys as well

Drug: Treatment of severe malaria with either RAS + ACT or RAS + injectable artesunate + ACT will each achieve the clinically acceptable cure rate of 97% ± 5% in remote areas; The Community Health Worker will give rectal artesunate (RAS) +artemisinin based combination Therapy (ACT) to children aged 6 months to less than or equal to 5 years who fail to make the referral trip. Those who make the referral trip will receive injectable artesunate and artemisinin based Combination Therapy for three days. Giving of RAS +ACT is unique to this study. Children with non malaria severe disease will also receive amoxicillin from the community health worker before they are referred to the next level of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The time from onset of symptoms to initiating treatment	The time from onset of symptoms to initiating treatment among children 6 months to ≤5 years with severe malaria and/or not able to take oral treatment that seek health care from the CHW or other HF system as primary first contact	The time from onset of symptoms to initiating treatment
PCR-corrected cure rate at 28 days from enrollment in patients aged 6 months to ≤5 years.	PCR-corrected cure rate at 28 Days from enrollment in patients aged 6 months to ≤5 years in areas where referral for follow-up treatment with injectable artesunate is not feasible, compared to outcomes obtained after full referral is completed	28 Days from enrollment
Change from baseline proportion of sick children 6 months - ≤5 years at population level that went to the formal health system during the last 6 months including suspected (severe) malaria at month 20 (phase 4).	Two cross section surveys one at month 1 (baseline) and the other at month 20 (phase 4) will be used to obtain the proportion of sick children 6 months to ≤5 years at population level that were either attended by a Community Health Worker, Health post or Health Centre in the last 6 months	At month 20 (phase 4)

Collaborators and Investigators

• Sponsor: Tropical Diseases Research Centre, Zambia
• Collaborators: Universiteit Antwerpen; Medicines for Malaria Venture; National Institute for Medical Research, Tanzania; University of Kinshasa; Université de Lubumbashi

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: November 29, 2024
• First Submitted That Met QC Criteria: January 30, 2025
• First Posted (Actual): February 4, 2025

Study Record Updates

• Last Update Posted (Actual): January 27, 2026
• Last Update Submitted That Met QC Criteria: January 24, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Community Health Worker; Artemisinin-based Combination Therapy; Rectal artesunate; Health Facility; Injectable artesunate
• Additional Relevant MeSH Terms: Vector Borne Diseases; Mosquito-Borne Diseases; Infections; Protozoan Infections; Parasitic Diseases; Malaria; Anti-Infective Agents; Antineoplastic Agents; Antiviral Agents; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Artesunate; Artemisinins; Artemisinin
• Other Study ID Numbers: Version 2.0 Dated 5 March 2024; 101103191 (Other Grant/Funding Number: HORIZON-JU-GH-EDCTP3-2022-CALL1-01-01)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We will only share aggregated data as IPD will not be useful to the research community

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No