Platform Study to Evaluate the Efficacy and Safety of Anti-malarial Agents in Patients With Uncomplicated Plasmodium Falciparum Malaria

Study Overview
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Brief Summary
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Platform study to evaluate the efficacy and safety of anti-malarial agents in patients with uncomplicated Plasmodium falciparum malaria

Detailed Description
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The purpose of this platform study is to evaluate the parasiticidal effect and potential for cure with different anti-malarial agents administered as monotherapy and/or in combination therapy with other anti-malarial agents in adult and adolescent patients with uncomplicated Plasmodium falciparum malaria. Additionally, the safety, tolerability, and pharmacokinetics of these anti-malarial agents will be evaluated for dose selection for future studies.

Official Title
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A Multi-part, Multi-center PLATform Study to Assess the Efficacy, Safety, Tolerability and Pharmacokinetics of Anti-malarial Agents Administered as Monotherapy and/or Combination Therapy IN Patients With Uncomplicated Plasmodium Falciparum Malaria

Conditions
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Uncomplicated Plasmodium Falciparum Malaria

Intervention / Treatment
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* Drug: INE963
* Drug: KAE609 (Cipargamin)
* Drug: SoC (Coartem)
* Drug: KLU156


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients ≥18 years of age for Part A and ≥12 years of age for Part B at screening. Patients must have acute uncomplicated P. falciparum malaria mono infection at screening confirmed by a parasite count between 5,000 to 150,000 asexual parasite count/μl of blood for P. falciparum for Part A and between 1,000 to 150,000 asexual parasite count/μl of blood for Part B Patients in Part A must weigh between 40 kg and 90 kg. Patients in Part B must weigh between 35 kg and 90 kg at screening. Exclusion Criteria: Patients with signs and symptoms of severe/complicated malaria at screening or mixed Plasmodium infection (i.e., infection with more than one malaria species) at screening Moderate to severe anemia, chronic hemoglobinopathy (Hemoglobin level < 8 g/dL), or known chronic underlying disease such as sickle cell disease at screening Known clinically significant liver disease (e.g., chronic hepatitis, liver cirrhosis (compensated or decompensated), history of hepatitis B or C, hepatitis A or B vaccination in the last 3 months, known gallbladder or bile duct disease, acute or chronic pancreatitis. Clinical or laboratory evidence of any of the following at screening: AST/ALT > 3 x the upper limit of normal range (ULN), regardless of the level of total bilirubin AST/ALT > 1.5 and ≤ 2 x ULN and total bilirubin is > ULN Total bilirubin > 2 x ULN, regardless of the level of AST/ALT Any known/suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection at screening. Pregnant or nursing (lactating) women, women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using methods of effective contraception, and sexually active patients not willing to practice effective contraception. History or current diagnosis of ECG abnormalities indicating significant risk of safety for patients participating in the study such as: Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker History of familial long QT syndrome or known family history of Torsades de Pointe. Resting heart rate (physical exam or 12 lead ECG) < 60 bpm Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 12 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A1: Dose Level 1 INE963<br>Cohort A1: Dose Level 1 INE963 | Drug: INE963<br>* oral INE963<br>|
| Experimental: Cohort A1: Dose Level 2 INE963<br>Cohort A1: Dose Level 2 INE963 | Drug: INE963<br>* oral INE963<br>|
| Experimental: Cohort A1: Dose Level 3 INE963<br>Cohort A1: Dose Level 3 INE963 | Drug: INE963<br>* oral INE963<br>|
| Experimental: Cohort B1: KAE609 + INE963<br>Cohort B1: KAE609 + INE963 | Drug: INE963<br>* oral INE963<br>Drug: KAE609 (Cipargamin)<br>* oral KAE609 (Cipargamin)<br>|
| Active Comparator: Cohort B1: SoC (Coartem)<br>Cohort B1: SoC (Coartem) | Drug: SoC (Coartem)<br>* SoC (Coartem)<br>|
| Experimental: Cohort B2: KAE609 + KLU156<br>Cohort B2: KAE609 + KLU156 | Drug: KAE609 (Cipargamin)<br>* oral KAE609 (Cipargamin)<br>Drug: KLU156<br>* oral sachet KLU156 (KAF156 + lumefantrine)<br>|
| Active Comparator: Cohort B2: SoC (Coartem)<br>Cohort B2: SoC (Coartem) | Drug: SoC (Coartem)<br>* SoC (Coartem)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: parasite clearance time (PCT) | Part A: To assess the parasite clearance time (PCT) of oral doses of an anti-malarial agent administered as monotherapy in patients with uncomplicated P. falciparum malaria. PCT is defined as the time from the first positive blood slide at inclusion to the time of the first negative slide followed by two consecutive slides. | up to Day 7 | 
| Part B: polymerase chain reaction (PCR) corrected adequate clinical and parasitological response (ACPR) | Part B: To assess the 28-day cure rate of an anti malarial agent administered orally as combination therapy versus the standard of care (SoC) in patients with uncomplicated P. falciparum malaria. ACPR is defined as the absence of parasitemia on Study Day 29 irrespective of axillary temperature, without previously meeting any of the criteria of Early Treatment Failure (ETF) or Late Clinical Failure (LCF) or Late Parasitological Failure (LPF). | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: PCR-corrected and uncorrected ACPR | Part A: To assess the 28-day cure rate of an anti malarial agent administered orally as monotherapy in patients with uncomplicated P. falciparum malaria | Day 29 | 
| Part B: PCT | Part B: To assess the parasite clearance time (PCT) of oral combinations of anti malarial agents versus the standard of care (SoC) in patients with uncomplicated P. falciparum malaria | up to Day 7 | 
| Part B: PCR-uncorrected ACPR | Part B: To assess the 28-day cure rate of an anti malarial agent administered orally as combination therapy versus the SoC in patients with uncomplicated P. falciparum malaria | Day 29 | 
| Area under the concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) of the anti-malarial agents | To characterize the pharmacokinetics (PK) of each anti-malarial agent administered orally as monotherapy [Part A] and/or as combination therapy [Part B] in patients with uncomplicated P. falciparum malaria. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sample time (tlast) | Day 22 | 
| Area under the concentration-time curve from time zero to infinity (AUCinf) of the anti-malarial agents | To characterize PK of each anti-malarial agent administered orally as monotherapy [Part A] and/or as combination therapy [Part B] in patients with uncomplicated P. falciparum malaria. AUCinf is the AUC from time zero to infinity. | Day 22 | 
| Maximum observed concentration (Cmax) of the anti-malarial agents | To characterize PK of each anti-malarial agent administered orally as monotherapy [Part A] and/or as combination therapy [Part B] in patients with uncomplicated P. falciparum malaria. Cmax is the maximum (peak) observed plasma, blood, serum, or other blood fluid drug concentration after single dose administration. | Day 22 | 
| Time to reach maximum observed concentration (Tmax) | To characterize PK of each anti-malarial agent administered orally as monotherapy [Part A] and/or as combination therapy [Part B] in patients with uncomplicated P. falciparum malaria. Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration. | Day 22 | 
| Elimination half-life (T1/2) of the anti-malarial agents | To characterize PK of each anti-malarial agent administered orally as monotherapy [Part A] and/or as combination therapy [Part B] in patients with uncomplicated P. falciparum malaria. T1/2 is the elimination half-life associated with the terminal slope of a semi-logarithmic concentration-time curve. | Day 22 | 
| Total body clearance (CL/F) of the anti-malarial agents | To characterize PK of each anti-malarial agent administered orally as monotherapy [Part A] and/or as combination therapy [Part B] in patients with uncomplicated P. falciparum malaria. Cl/F is the total body clearance of drug from the plasma. | Day 22 | 
| Apparent volume of distribution (Vz/F) of the anti-malarial agents | To characterize PK of each anti-malarial agent administered orally as monotherapy [Part A] and/or as combination therapy [Part B] in patients with uncomplicated P. falciparum malaria. Vz/F is the apparent volume of distribution during terminal phase. | Day 22 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malaria, uncomplicated malaria, Plasmodium falciparum, platform study, PLATINUM