Safety of KAE609 in Adults With Uncomplicated Plasmodium Falciparum Malaria.

Phase 2

Completed

Conditions: Malaria

Interventions: Drug: KAE609
Drug: Coartem

Registration Number: NCT03334747

Lead Sponsor: Novartis Pharmaceuticals

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 188

Inclusion Criteria

Male and female patients ≥ 18 years with a body weight ≥ 45 kg.
Microscopic confirmation of acute uncomplicated P. falciparum using by Giemsa-stained thick film.
P. falciparum parasitaemia of 500 to 50 000 parasites/µL.
Axillary temperature ≥ 37.5ºC or oral/tympanic/rectal temperature ≥ 38.0ºC; or history of fever during the previous 24 hours.
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

Mixed Plasmodium infections.
Signs and symptoms of severe malaria according to World Health Organization (WHO) 2016 criteria (WHO 2016).
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.
Clinical or laboratory evidence of any of the following:
AST/ALT > 1.5 x the upper limit of normal range (ULN), regardless of the level of total bilirubin
AST/ALT > 1.0 and ≤ 1.5 x ULN and total bilirubin is > ULN
Total bilirubin > 2 x ULN, regardless of the level of AST/ALT
History of photodermatitis/increased sensitivity to sun.
Pregnant or nursing (lactating) women.
Known disturbances of electrolyte balance, e.g. hypokalemia, hypocalcemia or hypomagnesemia.
Moderate to severe anemia (Hemoglobin level <8 g/dL).

Other protocol-defined inclusion/exclusion criteria may apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment arm 2:KAE609 25 mg SD	KAE609	KAE609 25 mg once daily (QD) for 1 day
Treatment arm 3:KAE609 10 mg 3 Days	KAE609	KAE609 10 mg (QD) for 3 days
Treatment arm 5:KAE609 25 mg 3 Days	KAE609	KAE609 25 mg once daily (QD) for 3 days
Treatment arm 8: KAE609 150 mg SD	KAE609	KAE609 150 mg once daily (QD) for 1 day
Treatment arm 4:KAE609 50 mg SD	KAE609	KAE609 50 mg once daily (QD) for 1 day
Treatment arm 1: KAE609 10 mg Single Dose (SD)	KAE609	KAE609 10 mg once daily (QD) for 1 day
Treatment arm 6:KAE609 75 mg SD	KAE609	KAE609 75 mg once daily (QD) for 1 day
Treatment arm 7:KAE609 50 mg 3 Days	KAE609	KAE609 50 mg once daily (QD) for 3 days
Treatment arm 9: Coartem Control	Coartem	Coartem® control

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Tmax	Day 1, Day 3	Tmax
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.
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.
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.
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.
Maximum Peak Observed Concentration (Cmax)	Day 1, Day 3	Maximum Peak Observed Concentration (Cmax)
AUC0-24	Day 1, Day 3	AUC0-24
Half-life (T^1/2)	Upto day 15 post dose	Half-life (T\^1/2)