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

Phase 2

Terminated

• Conditions: Plasmodium Falciparum Malaria

• Registration Number: NCT04300309
• Lead Sponsor: Novartis Pharmaceuticals

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.

Study Timeline

• Study First Submitted: 2020-02-18
• Study First Submitted QC: 2020-03-05
• Study First Posted: 2020-03-09
• Study Start: 2020-12-21
• Primary Completion: 2023-07-02
• Study Completion: 2024-05-10
• Results First Submitted: 2024-06-25
• Results First Submitted QC: 2024-06-25
• Status Verified: 2024-10
• Results First Posted: 2024-10-03
• Last Update Submitted: 2024-10-16
• Last Update Posted: 2024-11-11

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 28

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Artemether Cmax After First Dose	1 and 2 hours after first dose (Day 1)	Artemether Cmax represents the highest concentration between the concentrations at 1 hour and 2 hours after first dose.; Pharmacokinetic (PK) parameters were calculated by non-compartmental analysis based on artemether plasma concentrations.

Secondary Outcome Measures

Name	Time	Method
Lumefantrine Day 8 Concentration (C168h)	168 hours after first dose (corresponding to 108 hours after last dose)	Pharmacokinetic (PK) parameters were calculated by non-compartmental analysis based on lumefantrine plasma concentrations.; Dosing times were 0, 8, 24, 36, 48 and 60 hours.
Lumefantrine Cmax After Last Dose	62, 66, 68 and 84 hours after first dose (corresponding to 2, 6, 8 and 24 hours after last dose)	Lumefantrine Cmax represents the highest concentration among four sampling time points after last dose.; Pharmacokinetic (PK) parameters were calculated by non-compartmental analysis based on lumefantrine plasma concentrations.; Dosing times were 0, 8, 24, 36, 48 and 60 hours.
DHA Cmax After First Dose	1 and 2 hours after first dose (Day 1)	Dihydroartemisinin (DHA) is an active metabolite of artemether. DHA Cmax represents the highest concentration between the concentrations at 1 hour and 2 hours after first dose.; Pharmacokinetic (PK) parameters were calculated by non-compartmental analysis based on DHA plasma concentrations.
Parasite Clearance Time (PCT)	Up to 48 hours after first dose	PCT is defined as time from the first dose until the first total and continued disappearance of asexual parasite forms which remained at least a further 48 hours. PCT is based on uncorrected parasite counts.; Patients who received rescue medication before parasite clearance were censored at the first use of rescue medication.; Patients without parasite clearance were censored at the time of last parasite assessment.; PCT was calculated using the Kaplan-Meier method.
Fever Clearance Times (FCT)	Up to 36 hours after first dose	FCT is defined as time from the first dose until the first time the axillary body temperature decreased below and remained below 37.5°C axillary or 38.0°C oral/tympanic/rectal for at least a further 24 hours.; Patients who received rescue medication before fever clearance were censored at the first use of rescue medication.; Patients without fever clearance were censored at the time of last parasite assessment.; FCT was calculated using the Kaplan-Meier method.
PCR-corrected Adequate Clinical and Parasitological Response (ACPR) - PPS Analysis	Days 15, 29 and 43	PCR-corrected ACPR, defined as the absence of parasitemia, was evaluated on Days 15, 29 and 43. Microscopic species identification was confirmed and determined by polymerase chain reaction (PCR) genotyping methods to establish malaria recrudescence/reinfection.; A participant was considered as PCR-corrected ACPR if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and had absence of parasitemia on Days 15, 29 or 43 irrespective of axillary temperature unless the presence of parasitemia after 7 days was due to reinfection based on PCR. A presence of parasitemia after 7 days of treatment initiation was considered as a reinfection only if the parasitemia was clear before Day 8 and none of the parasite strain(s) detected on Day 8 or later matched with the parasite strain at baseline based on PCR.
PCR-corrected Adequate Clinical and Parasitological Response (ACPR) - FAS Analysis	Days 15, 29 and 43	PCR-corrected ACPR, defined as the absence of parasitemia, was evaluated on Days 15, 29 and 43. Microscopic species identification was confirmed and determined by polymerase chain reaction (PCR) genotyping methods to establish malaria recrudescence/reinfection.; A participant was considered as PCR-corrected ACPR if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and had absence of parasitemia on Days 15, 29 or 43 irrespective of axillary temperature unless the presence of parasitemia after 7 days was due to reinfection based on PCR. A presence of parasitemia after 7 days of treatment initiation was considered as a reinfection only if the parasitemia was clear before Day 8 and none of the parasite strain(s) detected on Day 8 or later matched with the parasite strain at baseline based on PCR.
PCR-uncorrected Adequate Clinical and Parasitological Response (ACPR)	Days 8, 15, 29 and 43	PCR-uncorrected ACPR, defined as the absence of parasitemia, was evaluated on Days 8, 15, 29 and 43.; A participant was considered as PCR-uncorrected ACPR if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and had absence of parasitemia on Days 8, 15, 29 or 43 irrespective of axillary temperature.
Number of Participants With Recrudescence Events	Days 15, 29 and 43	Recrudescence is defined as appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at baseline. Recrudescence had to be confirmed by PCR analysis.
Number of Participants With New Infections Events	Days 15, 29 and 43	New infection is defined as appearance of asexual parasites after clearance of initial infection with a genotype different from those parasites present at baseline. New infection had to be confirmed by PCR analysis.
Number of Participants With Adverse Events (AEs)	From first dose of study treatment until Day 43	Number of participants with adverse events (any AEs regardless of seriousness), including changes in laboratory results qualifying and reported as adverse events.
Number of Participants With Serious Adverse Events (SAEs)	From first dose of study treatment until 12 months of age (assessed up to maximum 1 year)	Number of participants with serious adverse events (SAEs), including changes in laboratory results qualifying and reported as serious adverse events.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇨🇩 Kisantu, Bas Kongo, Congo, The Democratic Republic of the