Clinical Trial Results:
A 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
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Summary
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EudraCT number |
2023-000804-21 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
10 May 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Nov 2024
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First version publication date |
01 Nov 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CCOA566B2307
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04300309 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
Novartis Campus, Basel, Switzerland, CH-4056
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Public contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
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Scientific contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 May 2024
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
10 May 2024
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective was to assess the key pharmacokinetics (PK) parameter of artemether in infants and neonates < 5 kg body weight dosed with the new formulation of artemether-lumefantrine dispersible tablet.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
21 Dec 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Burkina Faso: 7
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Country: Number of subjects enrolled |
Congo, The Democratic Republic of the: 21
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Worldwide total number of subjects |
28
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
6
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Infants and toddlers (28 days-23 months) |
22
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants took part in 3 investigative sites in 2 countries. | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
The Screening procedures began once the study informed consent had been obtained. Screening was performed within 12 hours before the first study drug administration. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Cohort 1 | ||||||||||||||||||||||||||||||
Arm description |
Infants >28 days of age treated with artemether-lumefantrine (5 mg:60 mg) twice daily for 3 days | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
artemether-lumefantrine
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Investigational medicinal product code |
COA566
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Other name |
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Pharmaceutical forms |
Dispersible tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The investigational product was artemether-lumefantrine 2.5 mg:30 mg (COA566 2.5 mg:30 mg), supplied in the form of oral dispersible tablets.
The study treatment was 2 oral dispersible tablets (i.e. artemether-lumefantrine 5 mg:60 mg), twice daily, for 3 days.
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Arm title
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Cohort 2 | ||||||||||||||||||||||||||||||
Arm description |
Term neonates 1-28 days of age treated with artemether-lumefantrine (5 mg:60 mg) twice daily for 3 days | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
artemether-lumefantrine
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Investigational medicinal product code |
COA566
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Other name |
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Pharmaceutical forms |
Dispersible tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The investigational product was artemether-lumefantrine 2.5 mg:30 mg (COA566 2.5 mg:30 mg), supplied in the form of oral dispersible tablets.
The study treatment was 2 oral dispersible tablets (i.e. artemether-lumefantrine 5 mg:60 mg), twice daily, for 3 days.
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| Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: FAS, PPS and PK Set are analysis sets |
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Baseline characteristics reporting groups
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Reporting group title |
Cohort 1
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Reporting group description |
Infants >28 days of age treated with artemether-lumefantrine (5 mg:60 mg) twice daily for 3 days | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort 2
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Reporting group description |
Term neonates 1-28 days of age treated with artemether-lumefantrine (5 mg:60 mg) twice daily for 3 days | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cohort 1
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Reporting group description |
Infants >28 days of age treated with artemether-lumefantrine (5 mg:60 mg) twice daily for 3 days | ||
Reporting group title |
Cohort 2
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Reporting group description |
Term neonates 1-28 days of age treated with artemether-lumefantrine (5 mg:60 mg) twice daily for 3 days | ||
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End point title |
Artemether Cmax after first dose [1] | ||||||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
1 and 2 hours after first dose (Day 1)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Lumefantrine Day 8 concentration (C168h) | ||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
168 hours after first dose (corresponding to 108 hours after last dose)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Lumefantrine Cmax after last dose | ||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
62, 66, 68 and 84 hours after first dose (corresponding to 2, 6, 8 and 24 hours after last dose)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
DHA Cmax after first dose | ||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
1 and 2 hours after first dose (Day 1)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Parasite Clearance Time (PCT) | ||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Up to 48 hours after first dose
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Fever clearance Times (FCT) | ||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Up to 36 hours after first dose
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| No statistical analyses for this end point | |||||||||||||
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End point title |
PCR-corrected Adequate Clinical and Parasitological Response (ACPR) – PPS analysis | |||||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Days 15, 29 and 43
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
PCR-corrected Adequate Clinical and Parasitological Response (ACPR) – FAS analysis | |||||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Days 15, 29 and 43
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
PCR-uncorrected Adequate Clinical and Parasitological Response (ACPR) | ||||||||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Days 8, 15, 29 and 43
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Number of participants with recrudescence events | ||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Days 15, 29 and 43
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of participants with new infections events | ||||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Days 15, 29 and 43
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of participants with Adverse Events (AEs) | |||||||||
End point description |
Number of participants with adverse events (any AEs regardless of seriousness), including changes in laboratory results qualifying and reported as adverse events.
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End point type |
Secondary
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End point timeframe |
From first dose of study treatment until Day 43
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of participants with Serious Adverse Events (SAEs) | |||||||||
End point description |
Number of participants with serious adverse events (SAEs), including changes in laboratory results qualifying and reported as serious adverse events.
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End point type |
Secondary
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End point timeframe |
From first dose of study treatment until 12 months of age (assessed up to maximum 1 year)
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Non-serious adverse events were collected from first dose of study treatment until Day 43. Deaths and serious adverse events were collected from first dose of study treatment until 1 year of age (assessed up to maximum 1 year).
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Adverse event reporting additional description |
Adverse events are assessed in the Safety Set, including all patients who received at least one dose of study treatment.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.1
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Reporting groups
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Reporting group title |
Cohort 1
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Reporting group description |
Infants >28 days of age treated with artemether-lumefantrine (5 mg:60 mg) twice daily for 3 days | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Pooled Cohort
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Reporting group description |
All infants and neonates who received at least one dose of artemether-lumefantrine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort 2
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Reporting group description |
Term neonates 1-28 days of age treated with artemether-lumefantrine (5 mg:60 mg) twice daily for 3 days | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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29 Jun 2023 |
To enable additional optional pharmacokinetics (PK) checks for artemether and lumefantrine and additional interim assessments by the data monitoring committee (DMC). In addition, text related to public health emergencies and safety reporting was updated. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
