Safety of KAE609 in Adults With Uncomplicated Plasmodium Falciparum Malaria.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03334747
• Collaborator: Supported by Wellcome Trust via Grant # Grant Number 207813/Z/17/Z (Other)
• Enrollment: 188
• Locations: 9
• Arms: 9
• Actual Duration (Months): 24.2
• Patients Per Site: 20.9
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Malaria	Drug: KAE609; Drug: Coartem	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 188 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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 cohortsPatients 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
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multi-center, Randomized, Open-label, Dose-escalation Study to Determine Safety of Single (QD) and Multiple (3 QD) Doses of KAE609, Given to Adults With Uncomplicated Plasmodium Falciparum Malaria.
• Actual Study Start Date: Nov 16, 2017
• Actual Primary Completion Date: Nov 23, 2019
• Actual Study Completion Date: Nov 23, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment arm 1: KAE609 10 mg Single Dose (SD) KAE609 10 mg once daily (QD) for 1 day	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Names: Cipargamin
Experimental: Treatment arm 2:KAE609 25 mg SD KAE609 25 mg once daily (QD) for 1 day	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Names: Cipargamin
Experimental: Treatment arm 3:KAE609 10 mg 3 Days KAE609 10 mg (QD) for 3 days	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Names: Cipargamin
Experimental: Treatment arm 4:KAE609 50 mg SD KAE609 50 mg once daily (QD) for 1 day	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Names: Cipargamin
Experimental: Treatment arm 5:KAE609 25 mg 3 Days KAE609 25 mg once daily (QD) for 3 days	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Names: Cipargamin
Experimental: Treatment arm 6:KAE609 75 mg SD KAE609 75 mg once daily (QD) for 1 day	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Names: Cipargamin
Experimental: Treatment arm 7:KAE609 50 mg 3 Days KAE609 50 mg once daily (QD) for 3 days	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Names: Cipargamin
Experimental: Treatment arm 8: KAE609 150 mg SD KAE609 150 mg once daily (QD) for 1 day	Drug: KAE609; Exploration of different doses of KAE609 to establish safety profile.; Other Names: Cipargamin
Active Comparator: Treatment arm 9: Coartem Control Coartem® control	Drug: Coartem; Control Arm; Other Names: Artemether Lumefantrine

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. Maximum Peak Observed Concentration (Cmax) [Day 1, Day 3]

   Maximum Peak Observed Concentration (Cmax)

6. Tmax [Day 1, Day 3]

   Tmax

7. AUC0-24 [Day 1, Day 3]

   AUC0-24

8. Half-life (T^1/2) [Upto day 15 post dose]

   Half-life (T^1/2)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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. 1. 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/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Lambarene		Gabon
2	Novartis Investigative Site	Kintampo		Ghana
3	Novartis Investigative Site	Navrango		Ghana
4	Novartis Investigative Site	Bamako		Mali
5	Novartis Investigative Site	Sotuba		Mali
6	Novartis Investigative Site	Kigali		Rwanda
7	Novartis Investigative Site	Bushenyi		Uganda
8	Novartis Investigative Site	Kampala		Uganda
9	Novartis Investigative Site	Tororo		Uganda

Sponsors and Collaborators

• Novartis Pharmaceuticals
• Supported by Wellcome Trust via Grant # Grant Number 207813/Z/17/Z

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - May 27, 2019
• Statistical Analysis Plan - Apr 7, 2020

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03334747
• Other Study ID Numbers: CKAE609A2202; 207813/Z/17/Z
• First Posted: Nov 7, 2017
• Last Update Posted: Oct 11, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: uncomplicated Plasmodium falciparum Malaria.
• Additional relevant MeSH terms: Malaria; Malaria, Falciparum; Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination

Study Results

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 Detail	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.

Arm/Group Title	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
Arm/Group Description	KAE609 10 mg once daily (QD) for 1 day	KAE609 10 mg (QD) for 3 days	KAE609 25 mg once daily (QD) for 1 day	KAE609 25 mg once daily (QD) for 3 days	KAE609 50 mg once daily (QD) for 1 day	KAE609 50 mg once daily (QD) for 3 days	KAE609 75 mg once daily (QD) for 1 day	KAE609 150 mg once daily (QD) for 1 day	control arm
Period Title: Treatment Phase
STARTED	10	10	12	20	22	20	21	22	51
COMPLETED	9	10	12	20	21	19	21	22	51
NOT COMPLETED	1	0	0	0	1	1	0	0	0
Period Title: Treatment Phase
STARTED	9	10	12	20	21	19	21	22	51
COMPLETED	9	10	12	20	21	19	20	22	50
NOT COMPLETED	0	0	0	0	0	0	1	0	1

Baseline Characteristics

Arm/Group Title	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
Arm/Group Description	KAE609 10 mg once daily (QD) for 1 day	KAE609 10 mg (QD) for 3 days	KAE609 25 mg once daily (QD) for 1 day	KAE609 25 mg once daily (QD) for 3 days	KAE609 50 mg once daily (QD) for 1 day	KAE609 50 mg once daily (QD) for 3 days	KAE609 75 mg once daily (QD) for 1 day	KAE609 150 mg once daily (QD) for 1 day	control arm	Total of all reporting groups
Overall Participants	10	10	12	20	22	20	21	22	51	188
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	31.5 (10.48)	35.4 (13.25)	33.0 (14.96)	31.9 (10.67)	33.9 (12.56)	26.4 (7.18)	28.2 (10.25)	30.6 (12.57)	26.2 (9.07)	29.7 (11.07)
Sex: Female, Male (Count of Participants)
Female	2 20%	6 60%	8 66.7%	11 55%	9 40.9%	8 40%	5 23.8%	6 27.3%	18 35.3%	73 38.8%
Male	8 80%	4 40%	4 33.3%	9 45%	13 59.1%	12 60%	16 76.2%	16 72.7%	33 64.7%	115 61.2%
Race/Ethnicity, Customized (Number) [Number]
Black or African American	10 100%	10 100%	12 100%	20 100%	22 100%	20 100%	21 100%	22 100%	51 100%	188 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With at Least 2 CTCAE Grades Increase From Baseline in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	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
Arm/Group Description	KAE609 10 mg once daily (QD) for 1 day	KAE609 10 mg (QD) for 3 days	KAE609 25 mg once daily (QD) for 1 day	KAE609 25 mg once daily (QD) for 3 days	KAE609 50 mg once daily (QD) for 1 day	KAE609 50 mg once daily (QD) for 3 days	KAE609 75 mg once daily (QD) for 1 day	KAE609 150 mg once daily (QD) for 1 day	control arm
Measure Participants	9	10	12	20	21	19	21	22	51
Number (95% Confidence Interval) [Percentage of Participants]	11.1 111%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	4.5 20.5%	3.9 7.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	KAE609 10 mg SD
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.391
	Comments
	Method	Fisher Exact
	Comments	2-sided p-value results from Fisher exact test for each KAE609 treatment group compared to Pooled Coartem

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	KAE609 10 mg QD 3 Days
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	Fisher Exact
	Comments	2-sided p-value results from Fisher exact test for each KAE609 treatment group compared to Pooled Coartem

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	KAE609 25 mg SD
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	Fisher Exact
	Comments	2-sided p-value results from Fisher exact test for each KAE609 treatment group compared to Pooled Coartem

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	KAE609 25 mg QD 3 Days
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	Fisher Exact
	Comments	2-sided p-value results from Fisher exact test for each KAE609 treatment group compared to Pooled Coartem

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	KAE609 50 mg SD
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	Fisher Exact
	Comments	2-sided p-value results from Fisher exact test for each KAE609 treatment group compared to Pooled Coartem

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	KAE609 50 mg QD 3 Days
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	Fisher Exact
	Comments	2-sided p-value results from Fisher exact test for each KAE609 treatment group compared to Pooled Coartem

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	KAE609 75 mg SD
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	Fisher Exact
	Comments	2-sided p-value results from Fisher exact test for each KAE609 treatment group compared to Pooled Coartem

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	KAE609 150 mg SD
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	Fisher Exact
	Comments	2-sided p-value results from Fisher exact test for each KAE609 treatment group compared to Pooled Coartem

2. Secondary Outcome

Title	Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected and Uncorrected Adequate Clinical and Parasitological Response (ACPR) at Day 15 and Day 29
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Only responders at each timepoint are included in the analysis.

Arm/Group Title	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
Arm/Group Description	KAE609 10 mg once daily (QD) for 1 day	KAE609 10 mg (QD) for 3 days	KAE609 25 mg once daily (QD) for 1 day	KAE609 25 mg once daily (QD) for 3 days	KAE609 50 mg once daily (QD) for 1 day	KAE609 50 mg once daily (QD) for 3 days	KAE609 75 mg once daily (QD) for 1 day	KAE609 150 mg once daily (QD) for 1 day	control arm
Measure Participants	10	10	12	20	21	19	21	22	51
Day 15: PCR corrected	90.0 900%	90.0 900%	83.3 694.2%	95.0 475%	95.2 432.7%	84.2 421%	90.5 431%	77.3 351.4%	96.1 188.4%
Day 15: PCR uncorrected	90.0 900%	90.0 900%	83.3 694.2%	95.0 475%	95.2 432.7%	84.2 421%	85.7 408.1%	77.3 351.4%	96.1 188.4%
Day 29: PCR corrected	80.0 800%	90.0 900%	83.3 694.2%	90.0 450%	85.7 389.5%	73.7 368.5%	81.0 385.7%	68.2 310%	94.1 184.5%
Day 29: PCR uncorrected	80.0 800%	90.0 900%	66.7 555.8%	80.0 400%	81.0 368.2%	68.4 342%	71.4 340%	59.1 268.6%	92.2 180.8%

3. Secondary Outcome

Title	Parasite Clearance Time (PCT)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	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
Arm/Group Description	KAE609 10 mg once daily (QD) for 1 day	KAE609 10 mg (QD) for 3 days	KAE609 25 mg once daily (QD) for 1 day	KAE609 25 mg once daily (QD) for 3 days	KAE609 50 mg once daily (QD) for 1 day	KAE609 50 mg once daily (QD) for 3 days	KAE609 75 mg once daily (QD) for 1 day	KAE609 150 mg once daily (QD) for 1 day	control arm
Measure Participants	10	10	12	20	21	19	21	22	51
Mean (Standard Error) [Hours]	26.8 (5.44)	27.7 (4.96)	14.0 (2.63)	11.4 (1.82)	11.1 (1.58)	9.8 (0.97)	8.7 (0.97)	8.0 (1.09)	36.2 (3.72)

4. Secondary Outcome

Title	Fever Clearance Time (FCT)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	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
Arm/Group Description	KAE609 10 mg once daily (QD) for 1 day	KAE609 10 mg (QD) for 3 days	KAE609 25 mg once daily (QD) for 1 day	KAE609 25 mg once daily (QD) for 3 days	KAE609 50 mg once daily (QD) for 1 day	KAE609 50 mg once daily (QD) for 3 days	KAE609 75 mg once daily (QD) for 1 day	KAE609 150 mg once daily (QD) for 1 day	control arm
Measure Participants	10	10	12	20	21	19	21	22	51
Mean (Standard Error) [Hours]	3.9 (NA)	2.0 (0.02)	NA (NA)	22.0 (14.03)	2.4 (0.93)	7.2 (1.47)	5.7 (2.02)	9.9 (3.88)	13.0 (4.29)

5. Secondary Outcome

Title	Time to Recrudescence and Reinfection at Study Day 29
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Only participants with clearance of initial infection before Day 15 and recrudescence/reinfection are included in the analysis.

Arm/Group Title	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
Arm/Group Description	KAE609 10 mg once daily (QD) for 1 day	KAE609 10 mg (QD) for 3 days	KAE609 25 mg once daily (QD) for 1 day	KAE609 25 mg once daily (QD) for 3 days	KAE609 50 mg once daily (QD) for 1 day	KAE609 50 mg once daily (QD) for 3 days	KAE609 75 mg once daily (QD) for 1 day	KAE609 150 mg once daily (QD) for 1 day	control arm
Measure Participants	8	10	12	20	21	19	21	22	51
Recrudescence	12.5	10.0	16.7	10.0	16.0	26.3	15.9	32.5	2.4
Reinfection	25.0	14.3	5.0	10.0	10.3	13.3	2.4

6. Secondary Outcome

Title	Maximum Peak Observed Concentration (Cmax)
Description	Maximum Peak Observed Concentration (Cmax)
Time Frame	Day 1, Day 3

Outcome Measure Data

Analysis Population Description

PK Analysis Set

Arm/Group Title	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
Arm/Group Description	KAE609 10 mg once daily (QD) for 1 day	KAE609 10 mg (QD) for 3 days	KAE609 25 mg once daily (QD) for 1 day	KAE609 25 mg once daily (QD) for 3 days	KAE609 50 mg once daily (QD) for 1 day	KAE609 50 mg once daily (QD) for 3 days	KAE609 75 mg once daily (QD) for 1 day	KAE609 150 mg once daily (QD) for 1 day
Measure Participants	9	10	12	20	21	19	20	22
Day 1	179 (38.2)	185 (51.2)	379 (42.1)	503 (44.3)	773 (32.4)	828 (35.4)	1270 (41.3)	2360 (28.5)
Day 3	235 (37.0)	655 (27.9)	1210 (30.7)

7. Secondary Outcome

Title	Tmax
Description	Tmax
Time Frame	Day 1, Day 3

Outcome Measure Data

Analysis Population Description

PK Analysis Set

Arm/Group Title	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
Arm/Group Description	KAE609 10 mg once daily (QD) for 1 day	KAE609 10 mg (QD) for 3 days	KAE609 25 mg once daily (QD) for 1 day	KAE609 25 mg once daily (QD) for 3 days	KAE609 50 mg once daily (QD) for 1 day	KAE609 50 mg once daily (QD) for 3 days	KAE609 75 mg once daily (QD) for 1 day	KAE609 150 mg once daily (QD) for 1 day
Measure Participants	9	10	12	20	21	19	20	22
Day 1	4.00	3.92	4.01	4.25	4.12	4.12	6.01	8.07
Day 3	52.7	52.1	52.0

8. Secondary Outcome

Title	AUC0-24
Description	AUC0-24
Time Frame	Day 1, Day 3

Outcome Measure Data

Analysis Population Description

PK Analysis Set

Arm/Group Title	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
Arm/Group Description	KAE609 10 mg once daily (QD) for 1 day	KAE609 10 mg (QD) for 3 days	KAE609 25 mg once daily (QD) for 1 day	KAE609 25 mg once daily (QD) for 3 days	KAE609 50 mg once daily (QD) for 1 day	KAE609 50 mg once daily (QD) for 3 days	KAE609 75 mg once daily (QD) for 1 day	KAE609 150 mg once daily (QD) for 1 day
Measure Participants	9	10	12	20	21	19	20	22
Day 1	2.77 (48.9)	2.59 (38.0)	5.14 (52.5)	8.39 (45.1)	11.6 (37.7)	15.6 (27.2)	21.4 (41.5)	40.4 (26.6)
Day 3	3.90 (38.5)	10.9 (29.7)	21.6 (31.3)

9. Secondary Outcome

Title	Half-life (T^1/2)
Description	Half-life (T^1/2)
Time Frame	Upto day 15 post dose

Outcome Measure Data

Analysis Population Description

PK Analysis Set

Arm/Group Title	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
Arm/Group Description	KAE609 10 mg once daily (QD) for 1 day	KAE609 10 mg (QD) for 3 days	KAE609 25 mg once daily (QD) for 1 day	KAE609 25 mg once daily (QD) for 3 days	KAE609 50 mg once daily (QD) for 1 day	KAE609 50 mg once daily (QD) for 3 days	KAE609 75 mg once daily (QD) for 1 day	KAE609 150 mg once daily (QD) for 1 day
Measure Participants	9	10	12	20	21	19	20	22
Day 1	24.4 (8.70)	18.5 (6.24)	35.1 (13.9)	17.4 (3.27)	31.5 (17.4)	32.8 (5.05)	25.3 (8.94)	29.9 (12.5)
Day 3	32.4 (14.8)	30.1 (14.0)	29.9 (22.0)

Adverse Events

Time Frame	All AEs reported in this record are treatment emergent AEs, collected from date of First Patient First Treatment until the completion of the safety follow-up ( 30 days after the Last Patient Last Treatment ) up to approximately 2 years.
Arm/Group Title	KAE609 10mg SD		KAE609 10mg QD@3 Days		KAE609 25mg SD		KAE609 25mg QD@3 Days		KAE609 50mg SD		KAE609 50mg QD@3 Days		KAE609 75mg SD		KAE609 150mg SD		Pooled Coartem
Arm/Group Description	KAE609 10mg SD		KAE609 10mg QD@3 days		KAE609 25mg SD		KAE609 25mg QD@3 days		KAE609 50mg SD		KAE609 50mg QD@3 days		KAE609 75mg SD		KAE609 150mg SD		Pooled Coartem
All Cause Mortality
	KAE609 10mg SD		KAE609 10mg QD@3 Days		KAE609 25mg SD		KAE609 25mg QD@3 Days		KAE609 50mg SD		KAE609 50mg QD@3 Days		KAE609 75mg SD		KAE609 150mg SD		Pooled Coartem
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Serious Adverse Events
	KAE609 10mg SD		KAE609 10mg QD@3 Days		KAE609 25mg SD		KAE609 25mg QD@3 Days		KAE609 50mg SD		KAE609 50mg QD@3 Days		KAE609 75mg SD		KAE609 150mg SD		Pooled Coartem
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		1/19 (5.3%)		2/21 (9.5%)		1/22 (4.5%)		1/51 (2%)
Blood and lymphatic system disorders
Thrombocytopenia	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		1/21 (4.8%)		0/22 (0%)		0/51 (0%)
Investigations
Alanine aminotransferase increased	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		1/22 (4.5%)		0/51 (0%)
Blood alkaline phosphatase increased	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		1/21 (4.8%)		0/22 (0%)		0/51 (0%)
Blood bilirubin increased	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		1/19 (5.3%)		0/21 (0%)		0/22 (0%)		1/51 (2%)
Other (Not Including Serious) Adverse Events
	KAE609 10mg SD		KAE609 10mg QD@3 Days		KAE609 25mg SD		KAE609 25mg QD@3 Days		KAE609 50mg SD		KAE609 50mg QD@3 Days		KAE609 75mg SD		KAE609 150mg SD		Pooled Coartem
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/10 (90%)		8/10 (80%)		10/12 (83.3%)		10/20 (50%)		9/21 (42.9%)		16/19 (84.2%)		15/21 (71.4%)		12/22 (54.5%)		25/51 (49%)
Blood and lymphatic system disorders
Anaemia	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		1/21 (4.8%)		0/19 (0%)		0/21 (0%)		1/22 (4.5%)		3/51 (5.9%)
Leukopenia	0/10 (0%)		1/10 (10%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Thrombocytopenia	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		1/22 (4.5%)		3/51 (5.9%)
Gastrointestinal disorders
Abdominal pain	1/10 (10%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		1/21 (4.8%)		0/22 (0%)		1/51 (2%)
Diarrhoea	1/10 (10%)		0/10 (0%)		1/12 (8.3%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		1/21 (4.8%)		0/22 (0%)		3/51 (5.9%)
Dyspepsia	0/10 (0%)		1/10 (10%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Gastritis	1/10 (10%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
General disorders
Asthenia	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		2/21 (9.5%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Pain	1/10 (10%)		0/10 (0%)		1/12 (8.3%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Pyrexia	0/10 (0%)		1/10 (10%)		0/12 (0%)		0/20 (0%)		1/21 (4.8%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		2/51 (3.9%)
Treatment failure	0/10 (0%)		1/10 (10%)		3/12 (25%)		1/20 (5%)		0/21 (0%)		1/19 (5.3%)		0/21 (0%)		0/22 (0%)		2/51 (3.9%)
Vessel puncture site pain	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		1/19 (5.3%)		0/21 (0%)		0/22 (0%)		2/51 (3.9%)
Infections and infestations
Bronchitis	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		1/19 (5.3%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Gastroenteritis	0/10 (0%)		1/10 (10%)		0/12 (0%)		1/20 (5%)		0/21 (0%)		1/19 (5.3%)		1/21 (4.8%)		0/22 (0%)		0/51 (0%)
Influenza	0/10 (0%)		0/10 (0%)		0/12 (0%)		1/20 (5%)		0/21 (0%)		3/19 (15.8%)		2/21 (9.5%)		3/22 (13.6%)		2/51 (3.9%)
Malaria	1/10 (10%)		0/10 (0%)		2/12 (16.7%)		4/20 (20%)		4/21 (19%)		5/19 (26.3%)		5/21 (23.8%)		9/22 (40.9%)		1/51 (2%)
Oral herpes	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		1/19 (5.3%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Parasitic gastroenteritis	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		1/19 (5.3%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Pneumonia	0/10 (0%)		1/10 (10%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Upper respiratory tract infection	0/10 (0%)		0/10 (0%)		1/12 (8.3%)		0/20 (0%)		0/21 (0%)		1/19 (5.3%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Urinary tract infection	0/10 (0%)		1/10 (10%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		1/22 (4.5%)		0/51 (0%)
Injury, poisoning and procedural complications
Mouth injury	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		1/19 (5.3%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Investigations
Alanine aminotransferase increased	1/10 (10%)		0/10 (0%)		0/12 (0%)		1/20 (5%)		1/21 (4.8%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		3/51 (5.9%)
Aspartate aminotransferase increased	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		1/21 (4.8%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		3/51 (5.9%)
Bacterial test positive	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		1/19 (5.3%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Gamma-glutamyltransferase increased	0/10 (0%)		1/10 (10%)		0/12 (0%)		1/20 (5%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		1/51 (2%)
Metabolism and nutrition disorders
Decreased appetite	0/10 (0%)		1/10 (10%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Hyperglycaemia	1/10 (10%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		1/22 (4.5%)		0/51 (0%)
Hypoglycaemia	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		2/21 (9.5%)		0/22 (0%)		0/51 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/10 (10%)		0/10 (0%)		1/12 (8.3%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		1/21 (4.8%)		0/22 (0%)		0/51 (0%)
Musculoskeletal pain	0/10 (0%)		1/10 (10%)		1/12 (8.3%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Myalgia	1/10 (10%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		0/51 (0%)
Nervous system disorders
Dizziness	1/10 (10%)		1/10 (10%)		1/12 (8.3%)		1/20 (5%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		1/51 (2%)
Headache	3/10 (30%)		5/10 (50%)		1/12 (8.3%)		1/20 (5%)		2/21 (9.5%)		2/19 (10.5%)		5/21 (23.8%)		0/22 (0%)		9/51 (17.6%)
Renal and urinary disorders
Haematuria	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		1/19 (5.3%)		1/21 (4.8%)		0/22 (0%)		0/51 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/10 (10%)		0/10 (0%)		1/12 (8.3%)		1/20 (5%)		1/21 (4.8%)		2/19 (10.5%)		0/21 (0%)		0/22 (0%)		1/51 (2%)
Skin and subcutaneous tissue disorders
Photosensitivity reaction	0/10 (0%)		0/10 (0%)		0/12 (0%)		0/20 (0%)		0/21 (0%)		1/19 (5.3%)		0/21 (0%)		1/22 (4.5%)		0/51 (0%)
Pruritus	0/10 (0%)		0/10 (0%)		0/12 (0%)		1/20 (5%)		0/21 (0%)		1/19 (5.3%)		1/21 (4.8%)		0/22 (0%)		0/51 (0%)
Rash	1/10 (10%)		0/10 (0%)		0/12 (0%)		1/20 (5%)		0/21 (0%)		0/19 (0%)		1/21 (4.8%)		0/22 (0%)		1/51 (2%)
Vascular disorders
Phlebitis	0/10 (0%)		0/10 (0%)		1/12 (8.3%)		0/20 (0%)		0/21 (0%)		0/19 (0%)		0/21 (0%)		0/22 (0%)		0/51 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.