Safety of KAE609 in Adults With Uncomplicated Plasmodium Falciparum Malaria.

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Malaria

Intervention / Treatment
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* Drug: KAE609
* Drug: Coartem


Participation Criteria
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Eligibility Criteria
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KEY 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 15, Day 29 | 
| 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. | Day 29 | 
| 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. | Day 29 | 
| 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. | Day 29 | 
| Maximum Peak Observed Concentration (Cmax) | Maximum Peak Observed Concentration (Cmax) | Day 1, Day 3 | 
| Tmax | Tmax | Day 1, Day 3 | 
| AUC0-24 | AUC0-24 | Day 1, Day 3 | 
| Half-life (T^1/2) | Half-life (T^1/2) | Upto day 15 post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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uncomplicated Plasmodium falciparum Malaria.