Efficacy and Safety of Artesunate-amodiaquine and Artemether-lumefantrine for the Treatment of Malaria in Cameroon

Efficacy and Safety of Artesunate-amodiaquine (ASAQ) and Artemether-lumefantrine (AL) for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in the Center Region of Cameroon

Malaria remains a major public health concern in Cameroon especially among vulnerable groups such as children less than five years and pregnant women. Artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have been used for the treatment of uncomplicated Plasmodium falciparum in Cameroon since 2004. Worldwide, several studies among children have reported high efficacy and safety of artemisinin-based combination therapies (ACTs). There is paucity of data to support the continuous use of ASAQ and AL in Cameroon. The main objective of this study is to assess 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 the Center Region of Cameroon. A randomized, open-labelled, controlled clinical trial comparing artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) will be carried out from 5th April to 31st December, 2021 at six hospitals in the Center Region of Cameroon. 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. However, since 6 sites will be involved, a minimum of 30 participants shall be enrolled per site. Drug intake will be done under strict supervision on days 0, 1 and 2. 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: Not yet recruiting
• Conditions: Falciparum Malaria
• Intervention / Treatment: Drug: Artesunate-amodiaquine drug combination; Drug: Artemether-lumefantrine drug combination

Detailed Description

Brief title: Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine for the treatment of malaria in Cameroon.

Official title: Monitoring the efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria among children in the Center Region of Cameroon.

Purpose: To monitor the efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria among children in the Center Region of Cameroon.

Background: Malaria remains a major public health concern in Cameroon especially among vulnerable groups such as children less than 5 years and pregnant women. artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are currently being used for the treatment of uncomplicated Plasmodium falciparum in Cameroon. Worldwide, several studies among children have reported high efficacy and safety of artemisinin-based combination therapies (ACTs). There is paucity of data to support the continuous use of ASAQ and AL in Cameroon.

Objective: To assess the efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine during a 28-day follow-up period among children with acute uncomplicated P. falciparum malaria in Center Region of Cameroon.

Study sites: District Hospital Akonolinga, District Hospital Mfou, District Hospital Soa, District Hospital Mbalmayo, District Hospital Mbandjock, and District Hospital Ngog-Mapubi in the Center Region of Cameroon.

Study period: 5th April to 31st December, 2021. 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. At least 30 participants shall be enrolled at each of the six study sites.

Treatment (s) and follow-up: Drug intake will be done under strict supervision on days 0, 1 and 2. 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 (Anticipated): 184
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Wilfred Fon Mbacham, PhD; Phone Number: (+237) 677579180; Email: wfmbacham@yahoo.com
• Study Contact Backup: Name: PeterThelma Ngwa Niba, MSc; Phone Number: (+237) 653254729; Email: thelma2009@yahoo.co.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 10 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Children of either gender, aged 6 months to 10 years will be recruited.
• 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 or mono-infection 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:

  1. Not able to drink or breastfeed.
  2. Persistent vomiting (>2 episodes within the previous 24 hours).
  3. Convulsions (>1 episode within the previous 24 hours).
  4. Lethargic/unconscious.
  5. Severe anemia (hemoglobin < 5 g/dl).
• Serious gastrointestinal disease.
• Presence of severe malnutrition defined as a child aged between 6-60 months whose weight-for-height is below -3 z-score (W/H < 70%) or has symmetrical oedema 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 within the last one month.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Artesunate-amodiaquine (Arm A); Artesunate-amodiaquine 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 drug combination; Artesunate-amodiaquine 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 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 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 ASAQ and AL during 28 days follow-up period in children with uncomplicated P. falciparum malaria	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.	10 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	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.	10 months
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	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.	10 months
Number of children with single nucleotide polymorphisms of P. falciparum genes responsible for resistance to ASAQ and AL	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.	10 months
Number of children with single nucleotide polymorphisms of P. falciparum histidine-rich protein 2 and 3 genes	Pre-treatment shall be used to detect single nucleotide polymorphisms present in Plasmodium falciparum histidine-rich protein 2 and 3 genes.	10 months

Collaborators and Investigators

• Sponsor: University of Yaounde 1
• Collaborators: Biotechnology Center (BTC), University of Yaounde I, Cameroon; National Malaria Control Program (NMCP), Cameroon; Association Camerounaise pour le Marketing Social (ACMS), Cameroon; Impact Malaria, Cameroon
• Investigators: Principal Investigator: Wilfred Fon Mbacham, PhD, University of Yaounde I

Study record dates

Study Major Dates

• Study Start (Anticipated): April 5, 2021
• Primary Completion (Anticipated): December 31, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: March 31, 2021
• First Submitted That Met QC Criteria: March 31, 2021
• First Posted (Actual): April 2, 2021

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: Malaria; Plasmodium falciparum; Artemether-lumefantrine; Artesunate-amodiaquine
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Lumefantrine; Artemether; Artesunate; Artemether, Lumefantrine Drug Combination; Amodiaquine
• Other Study ID Numbers: AAAL001/PMI/CMR

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: 31st December 2021 for at least 10 years
• IPD Sharing Access Criteria: Not available for now
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; 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