Clinical trial NCT04300309: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Plasmodium Falciparum Malaria
Keywords: Plasmodium falciparum
malaria
artemether
lumefantrine
neonates
infants
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: European and Developing Countries Clinical Trials Partnership (EDCTP)
name: Medicines for Malaria Venture
name: Groupe de Recherche Action en Sante
name: Institut de Recherche en Sciences de la Sante, Burkina Faso
First posted: 2020-03-09
Enrollment: 28
Sex: ALL
Maximum age (years): 365
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Artemether Cmax After First Dose
timeFrame: 1 and 2 hours after first dose (Day 1)
Secondary outcomes:
measure: Lumefantrine Day 8 Concentration (C168h)
timeFrame: 168 hours after first dose (corresponding to 108 hours after last dose)
measure: Lumefantrine Cmax After Last Dose
timeFrame: 62, 66, 68 and 84 hours after first dose (corresponding to 2, 6, 8 and 24 hours after last dose)
measure: DHA Cmax After First Dose
timeFrame: 1 and 2 hours after first dose (Day 1)
measure: Parasite Clearance Time (PCT)
timeFrame: Up to 48 hours after first dose
measure: Fever Clearance Times (FCT)
timeFrame: Up to 36 hours after first dose
measure: PCR-corrected Adequate Clinical and Parasitological Response (ACPR) - PPS Analysis
timeFrame: Days 15, 29 and 43
measure: PCR-corrected Adequate Clinical and Parasitological Response (ACPR) - FAS Analysis
timeFrame: Days 15, 29 and 43
measure: PCR-uncorrected Adequate Clinical and Parasitological Response (ACPR)
timeFrame: Days 8, 15, 29 and 43
measure: Number of Participants With Recrudescence Events
timeFrame: Days 15, 29 and 43
measure: Number of Participants With New Infections Events
timeFrame: Days 15, 29 and 43
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From first dose of study treatment until Day 43
measure: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: From first dose of study treatment until 12 months of age (assessed up to maximum 1 year)
Other outcomes:
Locations:
city: Nanoro
country: Burkina Faso
facility: Novartis Investigative Site
city: Ouagadougou
country: Burkina Faso
facility: Novartis Investigative Site
city: Kisantu
country: Congo, The Democratic Republic of the
facility: Novartis Investigative Site
state: Bas Kongo
Study officials:
References: