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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Plasmodium Falciparum Malaria
• Intervention / Treatment: Drug: artemether:lumefantrine (2.5 mg:30 mg)

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

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: +41613241111; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals

Study Locations

• Burkina Faso
  • Nanoro, Burkina Faso
    • Novartis Investigative Site
  • Ouagadougou, Burkina Faso
    • Novartis Investigative Site
• Congo, The Democratic Republic of the
  • Bas Kongo
    • Kisantu, Bas Kongo, Congo, The Democratic Republic of the
      • 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
   • in Cohort 2, 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 (2.5 mg:30 mg) bid over 3 days, from 1-4 tablets per dose	Drug: artemether:lumefantrine (2.5 mg:30 mg); artemether:lumefantrine (2.5 mg:30 mg); Other Names: bid over 3 days, from 1-4 tablets per dose

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: European and Developing Countries Clinical Trials Partnership (EDCTP); Medicines for Malaria Venture (MMV), Switzerland; Groupe de Recherche Action en Santé (GRAS), Ouagadougou, Burkina Faso; Institut de Recherche en sciences de la Santé - Unité de Recherche Clinique de Nanoro (IRSS-URCN), Burkina Faso
• 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

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2020
• Primary Completion (Actual): June 30, 2023
• Study Completion (Estimated): June 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): February 9, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Body Weight; Malaria; Malaria, Falciparum; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; 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