Pharmacokinetics, Safety, Tolerability and Efficacy of a New Artemether-lumefantrine Dispersible Tablet in Infants and Neonates <5 kg Body Weight With Acute Uncomplicated Plasmodium Falciparum Malaria

Study Overview
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Brief Summary
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This study aims to evaluate PK, safety, tolerability and efficacy of a new formulation of artemether-lumefantrine dispersible tablet in neonates and infants <5 kg body weight with acute uncomplicated Plasmodium falciparum malaria.

Official Title
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Multicenter, Open-label, Single-arm Study to Evaluate the PK, Safety, Tolerability and Efficacy of a New Artemether:Lumefantrine (2.5 mg:30 mg) Dispersible Tablet in the Treatment of Infants and Neonates <5 kg Body Weight With Acute Uncomplicated Plasmodium Falciparum Malaria

Conditions
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Plasmodium Falciparum Malaria

Intervention / Treatment
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* Drug: artemether:lumefantrine (2.5 mg:30 mg)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female neonates/infants Body weight <5 kg but ≥ 2 kg In Cohort 1, infants aged >28 days; in Cohort 2, neonates aged 1 to ≤28 days (3 subgroups: 1-7 days; 8-14 days; 15-28 days) Microscopically confirmed diagnosis of P. falciparum malaria (or mixed infections): in Cohort 1 of ≥500 and <100,000 parasites/µL asexual P. falciparum parasitemia in Cohort 2 of ≥100 and <100,000 parasites/µL asexual P. falciparum parasitemia in Cohort 2, either congenital or neonatal either symptomatic or asymptomatic Exclusion Criteria: Head circumference < - 2 SD z-score in cm following WHO age and sex-specific reference curves (suspicion of microcephaly) Presence of severe malaria (according to WHO 2015 definition) HIV status : in Cohort 1, patient's or patient's mother's current treatment with ARV in Cohort 2, mother's known HIV positive status at patient's birth or mother's current treatment with ARV Presence of the following signs of a critical condition: apnea-bradycardia, sustained bradycardia, tachycardia, desaturation, hypotension, hypothermia; or other severely deteriorated general condition (based on IMCI criteria in sick infants) (WHO 2005) Presence of any clinically significant neurological condition: any episode of convulsion during the present illness (in keeping with the IMCI list of general danger signs) known neurological disorders (e.g. chronic seizure disorders, cerebral palsy) Presence of clinically significant abnormality of the hepatic and renal systems Patients unable to swallow or whose drinking is impaired Known hypersensitivity of the patient or either patient's parent to artemether, lumefantrine, any of the excipients of Coartem®/Riamet® Dispersible tablet, or to drugs of similar chemical classes History of malabsorption or previous gastrointestinal surgery, or history of radiation therapy that could affect drug absorption or metabolism, or any other disorder or history of a condition that could interfere with drug absorption, distribution, metabolism, or excretion Known family history of congenital prolongation of the QTc interval or sudden death or with any other clinical condition known to be associated with prolongation of the QTc interval such as history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease Disturbances of electrolyte balance (e.g. hypokalaemia or hypomagnesaemia) Presence of any age-adjusted clinically or hematologically relevant laboratory and blood chemistry abnormalities Patients who received any antimalarial drug, including antibiotics with antimalarial activity, within 14 days of trial start, or any other prohibited drug (see Table 6-2) Patients who received an investigational drug within 5 half-lives of enrollment or participated in an investigational study or within 30 days, whichever is longer

Ages Eligible for Study
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Maximum Age: 365 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: artemether lumefantrine (2.5 mg:30 mg)<br>artemether lumefantrine (2.5 mg:30 mg) bid over 3 days, from 1-4 tablets per dose | Drug: artemether:lumefantrine (2.5 mg:30 mg)<br>* artemether:lumefantrine (2.5 mg:30 mg)<br>* Other names: bid over 3 days, from 1-4 tablets per dose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Artemether Cmax | ART Cmax (represents the higher concentration between the concentrations at 1 hour and 2 hours after first dose) | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lumefantrine Day 8 concentration (C168h) |  | 168h post first dose | 
| Artemether AUC |  | Up to Day 15 post first dose | 
| DHA AUC |  | Up to Day 15 post first dose | 
| Lumefantrine Cmax |  | Up to Day 8 post first dose | 
| Lumefantrine AUC | derived as appropriate | Up to Day 15 post first dose | 
| Parasite Clearance Time (PCT) | Parasite count will be performed by microscopy | Up to Day 8 | 
| Fever clearance Times (FCT) | Body temperature will be recorded | Up to Day 8 | 
| PCR-corrected Adequate Clinical and Parasitological Response (ACPR) | PCR-corrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 | Day 15 | 
| PCR-corrected Adequate Clinical and Parasitological Response (ACPR) | PCR-corrected Adequate Clinical and Parasitological Response (ACPR) at Day 43 | Day 43 | 
| PCR-corrected Adequate Clinical and Parasitological Response (ACPR) | PCR-corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | Day 29 | 
| Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 8 | Day 8 | 
| Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 | Day 15 | 
| Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | Day 29 | 
| Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 43 | Day 43 | 
| Incidence rate of recrudescence and new infections | Incidence rate of recrudescence and new infections at Days 15, 29 and 43 | Up to Day 43 | 
| Incidence rate of serious adverse events | safety by collecting serious adverse events (SAEs) | during the study period from Baseline up to age 365 days | 
| Incidence rate of adverse events | safety and tolerability by collecting adverse events (AEs) | during the study period from Baseline up to day 43 | 
| Incidence rate of abnormal laboratory values | Safety and tolerability by collecting routine safety laboratory assessments | during the study period from Baseline up to day 43 | 
| Change in head circumference | Head circumference will be measured | at Baseline and at age 365 days | 
| Neurodevelopmental assessment | Neurodevelopmental assessment (Shoklo Malaria Research Unit assessment) score will be derived | At Day 4 and at age 365 days |