A Phase 2 interventional study of KAF156 and Coartem in Acute Uncomplicated Plasmodium Falciparum Malaria, sponsored by Novartis Pharmaceuticals. Completed at 11 sites in 9 countries. Open to participants aged 2 Years and older. Per ClinicalTrials.gov, last updated 2022-02-10.
Sponsored by Novartis Pharmaceuticals · Phase 2, Interventional, and Treatment
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.
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.
Exclusion Criteria:
Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg
Drug: KAF156 · Drug: Lumefantrine Solid Dispersion Formulation
Participants received a single oral dose of KAF156 800 mg and LUM-SDF 960 mg
Drug: KAF156 · Drug: Lumefantrine Solid Dispersion Formulation
Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days
Drug: KAF156 · Drug: Lumefantrine Solid Dispersion Formulation
Participants received KAF156 200 mg and LUM-SDF 480 mg once daily via oral administration for 3 days
Drug: KAF156 · Drug: Lumefantrine Solid Dispersion Formulation
Participants received KAF156 400 mg and LUM-SDF 480 mg once daily via oral administration for 3 days
Drug: KAF156 · Drug: Lumefantrine Solid Dispersion Formulation
Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days
Drug: KAF156 · Drug: Lumefantrine Solid Dispersion Formulation
Participants received Coartem twice daily via oral administration for 3 days
Drug: Coartem
Participants received a single oral dose of KAF156 200 mg and LUM-SDF 960 mg
Drug: KAF156 · Drug: Lumefantrine Solid Dispersion Formulation
Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg
Drug: KAF156 · Drug: Lumefantrine Solid Dispersion Formulation
Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days
Drug: KAF156 · Drug: Lumefantrine Solid Dispersion Formulation
Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days
Drug: KAF156 · Drug: Lumefantrine Solid Dispersion Formulation
Participants received Coartem twice daily via oral administration for 3 days
Drug: Coartem
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.
Also known as: KAF
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.
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.
Also known as: LUM-SDF and LUM
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
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
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
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
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
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
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
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
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
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
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
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
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
Participants were recruited from 13 sites in 10 countries.
| Milestone | PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 7: Coartem | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 4: Coartem |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Started | 12 | 51 | 51 | 51 | 54 | 51 | 52 | 27 | 53 | 53 | 45 | 24 |
| Full analysis set (fas) | 12 | 51 | 51 | 51 | 54 | 51 | 52 | 27 | 52 | 53 | 45 | 24 |
| Pharmacokinetics (pk) analysis set | 12 | 47 | 51 | 46 | 48 | 46 | 45 | 24 | 48 | 46 | 41 | 24 |
| Per-protocol set (pps) | 12 | 50 | 48 | 48 | 47 | 44 | 43 | 25 | 48 | 46 | 40 | 22 |
| Rich pharmacokinetics (pk) analysis subset | 12 | 5 | 6 | 6 | 6 | 12 | 5 | 0 | 0 | 0 | 0 | 0 |
| Completed | 12 | 50 | 48 | 50 | 53 | 49 | 50 | 26 | 52 | 53 | 43 | 23 |
| Not completed | 0 | 1 | 3 | 1 | 1 | 2 | 2 | 1 | 1 | 0 | 2 | 1 |
| Withdrew: Patient/guardian decision | 0 | 1 | 2 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Lost to follow-up | 0 | 0 | 1 | 0 | 0 | 1 | 2 | 1 | 0 | 0 | 1 | 1 |
| Withdrew: Reason not provided | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
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.
| Participants | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 7: Coartem | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | 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 | 46 | 45 | 47 | 47 | 44 | 42 | 25 | 37 | 42 | 38 | 21 |
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.
| hours*μg/mL | PK Run-in Cohort: KAF 200 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 ± 34.8 |
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.
| Participants | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 7: Coartem | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 4: Coartem |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 14 post first dose | 49 | 47 | 51 | 53 | 50 | 51 | 27 | 51 | 52 | 43 | 24 |
| Day 28 post first dose | 46 | 40 | 48 | 51 | 45 | 47 | 26 | 34 | 41 | 36 | 15 |
| Day 42 post first dose | 42 | 36 | 45 | 45 | 41 | 45 | 19 | 29 | 33 | 31 | 11 |
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.
| Participants | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 7: Coartem | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 4: Coartem |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 14 post first dose | 48 | 46 | 48 | 47 | 44 | 43 | 25 | 47 | 45 | 40 | 22 |
| Day 42 post first dose | 45 | 44 | 46 | 46 | 43 | 41 | 24 | 36 | 37 | 37 | 20 |
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.
| Participants | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 7: Coartem | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 4: Coartem |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Part A and Part B: Number of Participants With Recrudescence Events | 4 | 3 | 1 | 1 | 0 | 2 | 0 | 12 | 7 | 3 | 2 |
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.
| Participants | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 7: Coartem | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 4: Coartem |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Part A and Part B: Number of Participants With Reinfection Events | 3 | 7 | 4 | 7 | 8 | 2 | 8 | 11 | 10 | 9 | 10 |
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.
| Hours | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 7: Coartem | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 4: Coartem |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Part A and Part B: Fever Clearance Time (FCT) | 18.7 ± 3.09 | 22.5 ± 6.09 | 20.3 ± 4.92 | 16.6 ± 3.48 | 17.5 ± 2.65 | 19.2 ± 2.92 | 26.3 ± 7.67 | 23.5 ± 10.26 | 17.3 ± 7.4 | 13.8 ± 3.68 | 22.9 ± 12.78 |
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.
| Hours | PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 7: Coartem | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 4: Coartem |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PK Run-in, Part A and Part B: Parasite Clearance Time (PCT) | 49.9 ± 4.35 | 48.4 ± 3.5 | 46.6 ± 3.93 | 39.9 ± 2.46 | 51.4 ± 3.97 | 49.7 ± 3.72 | 48.1 ± 4.24 | 50.0 ± 12.82 | 42.6 ± 2.62 | 47.0 ± 2.79 | 41.9 ± 2.58 | 35.6 ± 2.82 |
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.
| Participants | PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 7: Coartem | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 4: Coartem |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 12 hours post last dose | 12 | 46 | 46 | 44 | 52 | 49 | 49 | 22 | 48 | 48 | 42 | 22 |
| 24 hours post last dose | 11 | 39 | 41 | 38 | 46 | 42 | 34 | 14 | 41 | 42 | 36 | 17 |
| 48 hours post last dose | 3 | 13 | 9 | 8 | 12 | 10 | 11 | 4 | 4 | 10 | 5 | 1 |
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.
| hours*μg/mL | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: 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 | 9.84 ± 41.5 | 21.7 ± 41.7 | 9.95 ± 131.9 | 5.91 ± 29.2 | 11 ± 79.3 | 10.9 ± 57.4 | 11 ± 47.7 | — | — |
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.
| ng/mL | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days |
|---|---|---|---|---|---|---|---|---|---|
| Part A and Part B: Maximum Peak Observed Concentration (Cmax) of KAF156 | 653 ± 43.9 | 1470 ± 46.5 | 1060 ± 83.9 | 665 ± 30.3 | 1470 ± 30.9 | 1320 ± 32.7 | 714 ± 49.4 | 1060 ± 48.4 | 1380 ± 29.7 |
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.
| Hours | PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | 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 | 25.0 ± 8.81 | 25.4 ± 5.32 | 29.9 ± 9.95 | 31.0 ± 3.86 | 35.8 ± 19.4 | 28.4 ± 3.49 | 26.6 ± 4.15 |
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.
| Hours | PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | 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 | 4.23 ± 1.55 | 39.8 ± 77.3 | 5.99 ± 3.11 |
Collected over Adverse events were reported from Day 1 to Day 43, where Day 43 could be 42, 41 or 40 days after end of treatment depending on whether the participant received treatment during 1, 2 or 3 consecutive days respectively.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| PK Run-in: KAF 200 mg and LUM 960 mg QD for 1 Day | 0/12 (0%) | 0/12 (0%) | 7/12 (58.3%) |
| Part A: KAF 800 mg and LUM 960 mg QD for 1 Day | 0/51 (0%) | 1/51 (2%) | 37/51 (72.5%) |
| Part A: KAF 200 mg and LUM 480 mg QD for 3 Days | 0/54 (0%) | 2/54 (3.7%) | 30/54 (55.6%) |
| Part A: KAF 400 mg and LUM 480 mg QD for 3 Days | 0/51 (0%) | 1/51 (2%) | 32/51 (62.7%) |
| Part A and Part B: KAF 400 mg and LUM 960 mg QD for 1 Day | 0/103 (0%) | 7/103 (6.8%) | 69/103 (67%) |
| Part A and Part B: KAF 400 mg and LUM 960 mg QD for 2 Days | 0/104 (0%) | 5/104 (4.8%) | 68/104 (65.4%) |
| Part A and Part B: KAF 400 mg and LUM 960 mg QD for 3 Days | 0/97 (0%) | 2/97 (2.1%) | 59/97 (60.8%) |
| Part A and Part B: Coartem | 0/51 (0%) | 3/51 (5.9%) | 30/51 (58.8%) |
| Event | PK Run-in: KAF 200 mg and LUM 960 mg QD for 1 Day | Part A: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A and Part B: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Coartem |
|---|---|---|---|---|---|---|---|---|
| Blood alkaline phosphatase increasedInvestigations | 0/12 | 0/51 | 1/54 | 0/51 | 3/103 | 2/104 | 0/97 | 3/51 |
| Blood bilirubin increasedInvestigations | 0/12 | 0/51 | 0/54 | 0/51 | 2/103 | 2/104 | 1/97 | 2/51 |
| AnaemiaBlood and lymphatic system disorders | 0/12 | 0/51 | 0/54 | 1/51 | 0/103 | 1/104 | 0/97 | 0/51 |
| Plasmodium falciparum infectionInfections and infestations | 0/12 | 1/51 | 0/54 | 0/51 | 0/103 | 0/104 | 0/97 | 0/51 |
| Alanine aminotransferase increasedInvestigations | 0/12 | 0/51 | 0/54 | 0/51 | 0/103 | 0/104 | 0/97 | 1/51 |
| Aspartate aminotransferaseInvestigations | 0/12 | 0/51 | 1/54 | 0/51 | 0/103 | 0/104 | 0/97 | 0/51 |
| PneumoniaInfections and infestations | 0/12 | 0/51 | 0/54 | 0/51 | 0/103 | 0/104 | 1/97 | 0/51 |
| PetechiaeSkin and subcutaneous tissue disorders | 0/12 | 0/51 | 0/54 | 0/51 | 0/103 | 0/104 | 1/97 | 0/51 |
| Hepatitis acuteHepatobiliary disorders | 0/12 | 0/51 | 0/54 | 0/51 | 1/103 | 0/104 | 0/97 | 0/51 |
| JaundiceHepatobiliary disorders | 0/12 | 0/51 | 0/54 | 0/51 | 1/103 | 0/104 | 0/97 | 0/51 |
| Event | PK Run-in: KAF 200 mg and LUM 960 mg QD for 1 Day | Part A: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A and Part B: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A and Part B: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A and Part B: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A and Part B: Coartem |
|---|---|---|---|---|---|---|---|---|
| MalariaInfections and infestations | 0/12 | 8/51 | 4/54 | 6/51 | 28/103 | 25/104 | 16/97 | 18/51 |
| Blood phosphorus increasedInvestigations | 4/12 | 0/51 | 1/54 | 0/51 | 0/103 | 0/104 | 0/97 | 0/51 |
| HeadacheNervous system disorders | 0/12 | 10/51 | 15/54 | 7/51 | 16/103 | 13/104 | 14/97 | 7/51 |
| PyrexiaGeneral disorders | 0/12 | 5/51 | 4/54 | 6/51 | 20/103 | 18/104 | 9/97 | 13/51 |
| Electrocardiogram QT prolongedInvestigations | 1/12 | 5/51 | 9/54 | 9/51 | 5/103 | 6/104 | 9/97 | 3/51 |
| VomitingGastrointestinal disorders | 0/12 | 8/51 | 2/54 | 3/51 | 8/103 | 9/104 | 8/97 | 2/51 |
| Upper respiratory tract infectionInfections and infestations | 0/12 | 6/51 | 5/54 | 3/51 | 15/103 | 12/104 | 12/97 | 5/51 |
| Abdominal painGastrointestinal disorders | 0/12 | 3/51 | 2/54 | 7/51 | 3/103 | 5/104 | 4/97 | 0/51 |
| ThrombocytopeniaBlood and lymphatic system disorders | 0/12 | 3/51 | 1/54 | 5/51 | 1/103 | 1/104 | 0/97 | 2/51 |
| CoughRespiratory, thoracic and mediastinal disorders | 0/12 | 3/51 | 3/54 | 5/51 | 7/103 | 10/104 | 6/97 | 4/51 |
| Age, Continuous(Years) | PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 7: Coartem | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 4: Coartem | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean | 17.8 ± 10.25 | 22.3 ± 13.53 | 21.3 ± 10.69 | 21.1 ± 11.09 | 23.3 ± 14.68 | 20.3 ± 11.90 | 20.0 ± 9.49 | 20.9 ± 12.28 | 6.6 ± 2.86 | 6.2 ± 2.90 | 6.9 ± 2.60 | 5.9 ± 2.21 | 16.3 ± 12.10 |
| Sex: Female, Male(Participants) | PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 7: Coartem | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 4: Coartem | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Female | 6 | 26 | 24 | 21 | 26 | 25 | 20 | 13 | 31 | 29 | 20 | 15 | 256 |
| Male | 6 | 25 | 27 | 30 | 28 | 26 | 32 | 14 | 22 | 24 | 25 | 9 | 268 |
| Race (NIH/OMB)(Participants) | PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 Day | Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 Days | Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 Days | Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 Days | Part A - Cohort 7: Coartem | Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 Day | Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 Days | Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 Days | Part B - Cohort 4: Coartem | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 7 | 7 | 7 | 9 | 7 | 7 | 4 | 1 | 1 | 0 | 0 | 50 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 12 | 44 | 44 | 43 | 45 | 44 | 45 | 23 | 52 | 52 | 45 | 24 | 473 |
| White | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
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