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

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

The purpose of this study was 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.

This was a multicenter, open-label, single-arm, adaptive design with dose adaptation (deescalation or escalation) study in infants and neonates <5 kg body weight with P. falciparum malaria. There were two sequential and age-descending cohorts of participants, all <5 kg: Cohort 1 of infants >28 days of age, and Cohort 2 of neonates ≤ 28 days of age.

Inclusion Criteria:

1. Male or female neonates/infants

2. Body weight <5 kg but ≥ 2 kg

3. 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)

4. 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
   • either congenital or neonatal
   • either symptomatic or asymptomatic

Exclusion Criteria:

1. Head circumference < - 2 SD z-score in cm following WHO age and sex-specific reference curves (suspicion of microcephaly)

2. Presence of severe malaria (according to WHO 2015 definition)

3. 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

4. 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)

5. 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)

6. Presence of clinically significant abnormality of the hepatic and renal systems

7. Patients unable to swallow or whose drinking is impaired

8. 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

9. 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

10. 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

11. Disturbances of electrolyte balance (e.g. hypokalaemia or hypomagnesaemia)

12. Presence of any age-adjusted clinically or hematologically relevant laboratory and blood chemistry abnormalities

13. 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)

14. 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