Acute Uncomplicated Plasmodium Falciparum Malaria
Conditions
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.
Interventions
DRUGKAF156
KAF156 comes in 100 mg tablets for oral administration. KAF156 was administered in combination with LUM-SDF once daily (QD) for 1, 2 or 3 days at 200 mg, 400 mg or 800 mg doses.
DRUGCoartem
Coartem comes as 20/120 mg dispersible tablets or 80/480 mg tablets for oral administration. Coartem was administered twice daily for 3 days as active comparator.
DRUGLumefantrine Solid Dispersion Formulation
LUM-SDF comes in 240 mg or 480 mg sachets for oral administration. LUM-SDF was administered in combination with KAF156 once daily (QD) for 1, 2 or 3 days at 480 mg or 960 mg doses.
Sponsors
Medicines for Malaria Venture
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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, 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Burkina Faso, Gabon, India, Kenya, Mali, Mozambique, Thailand, Uganda, Vietnam
Participant flow
Recruitment details
Participants were recruited from 13 sites in 10 countries.
Pre-assignment details
Before being enrolled in the study, participants underwent a prescreening evaluation to ascertain the Plasmodium falciparum parasitemia count.
Participants by arm
| Arm | Count |
|---|---|
| PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 Day Participants received a single oral dose of KAF156 200 mg and LUM-SDF 960 mg | 12 |
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg | 51 |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day Participants received a single oral dose of KAF156 800 mg and LUM-SDF 960 mg | 51 |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days | 51 |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days Participants received KAF156 200 mg and LUM-SDF 480 mg once daily via oral administration for 3 days | 54 |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days Participants received KAF156 400 mg and LUM-SDF 480 mg once daily via oral administration for 3 days | 51 |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days | 52 |
| Part A - Cohort 7: Coartem Participants received Coartem twice daily via oral administration for 3 days | 27 |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg | 53 |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days | 53 |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days | 45 |
| Part B - Cohort 4: Coartem Participants received Coartem twice daily via oral administration for 3 days | 24 |
| Total | 524 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 1 | 2 | 1 | 0 | 0 | 1 | 1 |
| Overall Study | Patient/Guardian Decision | 0 | 1 | 2 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Reason not provided | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 Day | Total | Part B - Cohort 4: Coartem | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 7: Coartem | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 17.8 Years STANDARD_DEVIATION 10.25 | 16.3 Years STANDARD_DEVIATION 12.1 | 5.9 Years STANDARD_DEVIATION 2.21 | 6.9 Years STANDARD_DEVIATION 2.6 | 6.2 Years STANDARD_DEVIATION 2.9 | 6.6 Years STANDARD_DEVIATION 2.86 | 20.9 Years STANDARD_DEVIATION 12.28 | 20.0 Years STANDARD_DEVIATION 9.49 | 20.3 Years STANDARD_DEVIATION 11.9 | 23.3 Years STANDARD_DEVIATION 14.68 | 21.1 Years STANDARD_DEVIATION 11.09 | 21.3 Years STANDARD_DEVIATION 10.69 | 22.3 Years STANDARD_DEVIATION 13.53 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 50 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 7 Participants | 7 Participants | 9 Participants | 7 Participants | 7 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 473 Participants | 24 Participants | 45 Participants | 52 Participants | 52 Participants | 23 Participants | 45 Participants | 44 Participants | 45 Participants | 43 Participants | 44 Participants | 44 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 6 Participants | 256 Participants | 15 Participants | 20 Participants | 29 Participants | 31 Participants | 13 Participants | 20 Participants | 25 Participants | 26 Participants | 21 Participants | 24 Participants | 26 Participants |
| Sex: Female, Male Male | 6 Participants | 268 Participants | 9 Participants | 25 Participants | 24 Participants | 22 Participants | 14 Participants | 32 Participants | 26 Participants | 28 Participants | 30 Participants | 27 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 51 | 0 / 54 | 0 / 51 | 0 / 103 | 0 / 104 | 0 / 97 | 0 / 51 |
| other Total, other adverse events | 7 / 12 | 37 / 51 | 30 / 54 | 32 / 51 | 69 / 103 | 68 / 104 | 59 / 97 | 30 / 51 |
| serious Total, serious adverse events | 0 / 12 | 1 / 51 | 2 / 54 | 1 / 51 | 7 / 103 | 5 / 104 | 2 / 97 | 3 / 51 |
Outcome results
Primary
Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29
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.
Time frame: 28 days post first dose
Population: All participants comprised in Per-protocol Set (PPS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | 46 Participants |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | 45 Participants |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | 47 Participants |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | 47 Participants |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | 44 Participants |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | 42 Participants |
| Part A - Cohort 7: Coartem | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | 25 Participants |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | 37 Participants |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | 42 Participants |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | 38 Participants |
| Part B - Cohort 4: Coartem | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 29 | 21 Participants |
Primary
PK Run-in: Area Under the Blood Concentration-time Curve Over the Last 24 Hours After Treatment Dose (AUC0-24h) of KAF156
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.
Time frame: 0, 1, 3, 6, 12, 18 and 24 hours post-dose
Population: Pharmacokinetics (PK) Analysis Set. Only participants with available PK data at the specified time point were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | PK Run-in: Area Under the Blood Concentration-time Curve Over the Last 24 Hours After Treatment Dose (AUC0-24h) of KAF156 | 5.35 hours*μg/mL | Geometric Coefficient of Variation 34.8 |
Secondary
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
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.
Time frame: 3, 6, 18 and 24 hours post last dose
Population: Pharmacokinetics (PK) Analysis Set. Only participants with available PK data at the specified time point were included in the analysis. As per study design, AUC0-24h was not determined for Part B cohorts 2 and 3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | 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 | 9.84 hours*μg/mL | Geometric Coefficient of Variation 41.5 |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | 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 | 21.7 hours*μg/mL | Geometric Coefficient of Variation 41.7 |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | 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 | 9.95 hours*μg/mL | Geometric Coefficient of Variation 131.9 |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | 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 | 5.91 hours*μg/mL | Geometric Coefficient of Variation 29.2 |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | 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 | 11 hours*μg/mL | Geometric Coefficient of Variation 79.3 |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | 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 | 10.9 hours*μg/mL | Geometric Coefficient of Variation 57.4 |
| Part A - Cohort 7: Coartem | 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 | 11 hours*μg/mL | Geometric Coefficient of Variation 47.7 |
Secondary
Part A and Part B: Fever Clearance Time (FCT)
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.
Time frame: 42 days post first dose
Population: Full Analysis Set (FAS). Only participants with fever at baseline and post-baseline assessment of fever clearance at the time point were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Fever Clearance Time (FCT) | 18.7 Hours | Standard Error 3.09 |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Fever Clearance Time (FCT) | 22.5 Hours | Standard Error 6.09 |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Fever Clearance Time (FCT) | 20.3 Hours | Standard Error 4.92 |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Fever Clearance Time (FCT) | 16.6 Hours | Standard Error 3.48 |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Fever Clearance Time (FCT) | 17.5 Hours | Standard Error 2.65 |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Fever Clearance Time (FCT) | 19.2 Hours | Standard Error 2.92 |
| Part A - Cohort 7: Coartem | Part A and Part B: Fever Clearance Time (FCT) | 26.3 Hours | Standard Error 7.67 |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Fever Clearance Time (FCT) | 23.5 Hours | Standard Error 10.26 |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Fever Clearance Time (FCT) | 17.3 Hours | Standard Error 7.4 |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Fever Clearance Time (FCT) | 13.8 Hours | Standard Error 3.68 |
| Part B - Cohort 4: Coartem | Part A and Part B: Fever Clearance Time (FCT) | 22.9 Hours | Standard Error 12.78 |
Secondary
Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156
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.
Time frame: 3, 6, 18, 24, 27, 30, 48, 51, 54, 68, 72 and 168 hours post last dose
Population: Pharmacokinetics (PK) Analysis Set. Only participants with available PK data at the specified time point were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156 | 653 ng/mL | Geometric Coefficient of Variation 43.9 |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156 | 1470 ng/mL | Geometric Coefficient of Variation 46.5 |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156 | 1060 ng/mL | Geometric Coefficient of Variation 83.9 |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156 | 665 ng/mL | Geometric Coefficient of Variation 30.3 |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156 | 1470 ng/mL | Geometric Coefficient of Variation 30.9 |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156 | 1320 ng/mL | Geometric Coefficient of Variation 32.7 |
| Part A - Cohort 7: Coartem | Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156 | 714 ng/mL | Geometric Coefficient of Variation 49.4 |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156 | 1060 ng/mL | Geometric Coefficient of Variation 48.4 |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156 | 1380 ng/mL | Geometric Coefficient of Variation 29.7 |
Secondary
Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR)
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.
Time frame: 14 and 42 days post first dose
Population: All participants comprised in Per-protocol Set (PPS)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 48 Participants |
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 45 Participants |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 46 Participants |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 44 Participants |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 48 Participants |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 46 Participants |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 47 Participants |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 46 Participants |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 44 Participants |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 43 Participants |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 41 Participants |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 43 Participants |
| Part A - Cohort 7: Coartem | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 24 Participants |
| Part A - Cohort 7: Coartem | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 25 Participants |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 47 Participants |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 36 Participants |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 45 Participants |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 37 Participants |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 40 Participants |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 37 Participants |
| Part B - Cohort 4: Coartem | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 22 Participants |
| Part B - Cohort 4: Coartem | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 20 Participants |
Secondary
Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR)
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.
Time frame: 14, 28 and 42 days post first dose
Population: All participants comprised in Full Analysis Set (FAS)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 28 post first dose | 46 Participants |
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 49 Participants |
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 42 Participants |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 28 post first dose | 40 Participants |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 36 Participants |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 47 Participants |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 45 Participants |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 28 post first dose | 48 Participants |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 51 Participants |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 28 post first dose | 51 Participants |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 53 Participants |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 45 Participants |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 41 Participants |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 50 Participants |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 28 post first dose | 45 Participants |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 28 post first dose | 47 Participants |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 51 Participants |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 45 Participants |
| Part A - Cohort 7: Coartem | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 27 Participants |
| Part A - Cohort 7: Coartem | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 28 post first dose | 26 Participants |
| Part A - Cohort 7: Coartem | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 19 Participants |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 51 Participants |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 28 post first dose | 34 Participants |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 29 Participants |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 33 Participants |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 52 Participants |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 28 post first dose | 41 Participants |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 43 Participants |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 31 Participants |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 28 post first dose | 36 Participants |
| Part B - Cohort 4: Coartem | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 42 post first dose | 11 Participants |
| Part B - Cohort 4: Coartem | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 14 post first dose | 24 Participants |
| Part B - Cohort 4: Coartem | Part A and Part B: Number of Participants With Polymerase Chain Reaction (PCR)-Uncorrected Adequate Clinical and Parasitological Response (ACPR) | Day 28 post first dose | 15 Participants |
Secondary
Part A and Part B: 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 must be confirmed by PCR analysis.
Time frame: 42 days post first dose
Population: All participants comprised in Full Analysis Set (FAS).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Recrudescence Events | 4 Participants |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Recrudescence Events | 3 Participants |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Recrudescence Events | 1 Participants |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Recrudescence Events | 1 Participants |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Recrudescence Events | 0 Participants |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Recrudescence Events | 2 Participants |
| Part A - Cohort 7: Coartem | Part A and Part B: Number of Participants With Recrudescence Events | 0 Participants |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Recrudescence Events | 12 Participants |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Recrudescence Events | 7 Participants |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Recrudescence Events | 3 Participants |
| Part B - Cohort 4: Coartem | Part A and Part B: Number of Participants With Recrudescence Events | 2 Participants |
Secondary
Part A and Part B: Number of Participants With Reinfection Events
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.
Time frame: 42 days post first dose
Population: All participants comprised in Full Analysis Set (FAS).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Reinfection Events | 3 Participants |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Reinfection Events | 7 Participants |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Reinfection Events | 4 Participants |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Reinfection Events | 7 Participants |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A and Part B: Number of Participants With Reinfection Events | 8 Participants |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Reinfection Events | 2 Participants |
| Part A - Cohort 7: Coartem | Part A and Part B: Number of Participants With Reinfection Events | 8 Participants |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: Number of Participants With Reinfection Events | 11 Participants |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: Number of Participants With Reinfection Events | 10 Participants |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Number of Participants With Reinfection Events | 9 Participants |
| Part B - Cohort 4: Coartem | Part A and Part B: Number of Participants With Reinfection Events | 10 Participants |
Secondary
PK Run-in and Part A (Cohorts 1 and 2): Time to Reach Maximum Blood Concentrations (Tmax) of KAF156
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.
Time frame: 0, 1, 3, 6, 12, 18, 24, 30, 48, 96 and 168 hours post last dose
Population: Rich Pharmacokinetics (PK) Analysis subset. Only participants with available PK data at the specified time point were included in the analysis. As per study design, Tmax was only determined per PK Run-in and Part A cohorts 1 and 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | PK Run-in and Part A (Cohorts 1 and 2): Time to Reach Maximum Blood Concentrations (Tmax) of KAF156 | 4.23 Hours | Standard Deviation 1.55 |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | PK Run-in and Part A (Cohorts 1 and 2): Time to Reach Maximum Blood Concentrations (Tmax) of KAF156 | 39.8 Hours | Standard Deviation 77.3 |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | PK Run-in and Part A (Cohorts 1 and 2): Time to Reach Maximum Blood Concentrations (Tmax) of KAF156 | 5.99 Hours | Standard Deviation 3.11 |
Secondary
PK Run-in and Part A: Elimination Half-life (T½) of KAF156
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.
Time frame: 0, 1, 3, 6, 12, 18, 24, 27, 30, 36, 48, 72, 96 and 168 hours post last dose
Population: Rich Pharmacokinetics (PK) Analysis subset. Only participants with available PK data at the specified time point were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | PK Run-in and Part A: Elimination Half-life (T½) of KAF156 | 25.0 Hours | Standard Deviation 8.81 |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | PK Run-in and Part A: Elimination Half-life (T½) of KAF156 | 25.4 Hours | Standard Deviation 5.32 |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | PK Run-in and Part A: Elimination Half-life (T½) of KAF156 | 29.9 Hours | Standard Deviation 9.95 |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | PK Run-in and Part A: Elimination Half-life (T½) of KAF156 | 31.0 Hours | Standard Deviation 3.86 |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | PK Run-in and Part A: Elimination Half-life (T½) of KAF156 | 35.8 Hours | Standard Deviation 19.4 |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | PK Run-in and Part A: Elimination Half-life (T½) of KAF156 | 28.4 Hours | Standard Deviation 3.49 |
| Part A - Cohort 7: Coartem | PK Run-in and Part A: Elimination Half-life (T½) of KAF156 | 26.6 Hours | Standard Deviation 4.15 |
Secondary
PK Run-in, Part A and Part B: Number of Participants With Parasitaemia
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.
Time frame: 12, 24 and 48 hours post last dose
Population: Full Analysis Set (FAS). Only participants with assessment of parasitaemia at the timepoint were included in the analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 24 hours post last dose | 11 Participants |
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 12 hours post last dose | 12 Participants |
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 48 hours post last dose | 3 Participants |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 12 hours post last dose | 46 Participants |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 48 hours post last dose | 13 Participants |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 24 hours post last dose | 39 Participants |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 48 hours post last dose | 9 Participants |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 12 hours post last dose | 46 Participants |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 24 hours post last dose | 41 Participants |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 12 hours post last dose | 44 Participants |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 24 hours post last dose | 38 Participants |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 48 hours post last dose | 8 Participants |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 24 hours post last dose | 46 Participants |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 48 hours post last dose | 12 Participants |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 12 hours post last dose | 52 Participants |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 12 hours post last dose | 49 Participants |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 48 hours post last dose | 10 Participants |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 24 hours post last dose | 42 Participants |
| Part A - Cohort 7: Coartem | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 12 hours post last dose | 49 Participants |
| Part A - Cohort 7: Coartem | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 48 hours post last dose | 11 Participants |
| Part A - Cohort 7: Coartem | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 24 hours post last dose | 34 Participants |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 24 hours post last dose | 14 Participants |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 48 hours post last dose | 4 Participants |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 12 hours post last dose | 22 Participants |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 24 hours post last dose | 41 Participants |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 12 hours post last dose | 48 Participants |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 48 hours post last dose | 4 Participants |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 24 hours post last dose | 42 Participants |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 12 hours post last dose | 48 Participants |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 48 hours post last dose | 10 Participants |
| Part B - Cohort 4: Coartem | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 24 hours post last dose | 36 Participants |
| Part B - Cohort 4: Coartem | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 12 hours post last dose | 42 Participants |
| Part B - Cohort 4: Coartem | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 48 hours post last dose | 5 Participants |
| Part B - Cohort 4: Coartem | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 12 hours post last dose | 22 Participants |
| Part B - Cohort 4: Coartem | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 24 hours post last dose | 17 Participants |
| Part B - Cohort 4: Coartem | PK Run-in, Part A and Part B: Number of Participants With Parasitaemia | 48 hours post last dose | 1 Participants |
Secondary
PK Run-in, Part A and Part B: Parasite Clearance Time (PCT)
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.
Time frame: 42 days post first dose
Population: All participants comprised in Full Analysis Set (FAS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 49.9 Hours | Standard Error 4.35 |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 48.4 Hours | Standard Error 3.5 |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 46.6 Hours | Standard Error 3.93 |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 39.9 Hours | Standard Error 2.46 |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 51.4 Hours | Standard Error 3.97 |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 49.7 Hours | Standard Error 3.72 |
| Part A - Cohort 7: Coartem | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 48.1 Hours | Standard Error 4.24 |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 50.0 Hours | Standard Error 12.82 |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 42.6 Hours | Standard Error 2.62 |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 47.0 Hours | Standard Error 2.79 |
| Part B - Cohort 4: Coartem | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 41.9 Hours | Standard Error 2.58 |
| Part B - Cohort 4: Coartem | PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 35.6 Hours | Standard Error 2.82 |