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 (CALINA)

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.

Study Overview

• Status: Terminated
• Conditions: Plasmodium Falciparum Malaria
• Intervention / Treatment: Drug: artemether:lumefantrine (2.5 mg:30 mg)

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 Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Burkina Faso
  • Nanoro, Burkina Faso
    • Novartis Investigative Site
  • Ouagadougou, Burkina Faso
    • Novartis Investigative Site
• Democratic Republic of the Congo
  • Bas Kongo
    • Kisantu, Bas Kongo, Democratic Republic of the Congo
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: artemether lumefantrine (2.5 mg:30 mg); Artemether-lumefantrine (5 mg:60 mg) twice daily for 3 days	Drug: artemether:lumefantrine (2.5 mg:30 mg); Two oral dispersible tablets twice daily for three consecutive days. Each tablet contained artemether-lumefantrine 2.5 mg:30 mg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Artemether Cmax After First Dose	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.	1 and 2 hours after first dose (Day 1)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lumefantrine Day 8 Concentration (C168h)	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.	168 hours after first dose (corresponding to 108 hours after last dose)
Lumefantrine Cmax 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.	62, 66, 68 and 84 hours after first dose (corresponding to 2, 6, 8 and 24 hours after last dose)
DHA Cmax After First Dose	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.	1 and 2 hours after first dose (Day 1)
Parasite Clearance Time (PCT)	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.	Up to 48 hours after first dose
Fever Clearance Times (FCT)	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.	Up to 36 hours after first dose
PCR-corrected Adequate Clinical and Parasitological Response (ACPR) - PPS Analysis	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.	Days 15, 29 and 43
PCR-corrected Adequate Clinical and Parasitological Response (ACPR) - FAS Analysis	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.	Days 15, 29 and 43
PCR-uncorrected Adequate Clinical and Parasitological Response (ACPR)	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.	Days 8, 15, 29 and 43
Number of Participants With Recrudescence Events	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.	Days 15, 29 and 43
Number of Participants With New Infections Events	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.	Days 15, 29 and 43
Number of Participants With Adverse Events (AEs)	Number of participants with adverse events (any AEs regardless of seriousness), including changes in laboratory results qualifying and reported as adverse events.	From first dose of study treatment until Day 43
Number of Participants With Serious Adverse Events (SAEs)	Number of participants with serious adverse events (SAEs), including changes in laboratory results qualifying and reported as serious adverse events.	From first dose of study treatment until 12 months of age (assessed up to maximum 1 year)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: European and Developing Countries Clinical Trials Partnership (EDCTP); Institut de Recherche en Sciences de la Sante, Burkina Faso; Medicines for Malaria Venture; Groupe de Recherche Action en Sante
• Investigators: Principal Investigator: Alfred Tiono, Groupement de Recherche Action en Santé (GRAS), Ouagadougou, Burkina Faso; Principal Investigator: Halidou Tinto, Unité de Recherche Clinique, CMA St Camille, Nanoro, Burkina Faso; Principal Investigator: Bernhards Ogutu, Kondele Children Hospital, Kisumu , Kenya; Principal Investigator: Issaka Sagara, MRTC, Univ. of Science, Techniques and Technology, Bamako, Mali; Principal Investigator: Martin Meremikwu, Department of Paediatrics, University of Calabar, Calabar, Nigeria; Principal Investigator: Gildas Wounounou, Hôpital Général de Référence St Luc, Kisantu, DR Congo; Principal Investigator: Christine Manyando, St Pauls Mission Hospital, Nchelenge, Zambia

Publications and helpful links

General Publications

• Wounounou G, Tiono AB, Ogutu B, Manyando C, Sagara I, Schneitter S, Bassat Q, Gaaloul ME, Marrast AC, Demin I, Winnips C, Risterucci C, Hugot S, Hofstetter G, Qian Z, Su G, Zhang J, Renner KC, Cousin M, Venishetty VK, Sayyed S, Gandhi P, Kabore B; CALINA study group. Pharmacokinetics, safety and efficacy of an optimized dose of artemether-lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria in neonates and infants of less than 5 kg body weight: a multicentre, open-label, single-arm phase 2/3 study (CALINA). Trop Med Health. 2025 Nov 6;53(1):151. doi: 10.1186/s41182-025-00828-z.

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com
• A Pediatric Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2020
• Primary Completion (Actual): July 2, 2023
• Study Completion (Actual): May 10, 2024

Study Registration Dates

• First Submitted: February 18, 2020
• First Submitted That Met QC Criteria: March 5, 2020
• First Posted (Actual): March 9, 2020

Study Record Updates

• Last Update Posted (Estimated): January 13, 2026
• Last Update Submitted That Met QC Criteria: December 18, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Plasmodium falciparum; infants; malaria; neonates; artemether; lumefantrine
• Additional Relevant MeSH Terms: Vector Borne Diseases; Mosquito-Borne Diseases; Infections; Protozoan Infections; Parasitic Diseases; Malaria; Malaria, Falciparum; Anti-Infective Agents; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Lumefantrine; Artemether
• Other Study ID Numbers: CCOA566B2307; PACTR202004535453508 (Other Identifier: PACTR)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No