Efficacy, Safety and Tolerability of KAF156 in Combinatio... | NCT04546633

ID	Type	Description	Link
2021-003583-27	EudraCT Number

Name	Class
European and Developing Countries Clinical Trials Partnership (EDCTP)	OTHER_GOV

Description Module

Detailed Description

This Phase 2 study aimed to evaluate the efficacy, safety and tolerability of the investigational drug KAF156 and a Solid Dispersion Formulation of lumefantrine (LUM-SDF) when administered in combination in pediatric patients 6 months to < 18 years of age with uncomplicated Plasmodium falciparum malaria. In addition, pharmacokinetics (PK) of the drug combination was also evaluated.

There were three age-descending cohorts in the study: Run-in Cohort (12 years to < 18 years), Cohort 1 (2 years to < 12 years) and Cohort 2 (6 months to < 2 years). The rationale for separated cohorts 1 and 2 was to allow enrolment of the youngest patients (cohort 2) after safety and exposure review of older patients in cohort 1. Given the age-independent symptoms of acute malaria, and to increase statistical power, for all outcomes measures the cohorts 1 and 2 were pooled (cohort 1/2). This new study first explored the effect of food on lumefantrine and KAF156 pharmacokinetics (PK) in patients 12 to < 18 years old with malaria caused by P. falciparum. Based on the data from the Run-in Cohort, recommendation on dose, dosing regimen, dosage administration (with food) and duration were provided before younger patients in Cohorts 1 and 2 were dosed with KAF156/LUM-SDF. Then, efficacy, safety, tolerability and PK of the combination of KAF156/LUM-SDF in comparison with Coartem®(Artemether/Lumefantrine) were evaluated in younger patients, in pooled Cohort 1/2.

Label	Type	Description	Intervention Names
Run-in - KAF156 and LUM-SDF QD for 2 days in fasted condition	Experimental	KAF156 and LUM-SDF QD (once daily) for 2 days in fasted condition	Drug: KAF156 Drug: LUM-SDF
Run-in - KAF156 and LUM-SDF QD for 2 days in fed condition	Experimental	KAF156 and LUM-SDF QD (once daily) for 2 days in fed condition	Drug: KAF156 Drug: LUM-SDF
Cohort 1/2 - KAF156 and LUM-SDF QD (once daily) in 3-day dose regimen	Experimental	KAF156 and LUM-SDF QD (once daily) in 3-day dose regimen. It was administered with a light meal and the full dose was adjusted based on patient´s body weight.	Drug: KAF156 Drug: LUM-SDF
Cohort 1/2 - Coartem® BID (twice a day) for 3 days	Active Comparator	Coartem® BID twice a day for 3 days (It was administered with a light meal and doses were based on patient's body weight as per product label).	Drug: Coartem

Name	Type	Description	Arm Group Labels	Other Names
KAF156	Drug	Provided as 100 mg tablets, to be taken QD 2 or 3 Days in combination with LUM-SDF, dose is based on body weight	Cohort 1/2 - KAF156 and LUM-SDF QD (once daily) in 3-day dose regimen

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) - Cohorts 1 and 2 Pooled	PCR-corrected ACPR, defined as the absence of parasitemia(PS), was evaluated on Day29. Microscopic species identification was confirmed and determined by PCR genotyping methods to establish malaria recrudescence/reinfection.A participant was considered as PCR corrected ACPR at Day29 if the participant did not meet any of the criteria of early treatment failure (up to Day4), late clinical failure(Day5 to Day29) or late parasitological failure(Day8 to Day29), and had absence of PS on Day29 irrespective of axillary temperature unless the presence of PS after 7days(Day8 or later) was due to reinfection based on PCR genotyping.A presence of PS after 7days of treatment initiation was considered as a reinfection only if the PS was clear before Day8 and none of the parasite strain(s) detected on Day8 or later match with the parasite strain at baseline based on PCR genotyping.Given the age-independent symptoms of acute malaria, and to increase statistical power,the cohorts 1 and 2 were pooled.	Day 29

Secondary Outcomes

Measure	Description	Time Frame
PCR-corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR)	PCR-corrected ACPR, defined as the absence of parasitemia, was evaluated. 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. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

In run-in cohort: Male and female patients 12 to < 18 years of age, with a body weight
- 35.0 kg In Cohort 1: Male and female patients 2 to < 12 years of age, with a body weight ≥ 10.0 kg In Cohort 2: Male and female patients 6 months to < 2 years of age, with a body weight
- 5.0 kg
Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films
P. falciparum parasitemia of ≥ 1,000 and ≤ 150,000 parasites/μL at the time of prescreening for the Run-in Cohort; and P. falciparum parasitemia of ≥ 1,500 and ≤ 150,000 parasites/μL at the time of pre-screening for Cohorts 1 and 2
Axillary temperature ≥ 37.5 ºC or oral/tympanic/rectal temperature ≥ 38.0 ºC; or history of fever during the previous 24 hours (at least documented verbally)
Written informed consent has been obtained from parent / legal guardian before any assessment is performed. If the parent/legal guardian is unable to read and write, then a witnessed consent according to local ethical standards is permitted. Patients who are capable of providing assent, must provide assent with parental/legal guardian consent or as per local ethical guidelines
The patient and his/her parent/legal guardian is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned

Exclusion Criteria:

Mixed Plasmodium infections as per light microscopy results
Signs and symptoms of severe malaria according to WHO 2015 (see Section 16.4)
Significant, non-plasmodial co-infections including tuberculosis
Patients with concurrent febrile illnesses (e.g., typhoid fever, known or suspected COVID19)
Known relevant liver disease e.g. chronic hepatitis, cirrhosis, compensated or decompensated, history of hepatitis B or C, hepatitis B or A vaccination in last 3 months, known gallbladder or bile duct disease, acute or chronic pancreatitis
Major congenital defects
Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection or family history of congenital or hereditary immunodeficiency
Immunosuppressive therapy (steroids, immune modulators or immune suppressors) within 3 months prior to recruitment. (For corticosteroids, this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaled and topical steroids are allowed)
Repeated vomiting (defined as more than 3 times in the 24 hours prior to inclusion in the study) or severe diarrhea (defined as more than 3 watery stools in the 24 hours prior to inclusion in the study)
Active duodenal ulcer, ulcerative colitis, Crohn's disease, chronic (i.e., > 2 weeks) use of non-steroidal anti-inflammatory drugs (NSAIDs)
Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia
Anemia (hemoglobin level <7 g/dL)
Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs (e.g., HIV patients on ART therapy or TB patients on treatment), or which may jeopardize the patient in case of participation in the study. The investigator should make this determination in consideration of the patient's medical history and/or clinical or laboratory evidence of any of the following:
- AST/ALT > 3 x the upper limit of normal range (ULN), regardless of the level of total bilirubin
- AST/ALT > 1.5 and ≤ 2 x ULN and total bilirubin is > ULN Total bilirubin > 2 x ULN regardless of the level of AST/ALT
Resting QT interval corrected by Fridericia's formula (QTcF) > 450 ms at screening
Creatinine > 2 x ULN in the absence of dehydration. In case of dehydration, creatinine should be < 2 x ULN after oral/parenteral rehydration
Any severe disease condition which might prohibit participation in this study
Known chronic underlying disease such as sickle cell disease, and severe cardiac, renal, or hepatic impairment
Known active or uncontrolled thyroid disease
Inability to swallow oral medication (in tablet and/or liquid form)
Patients with prior antimalarial therapy or antibiotics with antimalarial activity within minimum of their five (5) plasma half-lives (or within 4 weeks of screening if half-life is unknown)
Use of other investigational drugs within 30 days of dosing or until the expected pharmacodynamic effect has returned to baseline, whichever is longer
Patients taking medications prohibited by the protocol
Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance within 3 months of dosing
History or family history of long QT syndrome or sudden cardiac death, or any other clinical condition known to prolong the QTc interval, such as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe heart disease
Use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study
History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes

For the Run-in Cohort only:
Pregnant or nursing (lactating) patients
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of investigational drug. Basic contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
- Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
- Male sterilization (at least 6 m prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient
- Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps).
Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking investigational drug. Women are considered not of child bearing potential if they have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

For Cohorts 1 and 2 only:
Patients of child bearing potential, defined as all girls post first menarche (except for Run-in Cohort)

Name	Affiliation	Role
Novartis Pharmaceuticals	Novartis Pharmaceuticals	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Novartis Investigative Site		Banfora			Burkina Faso
Novartis Investigative Site

PubMed Identifier	Type	Citation	Retractions
37327809	Derived	Ogutu B, Yeka A, Kusemererwa S, Thompson R, Tinto H, Toure AO, Uthaisin C, Verma A, Kibuuka A, Lingani M, Lourenco C, Mombo-Ngoma G, Nduba V, N'Guessan TL, Nassa GJW, Nyantaro M, Tina LO, Singh PK, El Gaaloul M, Marrast AC, Chikoto H, Csermak K, Demin I, Mehta D, Pathan R, Risterucci C, Su G, Winnips C, Kaguthi G, Fofana B, Grobusch MP. Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial. Lancet Infect Dis. 2023 Sep;23(9):1051-1061. doi: 10.1016/S1473-3099(23)00209-8. Epub 2023 Jun 13.

ID	Title	Description
FG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.
FG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jul 29, 2021	Feb 25, 2025

Arm/Group Information

ID	Title	Description
BG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.
BG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted	KAF156-400 mg and LUM-240 mg-SDF once daily for 2 days in fasted condition, via oral.
BG002	Run-in Cohort-KAF400mg/LUM480mg-QDx2-Fed	KAF156-400 mg and LUM-480 mg-SDF once daily for 2 days in fed condition, via oral.
BG003	Run-in Cohort-KAF400mg/LUM480mg-QDx2-Fasted	KAF156-400 mg and LUM-480 mg-SDF once daily for 2 days in fasted condition, via oral.
BG004	Cohort 1-KAF400mg/LUM480mg-QDx3	KAF156-400mg and LUM-480 mg-SDF once daily for 3 days, via oral. It was administered with a light meal and the full dose was adjusted based on patient´s body weight. Patients age: 2 years to < 12 years.
BG005	Cohort 2-KAF400mg/LUM480mg-QDx3	KAF156-400mg and LUM-480 mg-SDF once daily for 3 days, via oral. It was administered with a light meal and the full dose was adjusted based on patient´s body weight. Patients age: 6 months to < 2 years.
BG006	Cohort 1-Artemether80mg/LUM480mg	Artemether-80mg/LUM-480 mg, twice daily for 3 days, it was administered with food and the doses were based on patient's body weight as per product label. Patients age: 2 years to < 12 years.
BG007	Cohort 2-Artemether80mg/LUM480mg	Artemether-80mg/LUM-480 mg, twice daily for 3 days, it was administered with food and the doses were based on patient's body weight as per product label. Patients age: 6 months to < 2 years.
BG008	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) - Cohorts 1 and 2 Pooled

PCR-corrected ACPR, defined as the absence of parasitemia(PS), was evaluated on Day29. Microscopic species identification was confirmed and determined by PCR genotyping methods to establish malaria recrudescence/reinfection.A participant was considered as PCR corrected ACPR at Day29 if the participant did not meet any of the criteria of early treatment failure (up to Day4), late clinical failure(Day5 to Day29) or late parasitological failure(Day8 to Day29), and had absence of PS on Day29 irrespective of axillary temperature unless the presence of PS after 7days(Day8 or later) was due to reinfection based on PCR genotyping.A presence of PS after 7days of treatment initiation was considered as a reinfection only if the PS was clear before Day8 and none of the parasite strain(s) detected on Day8 or later match with the parasite strain at baseline based on PCR genotyping.Given the age-independent symptoms of acute malaria, and to increase statistical power,the cohorts 1 and 2 were pooled.

The Per-Protocol Set (PPS) was a subset of patients of the FAS and was characterized by the following criteria:

did not have important protocol deviations affecting efficacy,
took at least 80% of study medication,
did not take non-study drug antimalarial medications prior to Day 29 unless experiencing a treatment failure (ETF, LCF, LPF), and
PCR corrected ACPR status at Day 29 could be defined

Posted

Number

95% Confidence Interval

Percentage of participants

Day 29

ID	Title	Description
OG000	Cohort 1/2-KAF400mg/LUM480mg-QDx3	KAF156-400mg and LUM-480 mg-SDF once daily for 3 days, via oral. It was administered with a light meal and the full dose was adjusted based on patient´s body weight.
OG001	Cohort 1/2-Artemether80mg/LUM480mg	Artemether-80mg/LUM-480 mg, twice daily for 3 days, it was administered with food and the doses were based on patient's body weight as per product label.

Units	Counts
Participants	OG00098 OG00199

Title

Denominators

Categories

Title	Measurements
	OG00099.0(94.4 to 100.0) OG00199.0(94.5 to 100.0)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Cochran-Mantel-Haenszel				Risk Difference (RD)	-0.0			2-Sided	95	-2.9	2.8					Non-Inferiority	Non-inferiority was concluded if the lower limit of the 2-sided 95% CI was above the pre-defined -10% non-inferiority margin.

Secondary

PCR-corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR)

PCR-corrected ACPR, defined as the absence of parasitemia, was evaluated. 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. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

The Per-Protocol Set (PPS) was a subset of patients of the FAS and was characterized by the following criteria:

did not have important protocol deviations affecting efficacy,
took at least 80% of study medication,
did not take non-study drug antimalarial medications prior to Day 29 unless experiencing a treatment failure (ETF, LCF, LPF), and
PCR corrected ACPR status at Day 29 could be defined

Posted

Number

95% Confidence Interval

Percentage of participants

Corrected ACPR: Day 15, Day 43; Uncorrected ACPR: Day 15, Day 29 and Day 43

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.

Secondary

PCR-corrected Adequate Clinical and Parasitological Response (ACPR) - Run-in Cohort

PCR-corrected ACPR, defined as the absence of parasitemia, was evaluated on Day 29. 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 at Day 29 if the participant did not meet any of the criteria of early treatment failure (ETF) (up to Day 4), late clinical failure (LCF) (Day 5 to Day 29) or late parasitological failure (LPF) (Day 8 to Day 29), and had absence of parasitaemia on Day 29 irrespective of axillary temperature unless the presence of parasitaemia after 7 days (Day 8 or later) was due to reinfection based on PCR genotyping. A presence of parasitaemia after 7 days of treatment initiation was considered as a reinfection only if the parasitaemia was clear before Day 8 and none of the parasite strain(s) detected on Day 8 or later match with the parasite strain at baseline based on PCR genotyping.

The Per-Protocol Set (PPS) was a subset of patients of the FAS and was characterized by the following criteria:

did not have important protocol deviations affecting efficacy,
took at least 80% of study medication,
did not take non-study drug antimalarial medications prior to Day 29 unless experiencing a treatment failure (ETF, LCF, LPF), and
PCR corrected ACPR status at Day 29 could be defined

Posted

Number

95% Confidence Interval

Percentage of participants

Day 29

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.

Secondary

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. PCT was calculated using the Kaplan-Meier method. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization and who were treated with at least one dose of study drug with baseline P. falciparum asexual parasite count >0.

Posted

Median

95% Confidence Interval

hours

up to 43 days

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.
OG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted	KAF156-400 mg and LUM-240 mg-SDF once daily for 2 days in fasted condition, via oral.
OG002	Run-in Cohort-KAF400mg/LUM480mg-QDx2-Fed	KAF156-400 mg and LUM-480 mg-SDF once daily for 2 days in fed condition, via oral.

Secondary

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.

FCT was calculated using the Kaplan-Meier method. Participants who received any antimalarial medication (including rescue medication) before fever clearance are censored at the first use of antimalarial medication.

Participants without fever clearance are censored at the time of last fever assessment. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Posted

Median

95% Confidence Interval

hours

up to 43 days

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.
OG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted	KAF156-400 mg and LUM-240 mg-SDF once daily for 2 days in fasted condition, via oral.
OG002

Secondary

Percentage Early Treatment Failure (ETF)

Participants were defined as early treatment failures (ETFs) if they developed danger signs or severe malaria on Day 2, Day 3, or Day 4 in the presence of parasitemia, parasitemia on Day 3 with a count higher than the Day 1 count irrespective of axillary temperature, parasitemia on Day 4 with axillary temperature ≥ 37.5°C, or parasitemia on Day 4 with a count equal to or more than 25% of the count on Day 1. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Posted

Number

95% Confidence Interval

Percentage of participants

From Day 1 to Day 4

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.
OG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted	KAF156-400 mg and LUM-240 mg-SDF once daily for 2 days in fasted condition, via oral.
OG002	Run-in Cohort-KAF400mg/LUM480mg-QDx2-Fed

Secondary

Percentage Late Clinical Failure (LCF)

Participants were defined as late clinical failures (LCFs) if they developed danger signs or severe malaria on any day from Day 5 to Day 43 in the presence of parasitemia without previously meeting any of the criteria of ETF, or if they had parasitemia and an axillary temperature of ≥ 37.5°C on any day from Day 5 to Day 43 without previously meeting any of the criteria of ETF. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Posted

Number

95% Confidence Interval

Percentage of participants

Day 5 to Day 43

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.
OG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted	KAF156-400 mg and LUM-240 mg-SDF once daily for 2 days in fasted condition, via oral.
OG002	Run-in Cohort-KAF400mg/LUM480mg-QDx2-Fed

Secondary

Percentage Late Parasitological Failure (LPF)

Participants were defined as late parasitological failures (LPFs) if they had parasitemia on any day from Day 8 to Day 43 and an axillary temperature < 37.5°C without previously meeting any of the criteria of ETF or LCF. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Posted

Number

95% Confidence Interval

Percentage of participants

Day 8 to Day 43

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.
OG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted	KAF156-400 mg and LUM-240 mg-SDF once daily for 2 days in fasted condition, via oral.
OG002	Run-in Cohort-KAF400mg/LUM480mg-QDx2-Fed	KAF156-400 mg and LUM-480 mg-SDF once daily for 2 days in fed condition, via oral.

Secondary

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. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Posted

Count of Participants

Participants

Day 15, Day 29 and Day 43

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.
OG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted	KAF156-400 mg and LUM-240 mg-SDF once daily for 2 days in fasted condition, via oral.
OG002	Run-in Cohort-KAF400mg/LUM480mg-QDx2-Fed	KAF156-400 mg and LUM-480 mg-SDF once daily for 2 days in fed condition, via oral.

Secondary

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. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

Posted

Count of Participants

Participants

Day 15, Day 29 and Day 43

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.
OG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted	KAF156-400 mg and LUM-240 mg-SDF once daily for 2 days in fasted condition, via oral.
OG002	Run-in Cohort-KAF400mg/LUM480mg-QDx2-Fed	KAF156-400 mg and LUM-480 mg-SDF once daily for 2 days in fed condition, via oral.

Secondary

Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Number of participants with treatment emergent adverse events (any AE regardless of seriousness), and SAEs. Given the age-independent symptoms of acute malaria, and to increase statistical power, the cohorts 1 and 2 were pooled (cohort 1/2).

The Safety Set included all patients who received at least one dose of study treatment. Patients were analyzed according to the study treatment received.

Posted

Count of Participants

Participants

Adverse events were reported from first dose of study treatment until end of study treatment up to a maximum duration of approximately 43 days.

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.
OG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted	KAF156-400 mg and LUM-240 mg-SDF once daily for 2 days in fasted condition, via oral.
OG002	Run-in Cohort-KAF400mg/LUM480mg-QDx2-Fed	KAF156-400 mg and LUM-480 mg-SDF once daily for 2 days in fed condition, via oral.

Secondary

KAF156 and Lumefantrine (LUM) Cmax

Cmax is the maximum observed plasma concentration following drug administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods. Analyte KAF156 is not applicable for Artemether80mg/LUM480mg arm.

The PK set was a subset of the safety set who had at least 1 evaluable PK concentration. A profile was considered evaluable for that period if following conditions were satisfied:

Patients took at least 80% dosages of randomized study medication.
If a patient vomited the original dose but did not vomit the replacement dose.
Patients with no protocol deviations (PD) that had an impact on the PK data.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Run-in Cohort:Pre-dose,1,3,4,5,6,8,24,25,27,28,29,30,32,48,72,168 hours; Cohort 1 and 2 KAF400mg/LUM480mg-QDx3 6-12 years: 3,6,24,48,51,54,72,168 hours; 6 months -<6 years:24,48,51,54,72,168 hours;Cohort 1 and 2 Artemether80mg/LUM480mg:24,48,68,168 hours

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.
OG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted	KAF156-400 mg and LUM-240 mg-SDF once daily for 2 days in fasted condition, via oral.
OG002

Secondary

KAF156 and Lumefantrine Area Under Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast)

AUC is the area under the plasma concentration-time curve. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. The Artemether80mg/LUM480mg arms (standard of care) involved limited pharmacokinetic sampling at 24, 48, 68, and 168 hours following the first dose administration. In contrast, the KAF156 arms had a more extensive sampling, varying by age group, which included time points at 3, 6, 24, 48, 51, 54, 72, and 168 hours following first dose. Due to the limited sampling in the Artemether80mg/LUM480mg arms, it was not planned (per protocol) to calculate AUC values.

The PK set was a subset of the safety set who had at least 1 evaluable PK concentration. Artemether80mg/LUM480mg arms were excluded from the analysis due to limited PK sampling. A profile was considered evaluable for that period if following conditions were satisfied:

Patients took at least 80% dosages of randomized study medication.
If a patient vomited the original dose but did not vomit the replacement dose.
Patients with no protocol deviations (PD) that had an impact on the PK data.

Posted

Geometric Mean

Geometric Coefficient of Variation

h*ng/mL

Run-in Cohort:Pre-dose,1,3,4,5,6,8,24,25,27,28,29,30,32,48,72,168 hours; Cohort 1 and 2 KAF400mg/LUM480mg-QDx3 6-12 years: 3,6,24,48,51,54,72,168 hours; 6 months -< 6 years: 24,48,51,54,72,168 hours.

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.

Secondary

KAF156 and Lumefantrine Time to Reach the Maximum Plasma Concentration After Drug Administration (Tmax)

Tmax is the time to reach maximum plasma concentration following drug administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods. The Artemether80mg/LUM480mg arms (standard of care) involved limited pharmacokinetic sampling at 24, 48, 68, and 168 hours following the first dose administration. In contrast, the KAF156 arm had a more extensive sampling, varying by age group, which included time points at 3, 6, 24, 48, 51, 54, 72, and 168 hours following first dose. PK samples for the Artemether80mg/LUM480mg arms were collected around the expected Tmax (at 68 hours, i.e., 8 hours after the last dose, based on the known Tmax of lumefantrine in Coartem) to determine Cmax values; in line with the protocol, separate Tmax values were not calculated.

Patients took at least 80% dosages of randomized study medication.
If a patient vomited the original dose but did not vomit the replacement dose.
Patients with no protocol deviations (PD) that had an impact on the PK data.

Posted

Median

Full Range

hours

Run-in Cohort:Pre-dose,1,3,4,5,6,8,24,25,27,28,29,30,32,48,72,168 hours; Cohort 1 and 2 KAF400mg/LUM480mg-QDx3 6-12 years: 3,6,24,48,51,54,72,168 hours; 6 months -< 6 years: 24,48,51,54,72,168 hours.

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed

Secondary

KAF156 and Lumefantrine Plasma Drug Concentration 168 Hours Post First Dose Administration (C168h)

C168h is the plasma concentration at 168h post first dose administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods. Analyte KAF156 is not applicable for Artemether80mg/LUM480mg arm.

The PK set was a subset of the safety set who had at least 1 evaluable PK concentration. A profile was considered evaluable for that period if following conditions were satisfied:

Patients took at least 80% dosages of randomized study medication.
If a patient vomited the original dose but did not vomit the replacement dose.
Patients with no protocol deviations (PD) that had an impact on the PK data.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

at 168 hours

ID	Title	Description
OG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.
OG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted	KAF156-400 mg and LUM-240 mg-SDF once daily for 2 days in fasted condition, via oral.
OG002	Run-in Cohort-KAF400mg/LUM480mg-QDx2-Fed

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0011 affected26 at risk EG0021 affected11 at risk EG0031 affected13 at risk EG0045 affected110 at risk EG0056 affected110 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0010 affected26 at risk EG0020 affected11 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA (27.0)	Systematic Assessment	EG0001 affected25 at risk EG0012 affected26 at risk EG0020 affected11 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0010 affected26 at risk EG0021 affected11 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0010 affected26 at risk EG0020 affected11 at risk EG003
Toothache	Gastrointestinal disorders	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0010 affected26 at risk EG0021 affected11 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (27.0)	Systematic Assessment	EG0001 affected25 at risk EG0012 affected26 at risk EG0021 affected11 at risk EG003
Pyrexia	General disorders	MedDRA (27.0)	Systematic Assessment	EG0002 affected25 at risk EG0011 affected26 at risk EG0022 affected11 at risk EG003
Conjunctivitis	Infections and infestations	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0010 affected26 at risk EG0021 affected11 at risk EG003
Furuncle	Infections and infestations	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0010 affected26 at risk EG0020 affected11 at risk EG003
Malaria	Infections and infestations	MedDRA (27.0)	Systematic Assessment	EG0006 affected25 at risk EG0015 affected26 at risk EG0026 affected11 at risk EG003
Schistosomiasis	Infections and infestations	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0010 affected26 at risk EG0021 affected11 at risk EG003
Bilirubin conjugated increased	Investigations	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0010 affected26 at risk EG0021 affected11 at risk EG003
Blood alkaline phosphatase increased	Investigations	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0011 affected26 at risk EG0020 affected11 at risk EG003
Blood bilirubin increased	Investigations	MedDRA (27.0)	Systematic Assessment	EG0002 affected25 at risk EG0010 affected26 at risk EG0020 affected11 at risk EG003
Electrocardiogram QT prolonged	Investigations	MedDRA (27.0)	Systematic Assessment	EG0003 affected25 at risk EG0011 affected26 at risk EG0024 affected11 at risk EG003
Heart rate decreased	Investigations	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0010 affected26 at risk EG0020 affected11 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (27.0)	Systematic Assessment	EG0001 affected25 at risk EG0011 affected26 at risk EG0020 affected11 at risk EG003
Headache	Nervous system disorders	MedDRA (27.0)	Systematic Assessment	EG0002 affected25 at risk EG0010 affected26 at risk EG0020 affected11 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0011 affected26 at risk EG0020 affected11 at risk EG003
Urticaria	Skin and subcutaneous tissue disorders	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0010 affected26 at risk EG0021 affected11 at risk EG003

ID	Term
D008288	Malaria
D011528	Protozoan Infections
D010272	Parasitic Diseases
D007239	Infections
D000096724	Mosquito-Borne Diseases
D000079426	Vector Borne Diseases

ID	Term
C000599914	ganaplacide
D000077611	Artemether, Lumefantrine Drug Combination

ID	Term
D000077549	Artemether
D037621	Artemisinins
D017382	Reactive Oxygen Species
D005609	Free Radicals
D007287	Inorganic Chemicals
D009930	Organic Chemicals
D000078102	Lumefantrine
D005449	Fluorenes
D011084	Polycyclic Aromatic Hydrocarbons
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D012717	Sesquiterpenes
D013729	Terpenes
D011083	Polycyclic Compounds
D004338	Drug Combinations
D004364	Pharmaceutical Preparations

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fed	KAF156-400 mg and LUM-240 mg-solid dispersion formulation (SDF), once daily (QD) for 2 days in fed condition, via oral.	25	1	25	12	25
EG001	Run-in Cohort-KAF400mg/LUM240mg-QDx2-Fasted	KAF156-400 mg and LUM-240 mg-SDF once daily for 2 days in fasted condition, via oral.	26	0	26	12	26
EG002	Run-in Cohort-KAF400mg/LUM480mg-QDx2-Fed	KAF156-400 mg and LUM-480 mg-SDF once daily for 2 days in fed condition, via oral.	11	0	11	10	11
EG003	Run-in Cohort-KAF400mg/LUM480mg-QDx2-Fasted	KAF156-400 mg and LUM-480 mg-SDF once daily for 2 days in fasted condition, via oral.	13	1	13	9	13
EG004	Cohort 1/2-KAF400mg/LUM480mg-QDx3	KAF156-400mg and LUM-480 mg-SDF once daily for 3 days, via oral. It was administered with a light meal and the full dose was adjusted based on patient´s body weight.	110	0	110	69	110
EG005	Cohort 1/2-Artemether80mg/LUM480mg	Artemether-80mg/LUM-480 mg, twice daily for 3 days, it was administered with food and the doses were based on patient's body weight as per product label.	110	4	110	55	110

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Bronchitis	Infections and infestations	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0010 affected26 at risk EG0020 affected11 at risk EG0030 affected13 at risk EG0040 affected110 at risk EG0051 affected110 at risk
Blood bilirubin increased	Investigations	MedDRA (27.0)	Systematic Assessment	EG0001 affected25 at risk EG0010 affected26 at risk EG0020 affected11 at risk EG003
Liver function test increased	Investigations	MedDRA (27.0)	Systematic Assessment	EG0000 affected25 at risk EG0010 affected26 at risk EG0020 affected11 at risk EG003