Malaria
Conditions
Keywords
uncomplicated Plasmodium falciparum Malaria.
Brief summary
KAE609 will be evaluated primarily for hepatic safety of single and multiple doses in sequential cohorts with increasing doses.This study aims to determine the maximum safe dose of the investigational drug KAE609 in malaria patients.
Interventions
Sponsors
Wellcome Trust
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Patients were randomized to KAE609 and Coartem in parallel treatment arms. Increasing doses of KAE609 (single dose and multiple dose) were evaluated in dose escalated manner in sequential cohorts
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
KEY Inclusion Criteria: 1. Male and female patients ≥ 18 years with a body weight ≥ 45 kg. 2. Microscopic confirmation of acute uncomplicated P. falciparum using by Giemsa-stained thick film. 3. P. falciparum parasitaemia of 500 to 50 000 parasites/µL. 4. Axillary temperature ≥ 37.5ºC or oral/tympanic/rectal temperature ≥ 38.0ºC; or history of fever during the previous 24 hours. 5. Written informed consent must be obtained before any study assessment is performed. If the patient is unable to write, then a witnessed consent according to local ethical standards is permitted. KEY
Exclusion criteria
1. Mixed Plasmodium infections. 2. Signs and symptoms of severe malaria according to World Health Organization (WHO) 2016 criteria (WHO 2016). 3. Known liver abnormalities, liver cirrhosis (compensated or decompensated), known active or history of hepatitis B or C (testing not required), known gallbladder or bile duct disease, acute or chronic pancreatitis. 4. Clinical or laboratory evidence of any of the following: 5. AST/ALT \> 1.5 x the upper limit of normal range (ULN), regardless of the level of total bilirubin 6. AST/ALT \> 1.0 and ≤ 1.5 x ULN and total bilirubin is \> ULN 7. Total bilirubin \> 2 x ULN, regardless of the level of AST/ALT 8. History of photodermatitis/increased sensitivity to sun. 9. Pregnant or nursing (lactating) women. 10. Known disturbances of electrolyte balance, e.g. hypokalemia, hypocalcemia or hypomagnesemia. 11. Moderate to severe anemia (Hemoglobin level \<8 g/dL). Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) | Day 29 | The occurrence of at least 2 CTCAE grades increase from baseline in ALT or AST during the 4 weeks study period was evaluated to characterize hepatic safety aspects of single and multiple ascending doses of KAE609 in adult malaria subjects for treatment of uncomplicated malaria caused by plasmodium falciparum. If 2 patients in a 10 patient cohort (Cohorts 1 and 2) or 3 patients in a 20 patient cohort (Cohorts 3, 4 and 5) had at least 2 CTCAE grades increase from Baseline in ALT or AST, recruitment was suspended and a review of liver safety (and any other relevant data) by safety review committee was initiated. Any further progression of the study was based on the decision by the safety review committee. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parasite Clearance Time (PCT) | Day 29 | 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 patient received rescue medication before (parasite) clearance, the time to event was censored at the first use of rescue medication. |
| Fever Clearance Time (FCT) | Day 29 | 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 patient received rescue medication before (fever) clearance, the time to event was censored at the first use of rescue medication. |
| Time to Recrudescence and Reinfection at Study Day 29 | Day 29 | Time to recrudescence is calculated from the date of first study medication to the date of first event. Participants without recrudescence/reinfection after Day 7 are censored at the time of treatment failure or at the time of last parasite assessment if no treatment failure occured. |
| Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15, Day 29 | PCR-corrected and PCR-uncorrected were evaluated at Days 15 and 29 (i.e., 14 and 28 days post-dose). The presence of parasitaemia after 7 days due to reinfection was considered as PCR-corrected ACPR. Missing blood smear data at Day 15 visit and thereafter were not considered as responder for the visit unless there was a later blood smear test indicating no parasitaemia. |
| Tmax | Day 1, Day 3 | Tmax |
| AUC0-24 | Day 1, Day 3 | AUC0-24 |
| Half-life (T^1/2) | Upto day 15 post dose | Half-life (T\^1/2) |
| Maximum Peak Observed Concentration (Cmax) | Day 1, Day 3 | Maximum Peak Observed Concentration (Cmax) |
Countries
Gabon, Ghana, Mali, Rwanda, Uganda
Participant flow
Recruitment details
This study was conducted in 10 centers in 5 countries: Mali (2), Uganda (3), Ghana (2), Gabon (1), Rwanda (2).
Pre-assignment details
Approximately, 210 patients were planned to be randomized in six cohorts (KAE609: 150 and Coartem: 60). A total of 188 (KAE609: 137 and Coartem: 51) subjects were randomized in five cohorts. Cohort 6 was optional and never initiated. Two of the 188 randomized subjects were not treated and therefore were excluded from all analyses.
Participants by arm
| Arm | Count |
|---|---|
| KAE609 10 mg SD KAE609 10 mg once daily (QD) for 1 day | 10 |
| KAE609 10 mg QD 3 Days KAE609 10 mg (QD) for 3 days | 10 |
| KAE609 25 mg SD KAE609 25 mg once daily (QD) for 1 day | 12 |
| KAE609 25 mg QD 3 Days KAE609 25 mg once daily (QD) for 3 days | 20 |
| KAE609 50 mg SD KAE609 50 mg once daily (QD) for 1 day | 22 |
| KAE609 50 mg QD 3 Days KAE609 50 mg once daily (QD) for 3 days | 20 |
| KAE609 75 mg SD KAE609 75 mg once daily (QD) for 1 day | 21 |
| KAE609 150 mg SD KAE609 150 mg once daily (QD) for 1 day | 22 |
| Pooled Coartem Control control arm | 51 |
| Total | 188 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Follow-Up Phase | Subject/guardian decision | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| Treatment Phase | Subject/guardian decision | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Treatment Phase | Technical problems | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | KAE609 10 mg SD | KAE609 10 mg QD 3 Days | KAE609 25 mg SD | KAE609 25 mg QD 3 Days | KAE609 50 mg SD | KAE609 50 mg QD 3 Days | KAE609 75 mg SD | KAE609 150 mg SD | Pooled Coartem Control | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 31.5 Years STANDARD_DEVIATION 10.48 | 35.4 Years STANDARD_DEVIATION 13.25 | 33.0 Years STANDARD_DEVIATION 14.96 | 31.9 Years STANDARD_DEVIATION 10.67 | 33.9 Years STANDARD_DEVIATION 12.56 | 26.4 Years STANDARD_DEVIATION 7.18 | 28.2 Years STANDARD_DEVIATION 10.25 | 30.6 Years STANDARD_DEVIATION 12.57 | 26.2 Years STANDARD_DEVIATION 9.07 | 29.7 Years STANDARD_DEVIATION 11.07 |
| Race/Ethnicity, Customized Black or African American | 10 Participants | 10 Participants | 12 Participants | 20 Participants | 22 Participants | 20 Participants | 21 Participants | 22 Participants | 51 Participants | 188 Participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 8 Participants | 11 Participants | 9 Participants | 8 Participants | 5 Participants | 6 Participants | 18 Participants | 73 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 4 Participants | 9 Participants | 13 Participants | 12 Participants | 16 Participants | 16 Participants | 33 Participants | 115 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 | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 12 | 0 / 20 | 0 / 21 | 0 / 19 | 0 / 21 | 0 / 22 | 0 / 51 |
| other Total, other adverse events | 9 / 10 | 8 / 10 | 10 / 12 | 10 / 20 | 9 / 21 | 16 / 19 | 15 / 21 | 12 / 22 | 25 / 51 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 12 | 0 / 20 | 0 / 21 | 1 / 19 | 2 / 21 | 1 / 22 | 1 / 51 |
Outcome results
Primary
Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST)
The occurrence of at least 2 CTCAE grades increase from baseline in ALT or AST during the 4 weeks study period was evaluated to characterize hepatic safety aspects of single and multiple ascending doses of KAE609 in adult malaria subjects for treatment of uncomplicated malaria caused by plasmodium falciparum. If 2 patients in a 10 patient cohort (Cohorts 1 and 2) or 3 patients in a 20 patient cohort (Cohorts 3, 4 and 5) had at least 2 CTCAE grades increase from Baseline in ALT or AST, recruitment was suspended and a review of liver safety (and any other relevant data) by safety review committee was initiated. Any further progression of the study was based on the decision by the safety review committee.
Time frame: Day 29
Population: Safety Set (SAF). Only participants with baseline and at least one post-baseline assessment for either ALT or AST are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| KAE609 10 mg SD | Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) | 11.1 Percentage of Participants |
| KAE609 10 mg QD 3 Days | Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) | 0 Percentage of Participants |
| KAE609 25 mg SD | Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) | 0 Percentage of Participants |
| KAE609 25 mg QD 3 Days | Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) | 0 Percentage of Participants |
| KAE609 50 mg SD | Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) | 0 Percentage of Participants |
| KAE609 50 mg QD 3 Days | Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) | 0 Percentage of Participants |
| KAE609 75 mg SD | Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) | 0 Percentage of Participants |
| KAE609 150 mg SD | Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) | 4.5 Percentage of Participants |
| Pooled Coartem Control | Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) | 3.9 Percentage of Participants |
p-value: 0.391Fisher Exact
p-value: 1Fisher Exact
p-value: 1Fisher Exact
p-value: 1Fisher Exact
p-value: 1Fisher Exact
p-value: 1Fisher Exact
p-value: 1Fisher Exact
p-value: 1Fisher Exact
Secondary
AUC0-24
AUC0-24
Time frame: Day 1, Day 3
Population: PK Analysis Set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| KAE609 10 mg SD | AUC0-24 | Day 1 | 2.77 h*ug/mL | Geometric Coefficient of Variation 48.9 |
| KAE609 10 mg QD 3 Days | AUC0-24 | Day 1 | 2.59 h*ug/mL | Geometric Coefficient of Variation 38 |
| KAE609 10 mg QD 3 Days | AUC0-24 | Day 3 | 3.90 h*ug/mL | Geometric Coefficient of Variation 38.5 |
| KAE609 25 mg SD | AUC0-24 | Day 1 | 5.14 h*ug/mL | Geometric Coefficient of Variation 52.5 |
| KAE609 25 mg QD 3 Days | AUC0-24 | Day 1 | 8.39 h*ug/mL | Geometric Coefficient of Variation 45.1 |
| KAE609 25 mg QD 3 Days | AUC0-24 | Day 3 | 10.9 h*ug/mL | Geometric Coefficient of Variation 29.7 |
| KAE609 50 mg SD | AUC0-24 | Day 1 | 11.6 h*ug/mL | Geometric Coefficient of Variation 37.7 |
| KAE609 50 mg QD 3 Days | AUC0-24 | Day 3 | 21.6 h*ug/mL | Geometric Coefficient of Variation 31.3 |
| KAE609 50 mg QD 3 Days | AUC0-24 | Day 1 | 15.6 h*ug/mL | Geometric Coefficient of Variation 27.2 |
| KAE609 75 mg SD | AUC0-24 | Day 1 | 21.4 h*ug/mL | Geometric Coefficient of Variation 41.5 |
| KAE609 150 mg SD | AUC0-24 | Day 1 | 40.4 h*ug/mL | Geometric Coefficient of Variation 26.6 |
Secondary
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 patient received rescue medication before (fever) clearance, the time to event was censored at the first use of rescue medication.
Time frame: Day 29
Population: Full Analysis Set (FAS). Only participants with fever at baseline and post-baseline assessment of fever clearance at the time point are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KAE609 10 mg SD | Fever Clearance Time (FCT) | 3.9 Hours | — |
| KAE609 10 mg QD 3 Days | Fever Clearance Time (FCT) | 2.0 Hours | Standard Error 0.02 |
| KAE609 25 mg SD | Fever Clearance Time (FCT) | NA Hours | — |
| KAE609 25 mg QD 3 Days | Fever Clearance Time (FCT) | 22.0 Hours | Standard Error 14.03 |
| KAE609 50 mg SD | Fever Clearance Time (FCT) | 2.4 Hours | Standard Error 0.93 |
| KAE609 50 mg QD 3 Days | Fever Clearance Time (FCT) | 7.2 Hours | Standard Error 1.47 |
| KAE609 75 mg SD | Fever Clearance Time (FCT) | 5.7 Hours | Standard Error 2.02 |
| KAE609 150 mg SD | Fever Clearance Time (FCT) | 9.9 Hours | Standard Error 3.88 |
| Pooled Coartem Control | Fever Clearance Time (FCT) | 13.0 Hours | Standard Error 4.29 |
Secondary
Half-life (T^1/2)
Half-life (T\^1/2)
Time frame: Upto day 15 post dose
Population: PK Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| KAE609 10 mg SD | Half-life (T^1/2) | Day 1 | 24.4 Hour | Standard Deviation 8.7 |
| KAE609 10 mg QD 3 Days | Half-life (T^1/2) | Day 1 | 18.5 Hour | Standard Deviation 6.24 |
| KAE609 10 mg QD 3 Days | Half-life (T^1/2) | Day 3 | 32.4 Hour | Standard Deviation 14.8 |
| KAE609 25 mg SD | Half-life (T^1/2) | Day 1 | 35.1 Hour | Standard Deviation 13.9 |
| KAE609 25 mg QD 3 Days | Half-life (T^1/2) | Day 1 | 17.4 Hour | Standard Deviation 3.27 |
| KAE609 25 mg QD 3 Days | Half-life (T^1/2) | Day 3 | 30.1 Hour | Standard Deviation 14 |
| KAE609 50 mg SD | Half-life (T^1/2) | Day 1 | 31.5 Hour | Standard Deviation 17.4 |
| KAE609 50 mg QD 3 Days | Half-life (T^1/2) | Day 3 | 29.9 Hour | Standard Deviation 22 |
| KAE609 50 mg QD 3 Days | Half-life (T^1/2) | Day 1 | 32.8 Hour | Standard Deviation 5.05 |
| KAE609 75 mg SD | Half-life (T^1/2) | Day 1 | 25.3 Hour | Standard Deviation 8.94 |
| KAE609 150 mg SD | Half-life (T^1/2) | Day 1 | 29.9 Hour | Standard Deviation 12.5 |
Secondary
Maximum Peak Observed Concentration (Cmax)
Maximum Peak Observed Concentration (Cmax)
Time frame: Day 1, Day 3
Population: PK Analysis Set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| KAE609 10 mg SD | Maximum Peak Observed Concentration (Cmax) | Day 1 | 179 ng/mL | Geometric Coefficient of Variation 38.2 |
| KAE609 10 mg QD 3 Days | Maximum Peak Observed Concentration (Cmax) | Day 1 | 185 ng/mL | Geometric Coefficient of Variation 51.2 |
| KAE609 10 mg QD 3 Days | Maximum Peak Observed Concentration (Cmax) | Day 3 | 235 ng/mL | Geometric Coefficient of Variation 37 |
| KAE609 25 mg SD | Maximum Peak Observed Concentration (Cmax) | Day 1 | 379 ng/mL | Geometric Coefficient of Variation 42.1 |
| KAE609 25 mg QD 3 Days | Maximum Peak Observed Concentration (Cmax) | Day 1 | 503 ng/mL | Geometric Coefficient of Variation 44.3 |
| KAE609 25 mg QD 3 Days | Maximum Peak Observed Concentration (Cmax) | Day 3 | 655 ng/mL | Geometric Coefficient of Variation 27.9 |
| KAE609 50 mg SD | Maximum Peak Observed Concentration (Cmax) | Day 1 | 773 ng/mL | Geometric Coefficient of Variation 32.4 |
| KAE609 50 mg QD 3 Days | Maximum Peak Observed Concentration (Cmax) | Day 3 | 1210 ng/mL | Geometric Coefficient of Variation 30.7 |
| KAE609 50 mg QD 3 Days | Maximum Peak Observed Concentration (Cmax) | Day 1 | 828 ng/mL | Geometric Coefficient of Variation 35.4 |
| KAE609 75 mg SD | Maximum Peak Observed Concentration (Cmax) | Day 1 | 1270 ng/mL | Geometric Coefficient of Variation 41.3 |
| KAE609 150 mg SD | Maximum Peak Observed Concentration (Cmax) | Day 1 | 2360 ng/mL | Geometric Coefficient of Variation 28.5 |
Secondary
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 patient received rescue medication before (parasite) clearance, the time to event was censored at the first use of rescue medication.
Time frame: Day 29
Population: Full Analysis Set (FAS). Only participants with parasite at baseline and post-baseline assessment of parasite clearance at the time point are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KAE609 10 mg SD | Parasite Clearance Time (PCT) | 26.8 Hours | Standard Error 5.44 |
| KAE609 10 mg QD 3 Days | Parasite Clearance Time (PCT) | 27.7 Hours | Standard Error 4.96 |
| KAE609 25 mg SD | Parasite Clearance Time (PCT) | 14.0 Hours | Standard Error 2.63 |
| KAE609 25 mg QD 3 Days | Parasite Clearance Time (PCT) | 11.4 Hours | Standard Error 1.82 |
| KAE609 50 mg SD | Parasite Clearance Time (PCT) | 11.1 Hours | Standard Error 1.58 |
| KAE609 50 mg QD 3 Days | Parasite Clearance Time (PCT) | 9.8 Hours | Standard Error 0.97 |
| KAE609 75 mg SD | Parasite Clearance Time (PCT) | 8.7 Hours | Standard Error 0.97 |
| KAE609 150 mg SD | Parasite Clearance Time (PCT) | 8.0 Hours | Standard Error 1.09 |
| Pooled Coartem Control | Parasite Clearance Time (PCT) | 36.2 Hours | Standard Error 3.72 |
Secondary
Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29
PCR-corrected and PCR-uncorrected were evaluated at Days 15 and 29 (i.e., 14 and 28 days post-dose). The presence of parasitaemia after 7 days due to reinfection was considered as PCR-corrected ACPR. Missing blood smear data at Day 15 visit and thereafter were not considered as responder for the visit unless there was a later blood smear test indicating no parasitaemia.
Time frame: Day 15, Day 29
Population: Full Analysis Set (FAS). Only responders at each timepoint are included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| KAE609 10 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR corrected | 80.0 Percentage of Participants |
| KAE609 10 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR uncorrected | 90.0 Percentage of Participants |
| KAE609 10 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR uncorrected | 80.0 Percentage of Participants |
| KAE609 10 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR corrected | 90.0 Percentage of Participants |
| KAE609 10 mg QD 3 Days | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR corrected | 90.0 Percentage of Participants |
| KAE609 10 mg QD 3 Days | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR corrected | 90.0 Percentage of Participants |
| KAE609 10 mg QD 3 Days | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR uncorrected | 90.0 Percentage of Participants |
| KAE609 10 mg QD 3 Days | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR uncorrected | 90.0 Percentage of Participants |
| KAE609 25 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR corrected | 83.3 Percentage of Participants |
| KAE609 25 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR uncorrected | 66.7 Percentage of Participants |
| KAE609 25 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR uncorrected | 83.3 Percentage of Participants |
| KAE609 25 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR corrected | 83.3 Percentage of Participants |
| KAE609 25 mg QD 3 Days | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR uncorrected | 80.0 Percentage of Participants |
| KAE609 25 mg QD 3 Days | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR uncorrected | 95.0 Percentage of Participants |
| KAE609 25 mg QD 3 Days | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR corrected | 90.0 Percentage of Participants |
| KAE609 25 mg QD 3 Days | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR corrected | 95.0 Percentage of Participants |
| KAE609 50 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR uncorrected | 95.2 Percentage of Participants |
| KAE609 50 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR corrected | 95.2 Percentage of Participants |
| KAE609 50 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR corrected | 85.7 Percentage of Participants |
| KAE609 50 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR uncorrected | 81.0 Percentage of Participants |
| KAE609 50 mg QD 3 Days | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR corrected | 84.2 Percentage of Participants |
| KAE609 50 mg QD 3 Days | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR uncorrected | 84.2 Percentage of Participants |
| KAE609 50 mg QD 3 Days | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR corrected | 73.7 Percentage of Participants |
| KAE609 50 mg QD 3 Days | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR uncorrected | 68.4 Percentage of Participants |
| KAE609 75 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR corrected | 90.5 Percentage of Participants |
| KAE609 75 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR uncorrected | 85.7 Percentage of Participants |
| KAE609 75 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR uncorrected | 71.4 Percentage of Participants |
| KAE609 75 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR corrected | 81.0 Percentage of Participants |
| KAE609 150 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR corrected | 68.2 Percentage of Participants |
| KAE609 150 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR corrected | 77.3 Percentage of Participants |
| KAE609 150 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR uncorrected | 77.3 Percentage of Participants |
| KAE609 150 mg SD | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR uncorrected | 59.1 Percentage of Participants |
| Pooled Coartem Control | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR uncorrected | 92.2 Percentage of Participants |
| Pooled Coartem Control | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 29: PCR corrected | 94.1 Percentage of Participants |
| Pooled Coartem Control | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR uncorrected | 96.1 Percentage of Participants |
| Pooled Coartem Control | Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29 | Day 15: PCR corrected | 96.1 Percentage of Participants |
Secondary
Time to Recrudescence and Reinfection at Study Day 29
Time to recrudescence is calculated from the date of first study medication to the date of first event. Participants without recrudescence/reinfection after Day 7 are censored at the time of treatment failure or at the time of last parasite assessment if no treatment failure occured.
Time frame: Day 29
Population: Full Analysis Set (FAS). Only participants with clearance of initial infection before Day 15 and recrudescence/reinfection are included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| KAE609 10 mg SD | Time to Recrudescence and Reinfection at Study Day 29 | Recrudescence | 12.5 Event probability |
| KAE609 10 mg QD 3 Days | Time to Recrudescence and Reinfection at Study Day 29 | Recrudescence | 10.0 Event probability |
| KAE609 25 mg SD | Time to Recrudescence and Reinfection at Study Day 29 | Recrudescence | 16.7 Event probability |
| KAE609 25 mg SD | Time to Recrudescence and Reinfection at Study Day 29 | Reinfection | 25.0 Event probability |
| KAE609 25 mg QD 3 Days | Time to Recrudescence and Reinfection at Study Day 29 | Recrudescence | 10.0 Event probability |
| KAE609 25 mg QD 3 Days | Time to Recrudescence and Reinfection at Study Day 29 | Reinfection | 14.3 Event probability |
| KAE609 50 mg SD | Time to Recrudescence and Reinfection at Study Day 29 | Recrudescence | 16.0 Event probability |
| KAE609 50 mg SD | Time to Recrudescence and Reinfection at Study Day 29 | Reinfection | 5.0 Event probability |
| KAE609 50 mg QD 3 Days | Time to Recrudescence and Reinfection at Study Day 29 | Reinfection | 10.0 Event probability |
| KAE609 50 mg QD 3 Days | Time to Recrudescence and Reinfection at Study Day 29 | Recrudescence | 26.3 Event probability |
| KAE609 75 mg SD | Time to Recrudescence and Reinfection at Study Day 29 | Recrudescence | 15.9 Event probability |
| KAE609 75 mg SD | Time to Recrudescence and Reinfection at Study Day 29 | Reinfection | 10.3 Event probability |
| KAE609 150 mg SD | Time to Recrudescence and Reinfection at Study Day 29 | Recrudescence | 32.5 Event probability |
| KAE609 150 mg SD | Time to Recrudescence and Reinfection at Study Day 29 | Reinfection | 13.3 Event probability |
| Pooled Coartem Control | Time to Recrudescence and Reinfection at Study Day 29 | Reinfection | 2.4 Event probability |
| Pooled Coartem Control | Time to Recrudescence and Reinfection at Study Day 29 | Recrudescence | 2.4 Event probability |
Secondary
Tmax
Tmax
Time frame: Day 1, Day 3
Population: PK Analysis Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| KAE609 10 mg SD | Tmax | Day 1 | 4.00 Hour |
| KAE609 10 mg QD 3 Days | Tmax | Day 1 | 3.92 Hour |
| KAE609 10 mg QD 3 Days | Tmax | Day 3 | 52.7 Hour |
| KAE609 25 mg SD | Tmax | Day 1 | 4.01 Hour |
| KAE609 25 mg QD 3 Days | Tmax | Day 1 | 4.25 Hour |
| KAE609 25 mg QD 3 Days | Tmax | Day 3 | 52.1 Hour |
| KAE609 50 mg SD | Tmax | Day 1 | 4.12 Hour |
| KAE609 50 mg QD 3 Days | Tmax | Day 3 | 52.0 Hour |
| KAE609 50 mg QD 3 Days | Tmax | Day 1 | 4.12 Hour |
| KAE609 75 mg SD | Tmax | Day 1 | 6.01 Hour |
| KAE609 150 mg SD | Tmax | Day 1 | 8.07 Hour |