Efficacy, Safety, Tolerability and Pharmacokinetics of KAF156 in Adult Patients With Acute, Uncomplicated Plasmodium Falciparum or Vivax Malaria Mono-infection

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01753323
• Collaborator: (none)
• Enrollment: 43
• Locations: 5
• Arms: 3
• Duration (Months): 17
• Patients Per Site: 8.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This study will assess efficacy, safety , tolerability and PK in uncomplicated adult malaria patients with P. vivax or P. falciparum infection after 3 day dosing with KAF156 at 400 mg/day (Part 1) and single dosing with KAF156 at 800mg (Part 2)

Condition or Disease	Intervention/Treatment	Phase
Malaria	Drug: KAF156	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Proof-of-concept, Open Label Study to Assess Efficacy, Safety, Tolerability and Pharmacokinetics of KAF156 in Adult Patients With Acute, Uncomplicated Plasmodium Falciparum or Vivax Malaria Mono-infection
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1 - Cohort 1: P. vivax: KAF156 400mg QD Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Drug: KAF156; KAF156 was supplied as tablets for oral use.
Experimental: Part 1 - Cohort 2: P. falciparum: KAF156 400mg QD Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.	Drug: KAF156; KAF156 was supplied as tablets for oral use.
Experimental: Part 2 - Cohort 3: P. falciparum: KAF156 800mg single dose Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.	Drug: KAF156; KAF156 was supplied as tablets for oral use.

Outcome Measures

Primary Outcome Measures

1. Time to Parasite Clearance [Day 5]

   Parasite clearance was determined by assessing the parasite count in blood, using thin film, thick film and blood density assessments.

2. 28-day Cure Rate - Part 2 [Day 28]

   28-day cure rate was defined as the percentage of participants with blood parasite count of zero after 28 days of treatment.

Secondary Outcome Measures

1. Area Under the Curve (AUC)0-24h - Part 1 [Days 1 and 3]

   AUC0-24h was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. The 24h sampling of first post dose was taken before the second dose. On Day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

2. Maximum Concentration (Cmax) - Part 1 [Days 1 and 3]

   Cmax was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. The 24h sampling of first post dose should be taken before the second dose. On Day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

3. Time to Maximum Concentration (Tmax) - Part 1 [Days 1 and 3]

   Tmax was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. The 24h sampling of first post dose should be taken before the second dose. On Day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

4. Area Under the Curve (AUC)Last - Part 1 [Day 3]

   AUClast was analyzed using parent drug in plasma samples. On Day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

5. Area Under the Curve (AUC)Inf - Part 1 [Day 3]

   AUCinf was analyzed using parent drug in plasma samples. On Day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

6. Half-life (T1/2) - Part 1 [Day 3]

   T1/2 was analyzed using parent drug in plasma samples. On day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

7. Clearance (CL/F ) - Part 1 [Day 3]

   CL/F was analyzed using parent drug in plasma samples. On day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

8. Apparent Volume of Distribution During the Terminal Elimination Phase Following Extravascular Administration (Vz/F) - Part 1 [Day 3]

   Vz/F was analyzed using parent drug in plasma samples. On Day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

9. Accumulation Ratio (Racc) (=AUC0-24h, day3/AUC0-24h, day1) - Part 1 [Day 3]

   Racc was analyzed using parent drug in plasma samples. On day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

10. AUC0-24h - Part 2 [Day 1]

    AUC0-24h was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose.

11. AUC0-48h - Part 2 [Day 1]

    AUC0-48h was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

12. AUClast - Part 2 [Day 1]

    AUClast was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose

13. AUCinf - Part 2 [Day 1]

    AUCinf was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose

14. Cmax - Part 2 [Day 1]

    Cmax was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose.

15. Tmax - Part 2 [Day 1]

    Tmax was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose.

16. T1/2 - Part 2 [Day 1]

    T1/2 was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

17. CL/F - Part 2 [Day 1]

    CL/F was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

18. Vz/F - Part 2 [Day 1]

    Vz/F was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

-Male and female patients aged 20 to 60 years;Presence of mono-infection of P. falciparum or P. vivax; Weight between 40 kg to 90 kg.

Exclusion Criteria:

• Patients with signs and symptoms of severe/complicated malaria

• Infection with more than one parasite species

• Women of child-bearing potential; pregnant or nursing women

• Those who have taken any anti-malarial treatment in the preceding 14 days or other investigational drugs within 30 days or 5 half-lives

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Bangkok		Thailand	10400
2	Novartis Investigative Site	Srisaket		Thailand	33140
3	Novartis Investigative Site	Tak		Thailand	63110
4	Novartis Investigative Site	Tak		Thailand	63140
5	Novartis Investigative Site	Hanoi		Vietnam	10000

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01753323
• Other Study ID Numbers: CKAF156X2201
• First Posted: Dec 20, 2012
• Last Update Posted: Jun 7, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by Novartis Pharmaceuticals: acute malaria, KAF156
• Additional relevant MeSH terms: Malaria; Malaria, Vivax

Study Results

Participant Flow

Pre-assignment Detail	The enrollment of P. vivax malaria patients (Cohort 1) began first. Then the falciparum cohort began enrollment after four vivax patients had completed their dosing. Cohort 3 was enrolled after the completion of an interim analysis of safety, tolerability and efficacy data of seven completed patients in the second cohort of Part 1.

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD	Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
Period Title: Overall Study
STARTED	11	10	22
Pharmacodynamic (PD) Set	10	10	21
Pharmacokinetic(PK) Set	10	10	21
Safety Set	11	10	22
Intent-to-treat Analysis Set	11	10	22
COMPLETED	10	10	13
NOT COMPLETED	1	0	9

Baseline Characteristics

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD	Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose	Total
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.	Total of all reporting groups
Overall Participants	11	10	22	43
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	28.1 (8.42)	36.7 (10.90)	28.9 (7.00)	31.2 (8.77)
Sex/Gender, Customized (Number) [Number]
Number [Participants]	11 100%	10 100%	22 100%	43 100%

Outcome Measures

1. Primary Outcome

Title	Time to Parasite Clearance
Description	Parasite clearance was determined by assessing the parasite count in blood, using thin film, thick film and blood density assessments.
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set for Cohorts 1, 2 and 3: The PD set included all participants who received at least one dose of study medication except for 1 participant from Cohort 1, who was excluded due to a protocol deviation, and 1 participant from Cohort 3, who was withdrawn on Day 1.

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD	Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
Measure Participants	10	10	21
Median (95% Confidence Interval) [Hours]	23.63	44.97	48.75

2. Primary Outcome

Title	28-day Cure Rate - Part 2
Description	28-day cure rate was defined as the percentage of participants with blood parasite count of zero after 28 days of treatment.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set: the intent-to-treat analysis set included all randomized participants who received at least one dose of study medication.

Arm/Group Title	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
Measure Participants	22
Number [Percentage of participants]	63.6 578.2%

3. Secondary Outcome

Title	Area Under the Curve (AUC)0-24h - Part 1
Description	AUC0-24h was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. The 24h sampling of first post dose was taken before the second dose. On Day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Days 1 and 3

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set for Cohorts 1 and 2: The PK set included all participants who received at least one dose of study medication except for 1 participant from Cohort 1, who was excluded due to a protocol deviation.

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD	Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.
Measure Participants	10	10
Day 1	9470 (2140)	10100 (2440)
Day 3	20200 (3730)	21700 (6630)

4. Secondary Outcome

Title	Maximum Concentration (Cmax) - Part 1
Description	Cmax was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. The 24h sampling of first post dose should be taken before the second dose. On Day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Days 1 and 3

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set for Cohorts 1 and 2: The PK set included all participants who received at least one dose of study medication except for 1 participant from Cohort 1, who was excluded due to a protocol deviation.

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD	Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.
Measure Participants	10	10
Day 1	795 (182)	856 (158)
Day 3	1440 (299)	1620 (384)

5. Secondary Outcome

Title	Time to Maximum Concentration (Tmax) - Part 1
Description	Tmax was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. The 24h sampling of first post dose should be taken before the second dose. On Day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Days 1 and 3

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set for Cohorts 1 and 2: The PK set included all participants who received at least one dose of study medication except for 1 participant from Cohort 1, who was excluded due to a protocol deviation.

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD	Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.
Measure Participants	10	10
Day 1	3.00	3.00
Day 3	3.00	2.52

6. Secondary Outcome

Title	Area Under the Curve (AUC)Last - Part 1
Description	AUClast was analyzed using parent drug in plasma samples. On Day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set for Cohorts 1 and 2: The PK set included all participants who received at least one dose of study medication except for 1 participant from Cohort 1, who was excluded due to a protocol deviation.

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD	Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.
Measure Participants	10	10
Mean (Standard Error) [hr*ng/mL]	55800 (12800)	54300 (22500)

7. Secondary Outcome

Title	Area Under the Curve (AUC)Inf - Part 1
Description	AUCinf was analyzed using parent drug in plasma samples. On Day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set for Cohorts 1 and 2: The PK set included all participants who received at least one dose of study medication except for 1 participant from Cohort 1, who was excluded due to a protocol deviation.

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD	Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.
Measure Participants	10	10
Mean (Standard Deviation) [hr*ng/mL]	58300 (14500)	56700 (24800)

8. Secondary Outcome

Title	Half-life (T1/2) - Part 1
Description	T1/2 was analyzed using parent drug in plasma samples. On day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set for Cohorts 1 and 2: The PK set included all participants who received at least one dose of study medication except for 1 participant from Cohort 1, who was excluded due to a protocol deviation.

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD	Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.
Measure Participants	10	10
Mean (Standard Deviation) [hr]	39.0 (7.40)	40.8 (8.37)

9. Secondary Outcome

Title	Clearance (CL/F ) - Part 1
Description	CL/F was analyzed using parent drug in plasma samples. On day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set for Cohorts 1 and 2: The PK set included all participants who received at least one dose of study medication except for 1 participant from Cohort 1, who was excluded due to a protocol deviation.

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD	Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.
Measure Participants	10	10
Mean (Standard Deviation) [L/hr]	20.4 (4.04)	19.7 (5.12)

10. Secondary Outcome

Title	Apparent Volume of Distribution During the Terminal Elimination Phase Following Extravascular Administration (Vz/F) - Part 1
Description	Vz/F was analyzed using parent drug in plasma samples. On Day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set for Cohorts 1 and 2: The PK set included all participants who received at least one dose of study medication except for 1 participant from Cohort 1, who was excluded due to a protocol deviation.

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD	Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.
Measure Participants	10	10
Mean (Standard Deviation) [Liters]	1150 (286)	1140 (288)

11. Secondary Outcome

Title	Accumulation Ratio (Racc) (=AUC0-24h, day3/AUC0-24h, day1) - Part 1
Description	Racc was analyzed using parent drug in plasma samples. On day 3, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set for Cohorts 1 and 2: The PK set included all participants who received at least one dose of study medication except for 1 participant from Cohort 1, who was excluded due to a protocol deviation.

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD	Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.	Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.
Measure Participants	10	10
Mean (Standard Deviation) [ratio]	2.16 (0.256)	2.15 (0.384)

12. Secondary Outcome

Title	AUC0-24h - Part 2
Description	AUC0-24h was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set analysis set for Cohort 3: The PK set for Cohort 3 included participants who received at least one dose of study medication except for 1 participant who was withdrawn on Day 1 and 3 participants who vomited before 3 hours.

Arm/Group Title	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
Measure Participants	18
Mean (Standard Error) [hr*ng/mL]	21700 (5680)

13. Secondary Outcome

Title	AUC0-48h - Part 2
Description	AUC0-48h was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set analysis set for Cohort 3: The PK set for Cohort 3 included participants who received at least one dose of study medication except for 1 participant who was withdrawn on Day 1 and 3 participants who vomited before 3 hours.

Arm/Group Title	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
Measure Participants	18
Mean (Standard Error) [hr*ng/mL]	33600 (9150)

14. Secondary Outcome

Title	AUClast - Part 2
Description	AUClast was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set analysis set for Cohort 3: The PK set for Cohort 3 included participants who received at least one dose of study medication except for 1 participant who was withdrawn on Day 1 and 3 participants who vomited before 3 hours.

Arm/Group Title	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
Measure Participants	18
Mean (Standard Deviation) [hr*ng/mL]	54900 (16600)

15. Secondary Outcome

Title	AUCinf - Part 2
Description	AUCinf was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set analysis set for Cohort 3: The PK set for Cohort 3 included participants who received at least one dose of study medication except for 1 participant who was withdrawn on Day 1 and 3 participants who vomited before 3 hours.

Arm/Group Title	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
Measure Participants	18
Mean (Standard Deviation) [hr*ng/mL]	58300 (18600)

16. Secondary Outcome

Title	Cmax - Part 2
Description	Cmax was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set analysis set for Cohort 3: The PK set for Cohort 3 included participants who received at least one dose of study medication except for 1 participant who was withdrawn on Day 1 and 3 participants who vomited before 3 hours.

Arm/Group Title	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
Measure Participants	18
Mean (Standard Deviation) [ng/mL]	1800 (404)

17. Secondary Outcome

Title	Tmax - Part 2
Description	Tmax was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set analysis set for Cohort 3: The PK set for Cohort 3 included participants who received at least one dose of study medication except for 1 participant who was withdrawn on Day 1 and 3 participants who vomited before 3 hours.

Arm/Group Title	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
Measure Participants	18
Median (Full Range) [hours]	3.52

18. Secondary Outcome

Title	T1/2 - Part 2
Description	T1/2 was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set analysis set for Cohort 3: The PK set for Cohort 3 included participants who received at least one dose of study medication except for 1 participant who was withdrawn on Day 1 and 3 participants who vomited before 3 hours.

Arm/Group Title	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
Measure Participants	18
Mean (Standard Deviation) [hours]	48.7 (7.85)

19. Secondary Outcome

Title	CL/F - Part 2
Description	CL/F was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set analysis set for Cohort 3: The PK set for Cohort 3 included participants who received at least one dose of study medication except for 1 participant who was withdrawn on Day 1 and 3 participants who who vomited before 3 hours.

Arm/Group Title	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
Measure Participants	18
Mean (Standard Deviation) [L/hr]	15.1 (4.85)

20. Secondary Outcome

Title	Vz/F - Part 2
Description	Vz/F was analyzed using parent drug in plasma samples. On Day 1, samples were taken at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, 144, and 192 hours post dose.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set analysis set for Cohort 3: The PK set for Cohort 3 included participants who received at least one dose of study medication except for 1 participant who was withdrawn on Day 1 and 3 participants who vomited before 3 hours.

Arm/Group Title	Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
Measure Participants	18
Mean (Standard Deviation) [Liters]	1030 (264)

Adverse Events

Arm/Group Title	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD		Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD		Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
Arm/Group Description	Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days.		Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days.		Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg.
All Cause Mortality
	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD		Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD		Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD		Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD		Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/10 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	Part 1 - Cohort 1: P. Vivax: KAF156 400mg QD		Part 1 - Cohort 2: P. Falciparum: KAF156 400mg QD		Part 2 - Cohort 3: P. Falciparum: KAF156 800mg Single Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/11 (45.5%)		8/10 (80%)		22/22 (100%)
Blood and lymphatic system disorders
Anaemia	0/11 (0%)		1/10 (10%)		7/22 (31.8%)
Lymphopenia	0/11 (0%)		0/10 (0%)		1/22 (4.5%)
Neutropenia	0/11 (0%)		0/10 (0%)		4/22 (18.2%)
Thrombocytopenia	0/11 (0%)		1/10 (10%)		13/22 (59.1%)
Cardiac disorders
Atrioventricular block first degree	0/11 (0%)		0/10 (0%)		1/22 (4.5%)
Palpitations	0/11 (0%)		1/10 (10%)		0/22 (0%)
Sinus bradycardia	1/11 (9.1%)		3/10 (30%)		14/22 (63.6%)
Gastrointestinal disorders
Abdominal pain	0/11 (0%)		2/10 (20%)		1/22 (4.5%)
Diarrhoea	0/11 (0%)		0/10 (0%)		4/22 (18.2%)
Nausea	0/11 (0%)		1/10 (10%)		4/22 (18.2%)
Vomiting	0/11 (0%)		1/10 (10%)		6/22 (27.3%)
General disorders
Fatigue	0/11 (0%)		0/10 (0%)		2/22 (9.1%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/11 (0%)		1/10 (10%)		4/22 (18.2%)
Infections and infestations
Malaria	0/11 (0%)		0/10 (0%)		1/22 (4.5%)
Investigations
Alanine aminotransferase increased	1/11 (9.1%)		1/10 (10%)		5/22 (22.7%)
Aspartate aminotransferase increased	0/11 (0%)		1/10 (10%)		3/22 (13.6%)
Blood thyroid stimulating hormone decreased	0/11 (0%)		1/10 (10%)		0/22 (0%)
Electrocardiogram QT prolonged	1/11 (9.1%)		0/10 (0%)		3/22 (13.6%)
Eosinophil count increased	1/11 (9.1%)		0/10 (0%)		0/22 (0%)
Monocyte count decreased	0/11 (0%)		1/10 (10%)		0/22 (0%)
Monocyte count increased	2/11 (18.2%)		0/10 (0%)		0/22 (0%)
Thyroxine free increased	0/11 (0%)		1/10 (10%)		0/22 (0%)
White blood cell count decreased	0/11 (0%)		0/10 (0%)		4/22 (18.2%)
Metabolism and nutrition disorders
Decreased appetite	0/11 (0%)		1/10 (10%)		5/22 (22.7%)
Hyperglycaemia	0/11 (0%)		1/10 (10%)		0/22 (0%)
Hypokalaemia	0/11 (0%)		1/10 (10%)		11/22 (50%)
Hyponatraemia	0/11 (0%)		0/10 (0%)		1/22 (4.5%)
Nervous system disorders
Dizziness	0/11 (0%)		1/10 (10%)		2/22 (9.1%)
Renal and urinary disorders
Glycosuria	0/11 (0%)		1/10 (10%)		0/22 (0%)
Proteinuria	0/11 (0%)		0/10 (0%)		3/22 (13.6%)
Skin and subcutaneous tissue disorders
Dermatitis allergic	0/11 (0%)		1/10 (10%)		0/22 (0%)
Vascular disorders
Hypotension	0/11 (0%)		0/10 (0%)		2/22 (9.1%)

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 (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.