Efficacy, Safety and Tolerability of KLU156 in Adults and Children ≥ 5 kg Body Weight With Uncomplicated P. Falciparum Malaria

Study Overview
=================
Brief Summary
-----------------
This study aims to confirm the efficacy, safety and tolerability of KLU156, a fixed dose combination of ganaplacide (KAF156) and a solid dispersion formulation of lumefantrine (lumefantrine-SDF), when administered once daily for three days in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated P. falciparum malaria (with or without other Plasmodium spp. co-infection). In the Extension phase, the safety, tolerability and efficacy of repeated treatment with KLU156 will be assessed for a maximum of two years in patients who did not experience early treatment failure (ETF), who did not experience any study treatment-related SAE (Serious Adverse Event) previously and who gave informed consent to participate in the Extension phase.

Detailed Description
-----------------
The purpose of this study is to confirm the efficacy, safety and tolerability of KLU156 in patients with uncomplicated P. falciparum malaria (with or without other Plasmodium spp. co-infection) by demonstrating that KLU156 is non-inferior to Coartem. The study duration will be 43 days (Core phase) plus 24 months (Extension phase). The treatment duration will be 3 days for each malaria episode. The visit frequency will be Days 1-3 (hospitalized) and 5 follow-up visits (Days 4, 8, 22, 29 and 43) in the Core phase and Days 1-3 (hospitalized) and 3 follow-up visits (Days 4, 8 and 29) in the Extension phase.

Official Title
-----------------
A Randomized, Open-label, Multicenter Study to Compare Efficacy, Safety and Tolerability of KLU156 With Coartem® in the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Adults and Children ≥ 5 kg Body Weight Followed by an Extension Phase With Repeated KLU156 Treatment

Conditions
-----------------
Uncomplicated Plasmodium Falciparum Malaria

Intervention / Treatment
-----------------
* Drug: KLU156
* Drug: Coartem


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion criteria (Core phase) Male or female patients ≥ 5 kg of body weight and ≥ 2 months of age Microscopically confirmed diagnosis of uncomplicated P. falciparum malaria with an asexual P. falciparum parasitemia ≥ 1,000 and ≤ 200,000 parasites/µL at the time of pre-screening with or without other Plasmodium spp. co-infection. Axillary temperature ≥ 37.5 ºC or oral temperature ≥ 38.0 ºC or tympanic/rectal temperature ≥ 38.5 ºC; or history of fever during the previous 24 hours (at least documented verbally) Negative pregnancy test for patients of childbearing potential Signed informed consent must be obtained before any assessment is performed; for minors, signed informed consent must be obtained from parent/legal guardian. If the parent/legal guardian is unable to read and write, then a witnessed consent according to local ethical standards is permitted. Patients who are capable of providing assent, must provide it along with parent/legal guardian consent or as per local ethical standards The patient and/or their parent/legal guardian is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned. Key Exclusion criteria (Core phase) Signs and symptoms of severe malaria according to WHO 2015 (World Health Organization) Concurrent febrile illnesses (e.g., typhoid fever, known or suspected dengue fever, known COVID19) Severe malnutrition. For patients ≥ 12 years: body mass index (BMI) < 16.0. For children < 12 years: less than 70% of median normalized WHO reference weight or very low mid-upper arm circumference (MUAC < 115 mm) Repeated vomiting (defined as > 3 times in the 24 hours prior to start of screening) or severe diarrhea (defined as > 3 watery stools in the 24 hours prior to start of screening) Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia Anemia (hemoglobin level <7 g/dL) Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs (e.g., Human immunodeficiency virus (HIV) patients on antiretroviral therapy (ART) or tuberculosis (TB) patients on treatment), or which may jeopardize the patient in case of participation in the study. Any of the following: Aspartate Aminotransferase/ Alanine Aminotransferase (AST/ALT) > 3 x the upper limit of normal (ULN), regardless of the level of total bilirubin Total bilirubin > 3 x ULN Resting QT interval corrected by Fridericia's formula (QTcF) > 450 ms at screening Prior antimalarial therapy or antibiotics with antimalarial activity within minimum of their five plasma half-lives (or within 4 weeks of screening if half-life is unknown) History or family history of long QT syndrome or sudden cardiac death, or any other clinical condition known to prolong the QTc interval, such as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe heart disease Pregnant or nursing (lactating) patients. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 2 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KLU156<br>KLU156 once daily (QD) for 3 days under fed conditions (light meal). | Drug: KLU156<br>* Oral use. KLU156 (400/480 mg) is the dose for patients with a bodyweight ≥ 35kg. Patients < 35kg will take a fraction of the dose according to weight group as defined in the protocol.<br>|
| Active Comparator: Coartem<br>Coartem twice a day (BID) for 3 days under fed conditions. | Drug: Coartem<br>* Oral use. Dosing will be selected based on patient's body weight as per product's label.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR-corrected adequate clinical and parasitological response (ACPR) | To confirm the efficacy of KLU156 in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection) by demonstrating that KLU156 is non-inferior to Coartem (non-inferiority margin = 5%) based on the PCR-corrected ACPR at Day 29. | Day 29 (i.e., 28 days post-first dose administration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR-corrected and uncorrected ACPR | To confirm the efficacy of KLU156 by assessing uncorrected and PCR-corrected ACPR at additional time points | Days 22 and 43 (i.e., 21 and 42 days post-first dose administration) | 
| Uncorrected ACPR | To further confirm the efficacy of KLU156 by demonstrating non-inferiority of KLU156 to Coartem (NI margin 7.5%) based on the uncorrected ACPR at Day 29 | Day 29 | 
| Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence and severity of AEs and SAEs by treatment group, including changes in vital signs, electrocardiograms (ECGs), and laboratory results qualifying and reported as AEs. | Day 43 | 
| Fever Clearance Time | To confirm the efficacy of KLU156 by assessing fever clearance between the two treatment arms | Up to Day 3 | 
| Parasite Clearance Time | To assess parasite clearance time between the two treatment arms | Up to Day 3 | 
| Incidence rate of recrudescence and new infection | Proportion of patients with recrudescence and new infections between the two treatment arms | Days 22, 29 and 43 | 
| Proportion of patients with parasitemia | For the parasitemia assessment, blood sampling can be done by means of a finger prick except when the timing for parasitology assessments coincides with time for clinical laboratory tests, in which case, blood sample can be taken from the venous blood collected for clinical laboratory analyses. | 12, 24, 48 and 72 hours after treatment | 
| Gametocytemia | Disappearance or development of gametocytemia in patients with or without gametocytemia at baseline (pre-first dose administration), respectively | From baseline up to Day 43 | 
| Extension phase: PCR-corrected and uncorrected ACPR | To evaluate efficacy over repeated treatment with KLU156 in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection) for a maximum of 2 years | Day 29 of malaria episode | 
| Extension phase: KLU156-related AE/SAE incidence and severity by malaria episode | To assess the safety and tolerability over repeated treatment with KLU156 in adults and children ≥ 5 kg body weight and ≥ 2 months of age suffering from uncomplicated malaria caused by P. falciparum (with or without other Plasmodium spp. co-infection) for a maximum of 2 years | Up to 2 years | 
| Extension phase: Gametocyte carriage over time | To assess gametocyte carriage over time by malaria episode in the extension phase | Up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
malaria, Plasmodium falciparum, KLU156, Coartem, artemether, lumefantrine, ganaplacide