Effectiveness and Safety of Artesunate-Amodiaquine and Artemether-Lumefantrine for the Treatment of Malaria in Yaounde

March 31, 2021 updated by: Professor Wilfred Fon Mbacham, University of Yaounde 1

Monitoring the Effectiveness and Safety of Artesunate-Amodiaquine and Artemether-Lumefantrine During the Treatment of Uncomplicated Plasmodium Falciparum Malaria Among Children in Yaounde, Cameroon

Artesunate-amodiaquine and artemether-lumfantrine are currently being used for the treatment of uncomplicated Plasmodium falciparum in Cameroon. Globally, many studies have reported high efficacy and safety of artemisinin-based combination therapies (ACTs) mostly under strict supervision of drug intake and limited to children less than 5 years of age. Patients over 5 years of age are usually not involved in such studies. The main objective of this study is to assess the genetic markers of antimalarial drug resistance and drug metabolism subsequent to the efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine during a 28-day follow-up period in children with acute uncomplicated P. falciparum malaria in Yaounde, Cameroon. A randomized, open-labelled, controlled clinical trial comparing artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) will be carried out from 9th May 2019 to 30th November 2020 at two secondary health centres (Cité Verte and Minkoameyos) in Yaounde. The study participants shall include febrile patients aged 6 months to 10 years, with confirmed uncomplicated P. falciparum infection. Eligible children for whom parent/guardian informed consents are obtained will be randomized to receive either artesunate-amodiaquine (group A) or artemether-lumefantrine (group B) in the ratio 1:1. A minimum sample of 76 patients will be required for the study. With a 20 % increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, 92 patients will be enrolled for each of the two study arms. The study will recruit a total of 184 patients. Drug intake will be partially supervised only for the first dose and subsequent doses administered unsupervised as pertains in routine practice in the field. Patients or their parents/guardians will be advised on the time and mode of administration for the 3 days (D0, D1 and D2) treatment unobserved at home. Follow-up visits will be performed on days 3, 7, 14, 21, and 28 to evaluate clinical and parasitological resolution of their malaria episode as well as adverse events. Polymerase chain reaction (PCR) genotyping of merozoite surface proteins 1 and 2 (msp-1, msp-2) as well as glutamate rich protein (GLURP) will be used to differentiate between recrudescence and new infection.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Background: Artesunate-amodiaquine and artemether-lumfantrine are currently being used for the treatment of uncomplicated Plasmodium falciparum in Cameroon. Globally, many studies have reported high efficacy and safety of artemisinin-based combination therapies (ACTs) mostly under strict supervision of drug intake and limited to children less than 5 years of age. Patients over 5 years of age are usually not involved in such studies.

Objective: To assess the genetic markers of antimalarial drug resistance and drug metabolism subsequent to the efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine during a 28-day follow-up period in children with acute uncomplicated P. falciparum malaria in Yaounde, Cameroon.

Study sites: District Hospital Cité Verte and District Medical Centre Minkoa Meyos in Yaounde, Cameroon. The two drugs, artesunate-amodiaquine and artemether-lumefantrine will be tested in each site.

Study period: 9th May 2019 to 30th November 2020.

Study design: This surveillance study is a two-arm, open-label, randomized controlled clinical trial.

Patient population: Febrile patients aged 6 months to 10 years, with confirmed uncomplicated P. falciparum infection. Eligible children for whom parent/guardian informed consents are obtained will be randomized to receive either artesunate-amodiaquine (group A) or artemether-lumefantrine (group B) in the ratio 1:1.

Sample size: A minimum sample of 76 patients will be required for the study. With a 20 % increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, 92 patients will be enrolled for each of the two study arms. The study will recruit a total of 184 patients.

Treatment (s) and follow-up: Drug intake will be partially supervised only for the first dose and subsequent doses administered unsupervised as pertains in routine practice in the field. Patients or their parents/guardians will be advised on the time and mode of administration for the 3 days (D0, D1 and D2) treatment unobserved at home. Follow-up visits will be performed on days 3, 7, 14, 21, and 28 to evaluate clinical and parasitological resolution of their malaria episode as well as adverse events. Polymerase chain reaction (PCR) genotyping of merozoite surface proteins 1 and 2 (msp-1, msp-2) as well as glutamate rich protein (GLURP) will be used to differentiate between recrudescence and new infection.

Classification of treatment outcomes Classification of treatment outcomes will be done based on the WHO 2009 guidelines: treatment failure (Early Treatment Failure-ETF, Late Clinical failure-LCF and Late Parasitological Failure-LPF) and treatment success (Adequate Clinical and Parasitological Response-ACPR).

Study Type

Interventional

Enrollment (Actual)

242

Phase

  • Phase 4

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

  • Cameroon
    • Center
      • Yaoundé, Center, Cameroon, +237
        • District Medical Center Minkoa Meyos

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

10 months to 8 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Children of either gender, aged 6 months to 120 months will be recruited.
  • Acute uncomplicated P. falciparum malaria confirmed by microscopy using Giemsa-stained thick film with an asexual parasite density within the range 1000 to 200000 parasites/μl.
  • Presenting with fever (axillary temperature ≥ 37.5oC) or having a history of fever in the preceding 24 hours.
  • Able to ingest tablets orally (either suspended in water or uncrushed with food).
  • Willing to participate in the study with written informed consent from parent/guardian.
  • Willing and able to attend the clinic on stipulated regular follow-up visits.

Exclusion Criteria:

  • Mixed with another Plasmodium species detected by microscopy.
  • Children who are currently suffering or had the following within the last 2 months: tuberculosis, HIV, schistosomiasis, diabetes mellitus, cardiovascular disease, gout, rheumatoid arthritis, underlying chronic hepatic or renal disease, hypoglycaemia, jaundice, respiratory distress, and other inflammatory related diseases.
  • Signs/symptoms indicating severe/complicated malaria" according to WHO criteria (WHO definition) such as:

Not able to drink or breast feed. Persistent vomiting (>2 episodes within previous 24 hours). Convulsions (>1 episode within previous 24 hours). Lethargic/unconscious. Severe anaemia (haemoglobin < 5 g/dl).

  • Serious gastrointestinal disease.
  • Presence of severe malnutrition defined as a child aged between 6-60 months whose weight-for-high is below -3 z-score (W/H < 70%) or has symmetrical edema involving at least the feet or has a mid-upper arm circumference < 115 mm).
  • Regular medication, which may interfere with anti-malarial pharmacokinetics.
  • History of hypersensitivity reactions or contraindications to any of the medicine (s) being tested or used as alternative treatment (s).
  • Individuals who have taken part in anti-malarial efficacy and safety studies in the last 3 months.
  • Participants who have taken anti-malarial drugs in the last one month.

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: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Artesunate-amodiaquine (Arm A)
Artesunate-amodiaquine (Coarsucam®: Sanofi-Aventis, France) is co-packaged as artesunate 50 mg and amodiaquine hydrochloride USP equivalent to amodiaquine base of 153.1 mg. Each child shall be given one, two or three tablets depending on the weight.
Drug: Artesunate-amodiaquine combination
Artesunate-amodiaquine (Coarsucam®: Sanofi-Aventis, France) is co-packaged as artesunate 50 mg and amodiaquine hydrochloride USP equivalent to amodiaquine base of 153.1 mg. Each child shall be given one, two or three tablets depending on the weight.
Other Names:
  • Coarsucam
Active Comparator: Artemether-lumefantrine (Arm B)
Artemether-lumefantrine (Coartem®: Novartis, Switzerland) is formulated as tablets and will be provided in blister packs. Each tablet contains 20 mg artemether and 120 mg lumefantrine. Every pack has a picture showing how the drug should be given and contains two blisters for each day with one, two or three tablets depending on the weight of the child.
Drug: Artemether, Lumefantrine Drug Combination
Artemether-lumefantrine (Coartem®: Novartis, Switzerland) is formulated as tablets and will be provided in blister packs. Each tablet contains 20 mg artemether and 120 mg lumefantrine. Every pack has a picture showing how the drug should be given and contains two blisters for each day with one, two or three tablets depending on the weight of the child
Other Names:
  • Coartem®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants with treatment success and adverse events following treatment with artesunate-modiaquine and artemether-lumefantrine during 28 days follow-up period in children with acute uncomplicated P. falciparum malaria in Yaounde
Time Frame: 18 months
Eligible children for whom parent/guardian informed consents are obtained will be randomized to receive either artesunate-amodiaquine (group A) or artemether-lumefantrine (group B) and follow-up will be done for a duration of 28 days.
18 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of patients with early treatment failure, late clinical failure, late parasitological failure or an adequate clinical and parasitological response as indicators of efficacy according to the WHO 2009 guidelines
Time Frame: 18 months
Eligible children for whom parent/guardian informed consents are obtained will be randomized to receive either artesunate-amodiaquine (group A) or artemether-lumefantrine (group B) and follow-up will be done for a duration of 28 days. Recrudescence will be distinguished from re-infection by polymerase chain reaction (PCR) analysis
18 months
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame: 18 months
Eligible children for whom parent/guardian informed consents are obtained will be randomized to receive either artesunate-amodiaquine (group A) or artemether-lumefantrine (group B) and follow-up will be done for a duration of 28 days.
18 months
Number of children with single nucleotide polymorphisms of P. falciparum genes responsible for AS-AQ and AL resistance
Time Frame: 18 months
Pre-treatment and recrudescence/reinfection samples during follow-up shall be used to characterize the molecular markers of Plasmodium falciparum chloroquine resistant transporter(Pfcrt), Plasmodium falciparum multi-drug resistant 1 (Pfmdr1), and Plasmodium falciparum K13 (Pfk13) propellar domain conferring resistance to artemisinins or partner drugs.
18 months
Number of children haboring single nucleotide polymorphisms in key genes involved in the metabolism of AS-AQ and AL
Time Frame: 18 months
Pre-treatment samples shall be used to characterize the human pharmacogenomic biomarkers (N-acetyl transferase 2-NAT2 and cytochrome P450: CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and CYP3A5)
18 months

Collaborators and Investigators

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

Sponsor

University of Yaounde 1

Collaborators

Malaria Research Capacity Development in West and Central Africa Consortium
Developing Excellence in Leadership, Training and Science Africa Initiative
Wellcome Trust United Kingdom
United Kingdom Department for International Development

Investigators

  • Principal Investigator: Wilfred Fon Mbacham, PhD, Biotechnology Centre, University of Yaounde I

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 (Actual)

May 9, 2019

Primary Completion (Actual)

November 30, 2020

Study Completion (Actual)

November 30, 2020

Study Registration Dates

First Submitted

September 17, 2020

First Submitted That Met QC Criteria

September 23, 2020

First Posted (Actual)

September 25, 2020

Study Record Updates

Last Update Posted (Actual)

April 2, 2021

Last Update Submitted That Met QC Criteria

March 31, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MARCAD/UYI/NPTN/12/16

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Research findings will be communicated with the scientific community and policymakers. This will be done through public engagements and publications in peer-review journals.

IPD Sharing Time Frame

30th November 2020 for at least 10 years

IPD Sharing Access Criteria

Not available for now

IPD Sharing Supporting Information Type

  • Study Protocol
  • Clinical Study Report (CSR)

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

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.

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