Efficacy and Safety of Artemisinin-based Combination Treatments in the Democratic Republic of the Congo (TETRDC2016)

Efficacy and Safety of Artesunate-amodiaquine, Artemether-lumefantrine and Dihydroartemisinine-piperaquine in the Treatment of Uncomplicated Plasmodium Falciparum Malaria in the Democratic Republic of Congo: a Randomized Controlled Trial

The Democratic Republic of the Congo (DRC) is among the countries most affected by malaria in Sub-Saharan Africa. Condidering its size and the geographic position, the DRC is meant to play a major role in the malaria control in the region. The National Malaria Control program recommends artemisinin-based combination treatments (ACTs), in particular artesunate-amodiaquine or artemether-lumefrantrine for the treatment of uncomplicated malaria. Previous studies indicated that ACTs are still effective, with efficacy above the required threshold of 90%. It is required to assess regularly the efficacy of antimalarial drugs, in order to ascertain the relevance of treatment guidelines such that, in case of increasing failure rates, alternative options can be decided ontime.

The purpose of this trial is to assess efficacy and safety of artesunate-amodiaquine (ASAQ Winthrop®), artemether-lumefantrine (Coartem Dispersible®) and dihydro-artemisinin-piperaquine (Eurartesim®) at day 42 in the treatment of uncomplicated Plasmodium falciparum malaria in six surveillance sites around DRC.

Study Overview

• Status: Completed
• Conditions: Malaria
• Intervention / Treatment: Drug: artesunate-amodiaquine; Drug: artemether-lumefantrine; Drug: Dihydroartemisinine-piperaquine

Detailed Description

This is a phase 4, randomized, open labelled clinical trial, aiming to assess efficacy and safety of 3 ACTs in the treatment of uncomplicated malaria in the Democratic Republic of the Congo. Children diagnosed with uncomplicated Plasmodium falciparum uncomplicated malaria will be randomized and followed-up during 42 days.

• Study Type: Interventional
• Enrollment (Actual): 1615
• Phase: Phase 4

Contacts and Locations

Study Locations

• Congo, The Democratic Republic of the
  • Equateur
    • Bolenge, Equateur, Congo, The Democratic Republic of the
      • Centre de santé Bolenge
  • Haut-Katanga
    • Kapolowe, Haut-Katanga, Congo, The Democratic Republic of the
      • Centre de santé Lupidi 1
  • Kasai Central
    • Kazumba, Kasai Central, Congo, The Democratic Republic of the
      • Centre de Santé de Référence Mikalayi
  • Kongo Central
    • Kimpese, Kongo Central, Congo, The Democratic Republic of the
      • Centre Evangélique de Coopération
  • Nord-Kivu
    • Rutshuru, Nord-Kivu, Congo, The Democratic Republic of the
      • Centre de Santé de Référence Rutshuru
  • Tshopo
    • Kabondo, Tshopo, Congo, The Democratic Republic of the
      • Centre de Santé Foyer Social

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 4 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• children aged 6 to 59 months
• axillary temperature ≥ 37.5 °C or history of fever during the 24 h before recruitment
• monoinfection with Plasmodium falciparum with asexual parasite count of 2,000 to 200,000/µL
• ability to swallow oral medication
• ability and willingness to comply with the protocol for the duration of the study and to comply with the study visit schedule
• informed consent from a parent/guardian
• absence of general danger signs or signs of severe falciparum malaria according to the definitions of WHO (2000)
• absence of severe malnutrition according to WHO child growth standards
• absence of febrile condition due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration) or other known underlying chronic or severe diseases (e.g. cardiac, renal or hepatic diseases, HIV/AIDS)
• absence of regular medication, which might interfere with antimalarial pharmacokinetics
• absence of history of hypersensitivity reactions or contraindication to any medicine being tested or used as alternative treatment

Exclusion Criteria:

• presence of general danger signs in children aged under 5 years or signs of severe falciparum malaria according to the definitions of WHO
• body weight < 5kg
• hemoglobin level < 5g/ dL
• mixed or monoinfection with another Plasmodium species detected by microscopy
• presence of severe malnutrition
• presence of febrile conditions due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration) or other known underlying chronic or severe diseases (e.g. cardiac, renal and hepatic diseases, HIV/AIDS)
• regular medication, which may interfere with antimalarial pharmacokinetics;
• history of hypersensitivity reactions or contraindications to any of the medicine(s) being tested or used as alternative treatment(s)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: artesunate-amodiaquine; Tablets containing 25 mg of artesunate and 67.5 mg of amodiaquine: one tablet daily for three days children weighing 4.5 to 8 kg, and tablets containing 50 mg of artesunate and 135 mg of amodiaquine: one tablet daily for three days for children weighing 9 to 17 kg.	Drug: artesunate-amodiaquine; Tablets containing 25 mg of artesunate and 67.5 mg of amodiaquine: one tablet daily for three days children weighing 4.5 to 8 kg, and tablets containing 50 mg of artesunate and 135 mg of amodiaquine: one tablet daily for three days for children weighing 9 to 17 kg.; Other Names: artesunate-amodiaquine Winthrop®
Experimental: artemether-lumefantrine; Tablets containing 20 mg of Artemether and 120 mg of Lumefantrine. Each dose to be taken with high-fat food or drinks (for example milk). One tablet twice daily for children weighing 5 to <15 kg, two tablets twice daily for those weighing 15 to <25 kg and three tablets twice daily for those weighing 25 to < 35 kg, for three days.	Drug: artemether-lumefantrine; Tablets containing 20 mg of Artemether and 120 mg of Lumefantrine. Each dose to be taken with high-fat food or drinks (for example milk). One tablet twice daily for children weighing 5 to <15 kg, two tablets twice daily for those weighing 15 to <25 kg and three tablets twice daily for those weighing 25 to < 35 kg, for three days.; Other Names: Coartem®
Experimental: Dihydroartemisinine-piperaquine; Tablets containing 20 mg of dihydroartemisinine and 160 mg of piperaquine. Half a tablet once daily for children weighing 5 to <7 kg, one tablet once daily for those weighing 7 to <13 kg, and two tablets once daily for those weighing 13 to <24 kg, for three days.	Drug: Dihydroartemisinine-piperaquine; Tablets containing 20 mg of dihydroartemisinine and 160 mg of piperaquine. Half a tablet once daily for children weighing 5 to <7 kg, one tablet once daily for those weighing 7 to <13 kg, and two tablets once daily for those weighing 13 to <24 kg, for three days.; Other Names: Eurartesim®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PCR-adjusted efficacy	the proportion of children with PCR adequate clinical and parasitological response	day 42

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PCR-unadjusted efficacy	the proportion of children with treatment failure: all treatment failures detected during the follow-up, regardless of genotyping	day 42
K-13 propeller polymorphisms	the proportion of mutations in portions of P. falciparum gene encoding kelch(K-13)-propeller domains (confering resistance to artemisinin)	day 42
incidence of adverse events	monitoring of all adverse events experienced by participants	day 42

Collaborators and Investigators

• Sponsor: Ministry of Public Health, Democratic Republic of the Congo
• Investigators: Principal Investigator: Gauthier Mesia Kahunu, PhD, University of Kinshasa

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2017
• Primary Completion (Actual): January 2, 2018
• Study Completion (Actual): January 2, 2018

Study Registration Dates

• First Submitted: October 19, 2016
• First Submitted That Met QC Criteria: October 20, 2016
• First Posted (Estimate): October 21, 2016

Study Record Updates

• Last Update Posted (Actual): January 3, 2018
• Last Update Submitted That Met QC Criteria: January 2, 2018
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: Malaria, efficacy, safety, ACT, DR Congo
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Lumefantrine; Artemether; Artesunate; Artemether, Lumefantrine Drug Combination; Piperaquine; Amodiaquine; Artenimol
• Other Study ID Numbers: ASAQ-LA-DHAPQP 2015 DRC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No