Efficacy, Safety and Pharmacokinetics of Artemether-lumefantrine Dispersible Tablet in the Treatment of Malaria in Infants < 5 kg

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01619878
• Collaborator: Medicines for Malaria Venture (Other)
• Enrollment: 20
• Locations: 7
• Arm: 1
• Duration (Months): 21
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of the study is to obtain efficacy, safety and pharmacokinetic (PK) data following treatment with artemether-lumefantrine dispersible tablet in infants < 5 kg of body weight (BW) with uncomplicated falciparum malaria.

Condition or Disease	Intervention/Treatment	Phase
Acute Uncomplicated Falciparum Malaria	Drug: Artemether-lumefantrine (COA566)	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Single-arm Study to Evaluate the Efficacy, Safety and PK of Artemether-lumefantrine Dispersible Tablet in the Treatment of Acute Uncomplicated Plasmodium Falciparum Malaria in Infants <5 kg Body Weight
• Study Start Date: Oct 1, 2012
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.	Drug: Artemether-lumefantrine (COA566); One dispersible tablet taken orally twice a day during 3 days.; Other Names: Artemether-lumefantrine, COA566

Outcome Measures

Primary Outcome Measures

1. Polymerase Chain Reaction (PCR) Corrected 28 Day Parasitological Cure Rate [28 days]

   Number of participants with clearance of asexual parasites by day 7 after initiating study treatment without recrudescence at day 28, corrected for re-infection by Polymerase Chain Reaction (PCR) assay.

Secondary Outcome Measures

1. Polymerase Chain Reaction (PCR) Corrected Parasitological Cure Rate at Day 14 and 42 [Day 14 and 42]

   Number of participants with clearance of asexual parasites by day 7 after initiating study treatment without recrudescence at day 14 and day 42, corrected for re-infection by Polymerase Chain Reaction (PCR) assay.

2. Number of Participants With Parasitological Uncorrected Cure Rate at Day 3, 7, 14, 28 and 42 [Day 3, 7, 14, 28 and 42]

   Number of patients with clearance of asexual parasites at day 3, 7, 14, 28 and 42 after initiating study treatment.

3. Percent Change of Parasite Count From Baseline at 24 Hours [baseline, 24 hours]

   Percent change of parasite count from baseline at 24 hours

4. Number of Participants With Parasitaemia at 48 Hours After Treatment Initiation Greater Than at Baseline [48 hours]

   Number of participants with parasite density at 48 hours after treatment initiation greater than parasite density at baseline.

5. Number of Participants With Parasitaemia at 72 Hours After Treatment Initiation Greater Than or Equal to 25 Percent of Count at Baseline [72 hours]

   Number of participants with parasite density at 72 hours after treatment initiation greater than or equal to 25 percent of parasite density at baseline.

6. Time to Parasite Clearance (PCT) [Up to 7 days]

   Time from first dose until first total and continued disappearance of asexual parasite forms which remains at least a further 48 hours.

7. Time to Fever Clearance (FCT) [Up to 7 days]

   Time from first dose to the first time the axillary body temperature decreased below and remained below 37.5° C for at least 48 hours.

8. Time to Gametocyte Clearance (GCT) [Up to 7 days]

   Time from first dose until first total and continued disappearance of gametocytes which remains at least a further 48 hours.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Neonates / infants

• Body weight < 5 kg

• In cohort 1, infants aged > 28 days; in cohort 2, neonates of a term age 0 to ≤ 28 days

• Microscopically confirmed diagnosis of acute uncomplicated Plasmodium falciparum malaria or mixed infections with an asexual Plasmodium falciparum parasitaemia of > 1,000 and < 100,000 parasites/µL

Exclusion Criteria:

• Presence of severe malaria (according to World Health Organization definition)

• 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)

• Presence of any clinically significant neurological condition

• Presence of clinically significant abnormality of the hepatic and renal systems

• Patients who sustained a significant blood volume loss (> 3% of calculated blood volume) in the past 30 days

• Patients unable to swallow or whose drinking is impaired

• 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

• Disturbances of electrolyte balance (e.g. hypokalaemia or hypomagnesaemia)

• Presence of any age-adjusted clinically or hematologically relevant laboratory and blood chemistry abnormalities

• Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Cotonou		Benin	01 BP 107
2	Novartis investigative site	Cotonou		Benin
3	Novartis Investigative Site	Burkina Faso		Burkina Faso	2208
4	Novartis investigative site	Ouagadougou		Burkina Faso
5	Novartis investigative site	Kinshasa		Congo
6	Novartis investigative site	Calabar		Nigeria
7	Novartis investigative site	Lome		Togo

Sponsors and Collaborators

• Novartis Pharmaceuticals
• Medicines for Malaria Venture

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01619878
• Other Study ID Numbers: CCOA566B2306; 2011-005852-33; 2011-005858-33
• First Posted: Jun 14, 2012
• Last Update Posted: Jun 17, 2015
• Last Verified: Jun 1, 2015

• Keywords provided by Novartis Pharmaceuticals: plasmodium; P. falciparum; malaria; infant; neonate
• Additional relevant MeSH terms: Malaria; Malaria, Falciparum; Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination

Study Results

Participant Flow

Recruitment Details	The participant that did not complete in the "6 week follow-up phase" was also included in "Follow-up at 12 Months of Age" and was lost to follow-up

Arm/Group Title	Cohort 1
Arm/Group Description	One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.
Period Title: 6 Week Follow-up Phase
STARTED	20
COMPLETED	19
NOT COMPLETED	1
Period Title: 6 Week Follow-up Phase
STARTED	20
COMPLETED	17
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Cohort 1
Arm/Group Description	One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.
Overall Participants	20
Age (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	99.1 (51.75)
Sex: Female, Male (Count of Participants)
Female	10 50%
Male	10 50%

Outcome Measures

1. Primary Outcome

Title	Polymerase Chain Reaction (PCR) Corrected 28 Day Parasitological Cure Rate
Description	Number of participants with clearance of asexual parasites by day 7 after initiating study treatment without recrudescence at day 28, corrected for re-infection by Polymerase Chain Reaction (PCR) assay.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all subjects receiving at least one dose of study drug and who are confirmed to have P. falciparum malaria at baseline.

Arm/Group Title	Cohort 1
Arm/Group Description	One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.
Measure Participants	20
Number [number of participants]	16 80%

2. Secondary Outcome

Title	Polymerase Chain Reaction (PCR) Corrected Parasitological Cure Rate at Day 14 and 42
Description	Number of participants with clearance of asexual parasites by day 7 after initiating study treatment without recrudescence at day 14 and day 42, corrected for re-infection by Polymerase Chain Reaction (PCR) assay.
Time Frame	Day 14 and 42

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all subjects receiving at least one dose of study drug and who are confirmed to have P. falciparum malaria at baseline.

Arm/Group Title	Cohort 1
Arm/Group Description	One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.
Measure Participants	20
Day 14	16 80%
Day 42	16 80%

3. Secondary Outcome

Title	Number of Participants With Parasitological Uncorrected Cure Rate at Day 3, 7, 14, 28 and 42
Description	Number of patients with clearance of asexual parasites at day 3, 7, 14, 28 and 42 after initiating study treatment.
Time Frame	Day 3, 7, 14, 28 and 42

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all subjects receiving at least one dose of study drug and who are confirmed to have P. falciparum malaria at baseline.

Arm/Group Title	Cohort 1
Arm/Group Description	One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.
Measure Participants	20
Day 3	20 100%
Day 7	16 80%
Day 14	16 80%
Day 28	10 50%
Day 42	7 35%

4. Secondary Outcome

Title	Percent Change of Parasite Count From Baseline at 24 Hours
Description	Percent change of parasite count from baseline at 24 hours
Time Frame	baseline, 24 hours

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all subjects receiving at least one dose of study drug and who are confirmed to have P. falciparum malaria at baseline.

Arm/Group Title	Cohort 1
Arm/Group Description	One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.
Measure Participants	20
Mean (Standard Deviation) [Percent Change]	-99.4 (1.19)

5. Secondary Outcome

Title	Number of Participants With Parasitaemia at 48 Hours After Treatment Initiation Greater Than at Baseline
Description	Number of participants with parasite density at 48 hours after treatment initiation greater than parasite density at baseline.
Time Frame	48 hours

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all subjects receiving at least one dose of study drug and who are confirmed to have P. falciparum malaria at baseline.

Arm/Group Title	Cohort 1
Arm/Group Description	One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.
Measure Participants	20
Number [participants]	0 0%

6. Secondary Outcome

Title	Number of Participants With Parasitaemia at 72 Hours After Treatment Initiation Greater Than or Equal to 25 Percent of Count at Baseline
Description	Number of participants with parasite density at 72 hours after treatment initiation greater than or equal to 25 percent of parasite density at baseline.
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all subjects receiving at least one dose of study drug and who are confirmed to have P. falciparum malaria at baseline.

Arm/Group Title	Cohort 1
Arm/Group Description	One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.
Measure Participants	20
Number [participants]	0 0%

7. Secondary Outcome

Title	Time to Parasite Clearance (PCT)
Description	Time from first dose until first total and continued disappearance of asexual parasite forms which remains at least a further 48 hours.
Time Frame	Up to 7 days

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all subjects receiving at least one dose of study drug and who are confirmed to have P. falciparum malaria at baseline.

Arm/Group Title	Cohort 1
Arm/Group Description	One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.
Measure Participants	20
Mean (Standard Deviation) [hours]	29.1 (9.6)

8. Secondary Outcome

Title	Time to Fever Clearance (FCT)
Description	Time from first dose to the first time the axillary body temperature decreased below and remained below 37.5° C for at least 48 hours.
Time Frame	Up to 7 days

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all subjects receiving at least one dose of study drug and who are confirmed to have P. falciparum malaria at baseline.

Arm/Group Title	Cohort 1
Arm/Group Description	One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.
Measure Participants	20
Mean (Standard Deviation) [hours]	4.02 (6.433)

9. Secondary Outcome

Title	Time to Gametocyte Clearance (GCT)
Description	Time from first dose until first total and continued disappearance of gametocytes which remains at least a further 48 hours.
Time Frame	Up to 7 days

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - all subjects receiving at least one dose of study drug and who are confirmed to have P. falciparum malaria at baseline.

Arm/Group Title	Cohort 1
Arm/Group Description	One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.
Measure Participants	20
Mean (Standard Deviation) [hours]	36.32 (77.294)

Adverse Events

Arm/Group Title	Cohort 1
Arm/Group Description	One Artemether-lumefantrine (COA566) dispersible tablet taken orally twice a day during 3 days. Infants age >28 days.
All Cause Mortality
	Cohort 1
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Cohort 1
	Affected / at Risk (%)	# Events
Total	3/20 (15%)
Blood and lymphatic system disorders
Anaemia	1/20 (5%)
Gastrointestinal disorders
Diarrhoea	1/20 (5%)
General disorders
Death	1/20 (5%)
Infections and infestations
Cerebral malaria	1/20 (5%)
Meningitis	1/20 (5%)
Other (Not Including Serious) Adverse Events
	Cohort 1
	Affected / at Risk (%)	# Events
Total	16/20 (80%)
Blood and lymphatic system disorders
Anaemia	6/20 (30%)
Gastrointestinal disorders
Enteritis	1/20 (5%)
Vomiting	4/20 (20%)
General disorders
Pyrexia	5/20 (25%)
Infections and infestations
Bronchitis	6/20 (30%)
Gastroenteritis	2/20 (10%)
Malaria	11/20 (55%)
Rash pustular	1/20 (5%)
Rhinitis	2/20 (10%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.