Efficacy and Safety of KAF156 in Combination With LUM-SDF in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria

Phase 2

Completed

Conditions: Acute Uncomplicated Plasmodium Falciparum Malaria

Interventions: Drug: KAF156
Drug: Coartem
Drug: Lumefantrine Solid Dispersion Formulation

Registration Number: NCT03167242

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This study was designed to determine the most effective and tolerable dose at the shortest dosing regimen of the investigational drug KAF156 in combination with a solid dispersion formulation of lumefantrine (LUM-SDF) in adult/adolescent and pediatric patients with uncomplicated Plasmodium falciparum malaria.

There is unmet medical need for anti-malarial treatment with new mechanism of action to reduce probability of developing resistance, and for duration shorter than 3 days of treatment and/or reduced pill burden.

Detailed Description: This was a Phase 2 multi-center and open-label study with a single cohort pharmacokinetic (PK) Run-in Part followed by 2 randomized parallel-group parts, Part A and Part B, in adults and children with confirmed and uncomplicated Plasmodium falciparum malaria. Each part (PK Run-in, Part A and Part B) had the same design structure: A screening phase of up to 24 hours where participants were evaluated for eligibility and randomized (Part A and B) into different cohorts. A treatment phase of up to 3 days where participants were treated for 1, 2 or 3 consecutive days. Finally, participants were followed up until Day 43, where the rescue medication was the local standard at the discretion of the Investigator and participants

PK Run-in part: Adult/adolescent participants (≥ 12 years old) were dosed with a single dose of 200 mg KAF156 and 960 mg LUM-SDF at Day 1. The purpose of this part was to assess potential PK interactions between the compounds when dosed together.

Part A: Adult/adolescent participants (≥ 12 years old) were randomized into one of seven cohorts in a 2:2:2:2:2:2:1 ratio: six KAF156 and LUM-SDF cohorts at starting doses of 400 mg and 480 mg once daily (QD) for 1 day respectively and a control arm (Coartem twice a day (BID) for 3 days). Upon completion of Part A, all the dosing groups were evaluated in an interim assessment to determine the effective and tolerated KAF156 and LUM-SDF dosing regimen and dosages to be used in Part B.

Part B: Children participants (2 to \< 12 years old) were randomized to three KAF156 and LUM-SDF cohorts at dosages and dosing regimens selected from Part A and the control arm (Coartem) in a 2:2:2:1 ratio.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 524

Inclusion Criteria

Part A: male and female patients ≥ 12 years and with a body weight ≥ 35.0 kg. Part B: after determining the effective/tolerated doses and regimens in adolescent and adult patients, male and female patients ≥ 2 and < 12 years and with a body weight ≥ 10.0 kg will be included.
Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films.
P. falciparum parasitaemia of more than 1000 and less than 150 000 parasites/µL at the time of pre-screening (i.e., Study Visit 1).
Axillary temperature ≥ 37.5 ºC or oral/tympanic/rectal temperature ≥ 38.3 ºC; or similar history of fever during the previous 24 hours (history of fever must be documented).
Written informed consent must be obtained before any assessment is performed. If the patient is unable to read and write, then a witnessed consent according to local ethical standards is permitted. Patients < 18 years old, who are capable of providing assent, must provide assent with parental/legal guardian consent or as per local ethical guidelines.

Exclusion Criteria

Mixed Plasmodium infections.
Signs and symptoms of severe malaria according to WHO (World Health Organization) 2015 criteria unless characterized by high parasitaemia only.
Patients with concurrent febrile illnesses (e.g., typhoid fever).
Severe 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 per day.
Pregnant or nursing (lactating) women.
Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia.
Anemia (Hemoglobin level < 8 g/dL).
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).
History or family history of long QT syndrome or sudden cardiac death, or any other clinical condition known to prolong the QTc (heart rate-corrected QT) interval, such as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe heart disease.
Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, 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 > 2 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day	KAF156	Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg
Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day	Lumefantrine Solid Dispersion Formulation	Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg
Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 days	KAF156	Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days
Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 days	Lumefantrine Solid Dispersion Formulation	Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days
Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 days	Lumefantrine Solid Dispersion Formulation	Participants received KAF156 400 mg and LUM-SDF 480 mg once daily via oral administration for 3 days
Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 days	KAF156	Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days
PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 day	KAF156	Participants received a single oral dose of KAF156 200 mg and LUM-SDF 960 mg
Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day	KAF156	Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg
Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 days	KAF156	Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days
Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 days	KAF156	Participants received KAF156 400 mg and LUM-SDF 480 mg once daily via oral administration for 3 days
Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 days	Lumefantrine Solid Dispersion Formulation	Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days
Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 days	KAF156	Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days
Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 days	Lumefantrine Solid Dispersion Formulation	Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days
Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 day	Lumefantrine Solid Dispersion Formulation	Participants received a single oral dose of KAF156 800 mg and LUM-SDF 960 mg
Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 days	Lumefantrine Solid Dispersion Formulation	Participants received KAF156 200 mg and LUM-SDF 480 mg once daily via oral administration for 3 days
Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 days	Lumefantrine Solid Dispersion Formulation	Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days
PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 day	Lumefantrine Solid Dispersion Formulation	Participants received a single oral dose of KAF156 200 mg and LUM-SDF 960 mg
Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day	Lumefantrine Solid Dispersion Formulation	Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg
Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 day	KAF156	Participants received a single oral dose of KAF156 800 mg and LUM-SDF 960 mg
Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 days	KAF156	Participants received KAF156 200 mg and LUM-SDF 480 mg once daily via oral administration for 3 days
Part A - Cohort 7: Coartem	Coartem	Participants received Coartem twice daily via oral administration for 3 days
Part B - Cohort 4: Coartem	Coartem	Participants received Coartem twice daily via oral administration for 3 days

Primary Outcome Measures

Name	Time	Method
Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29	28 days post first dose	PCR-corrected ACPR defined as the absence of parasitaemia was evaluated at Day 29 (i.e., 28 days post first dose) based on the short half-life of the study drugs. 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 Day 29 if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and was absence of parasitaemia on Day 29 irrespective of axillary temperature unless the presence of parasitaemia after 7 days was due to reinfection based on PCR. 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 matched with the parasite strain at baseline based on PCR.
PK Run-in: Area Under the Blood Concentration-time Curve Over the Last 24 Hours After Treatment Dose (AUC0-24h) of KAF156	0, 1, 3, 6, 12, 18 and 24 hours post-dose	Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. AUC0-24h was determined using non-compartmental methods.

Secondary Outcome Measures

Name	Time	Method
PK Run-in, Part A and Part B: Number of Participants With Parasitaemia	12, 24 and 48 hours post last dose	Parasitaemia is the quantitative content of parasites in the blood determined by microscopy examination validated methods. Only Plasmodium Falciparum asexual form is used for parasitaemia assessments.
PK Run-in, Part A and Part B: Parasite Clearance Time (PCT)	42 days post first dose	Parasite Clearance Time (PCT) is defined as the time from the first dose until the first total and continued disappearance of asexual parasite forms which remained at least a further 48 hours. In case a participant received rescue medication before (parasite) clearance, the time to event was censored at the first use of rescue medication.
Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR)	14, 28 and 42 days post first dose	PCR-uncorrected ACPR defined as the absence of parasitaemia was evaluated at days 15, 29 and 43 (i.e., 14, 28 and 42 days post first dose). A participant was considered as PCR-uncorrected ACPR at Days 15, 29 or 43 if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and was absence of parasitaemia on Days 15, 29 or 43 irrespective of axillary temperature.
Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR)	14 and 42 days post first dose	PCR-corrected ACPR defined as the absence of parasitaemia was evaluated at days 15 and 43 (i.e., 14 and 42 days post first dose). 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 Day 15 or Day 43 if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and was absence of parasitaemia on Day 15 or Day 43 irrespective of axillary temperature unless the presence of parasitaemia after 7 days was due to reinfection based on PCR. 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 matched with the parasite strain at baseline based on PCR.
Part A and Part B: Number of Participants With Recrudescence Events	42 days post first dose	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 must be confirmed by PCR analysis.
Part A and Part B: Number of Participants With Reinfection Events	42 days post first dose	Reinfection is defined as appearance of asexual parasites after clearance of initial infection with a genotype different from those parasites present at baseline. Reinfection must be confirmed by PCR analysis.
Part A and Part B: Fever Clearance Time (FCT)	42 days post first dose	Fever Clearance Time (FCT) is defined as the 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. In case a participant received rescue medication before (fever) clearance, the time to event was censored at the first use of rescue medication.
Part A and Part B: Area Under the Blood Concentration-time Curve Over the Last 24 Hours After Last Treatment Dose (AUC0-24h) of KAF156	3, 6, 18 and 24 hours post last dose	Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. AUC0-24h was determined using non-compartmental methods.
Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156	3, 6, 18, 24, 27, 30, 48, 51, 54, 68, 72 and 168 hours post last dose	Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. Cmax was determined using non-compartmental methods.
PK Run-in and Part A: Elimination Half-life (T½) of KAF156	0, 1, 3, 6, 12, 18, 24, 27, 30, 36, 48, 72, 96 and 168 hours post last dose	Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. T½ was determined using non-compartmental methods.
PK Run-in and Part A (Cohorts 1 and 2): Time to Reach Maximum Blood Concentrations (Tmax) of KAF156	0, 1, 3, 6, 12, 18, 24, 30, 48, 96 and 168 hours post last dose	Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. Tmax was determined using non-compartmental methods.