Clinical trial NCT04565184: Effectiveness and Safety of Artesunate-Amodiaquine and Artemether-Lumefantrine for the Treatment of Malaria in Yaounde
Official title: Monitoring the Effectiveness and Safety of Artesunate-Amodiaquine and Artemether-Lumefantrine During the Treatment of Uncomplicated Plasmodium Falciparum Malaria Among Children in Yaounde, Cameroon
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Malaria,Falciparum
Keywords: Malaria
Plasmodium falciparum
Artesunate-amodiaquine
Artemether-lumefantrine
Effectiveness
Safety
Lead sponsor: University of Yaounde 1
Sponsor class: OTHER
Collaborators: name: Malaria Research Capacity Development in West and Central Africa Consortium
name: Developing Excellence in Leadership, Training and Science Africa Initiative
name: Wellcome Trust
name: United Kingdom Department for International Development
First posted: 2020-09-25
Enrollment: 242
Sex: ALL
Minimum age (years): 6
Maximum age (years): 120
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eligible children for whom parent/guardian informed consent are obtained will be randomized to receive either artesunate-amodiaquine (group A) or artemether-lumefantrine (group B) in the ratio 1:1.
Primary purpose: TREATMENT

Brief summary: 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.

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).

Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: 18 months
Secondary outcomes:
measure: 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
timeFrame: 18 months
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 18 months
measure: Number of children with single nucleotide polymorphisms of P. falciparum genes responsible for AS-AQ and AL resistance
timeFrame: 18 months
measure: Number of children haboring single nucleotide polymorphisms in key genes involved in the metabolism of AS-AQ and AL
timeFrame: 18 months
Other outcomes:
Locations:
city: Yaoundé
country: Cameroon
facility: District Medical Center Minkoa Meyos
state: Center
Study officials:
affiliation: Biotechnology Centre, University of Yaounde I
name: Wilfred Fon Mbacham, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Niba PTN, Nji AM, Ali IM, Akam LF, Dongmo CH, Chedjou JPK, Fomboh CT, Nana WD, Oben OLA, Selly-Ngaloumo AA, Moyeh MN, Ngu JA, Ludovic AJ, Aboh PM, Ambani MCE, Omgba PAM, Kotcholi GB, Adzemye LM, Nna DRA, Douanla A, Ango Z, Ewane MS, Ticha JT, Tatah FM, Dinza G, Ndikum VN, Fosah DA, Bigoga JD, Alifrangis M, Mbacham WF. Effectiveness and safety of artesunate-amodiaquine versus artemether-lumefantrine for home-based treatment of uncomplicated Plasmodium falciparum malaria among children 6-120 months in Yaounde, Cameroon: a randomized trial. BMC Infect Dis. 2022 Feb 21;22(1):166. doi: 10.1186/s12879-022-07101-2.