Phase IIa Proof of Concept Study of M5717-Pyronaridine in Adults and Adolescents With Acute Uncomplicated Plasmodium Falciparum Malaria (CAPTURE 1)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, efficacy, and pharmacokinetic of the combination M5717 plus pyronaridine in participants with acute uncomplicated Plasmodium falciparum malaria. Pyramax (Artesunate/Pyronaridine) will act as an internal control providing reference safety data and a benchmark for the efficacy evaluation.

Official Title
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Phase IIa Proof of Concept, Multicenter, Randomized, Open-label Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of the Combination M5717 Plus Pyronaridine Administered Once Daily for 1 or 2 Days to Adults and Adolescents With Acute Uncomplicated Plasmodium Falciparum Malaria (CAPTURE 1)

Conditions
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Acute Malaria

Intervention / Treatment
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* Drug: M5717 330 mg
* Drug: M5717 500 mg
* Drug: M5717 660 mg
* Drug: Pyronaridine 360 mg
* Drug: Pyronaridine 360 mg
* Drug: Pyronaridine 540 mg
* Drug: Pyronaridine 720 mg
* Drug: Pyronaridine-artesunate (Pyramax) 360 mg/120 mg
* Drug: Pyronaridine- artesunate (Pyramax) 540 mg/180 mg
* Drug: Pyronaridine-artesunate (Pyramax) 720 mg/240 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with microscopic confirmation of acute uncomplicated Plasmodium falciparum using Giemsa-stained thick and thin film P. falciparum parasitemia of 1,000 to 50,000 asexual parasites/microliter of blood in Part A and P. falciparum parasitemia of >1,000 to <= 150,000 asexual parasites/microliter of blood in Part B Axillary temperature >= 37.5 degree Celsius or tympanic temperature >= 38.0 degree Celsius (use as per Coronavirus disease 2019 (COVID-19) protocols at the site [only at Screening]), or history of fever during the previous 24 hours (at least documented verbally) The Investigator confirms that each participant agrees to use appropriate contraception and barriers, if applicable Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and this protocol Other protocol defined inclusion criteria could apply Exclusion Criteria: Mixed Plasmodium infections as per thin film microscopy results Signs and symptoms of severe malaria according to World Health Organisation (WHO) 2021 criteria (WHO 2021) Known liver abnormalities, liver cirrhosis (compensated or decompensated), known active or history of hepatitis B or C (testing not required), underlying hepatic injury or known severe liver disease, known gallbladder or bile duct disease, acute or chronic pancreatitis, or severe malnutrition Known history or evidence of clinically significant disorders such as, cardiovascular, respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological [including known Human Immunodeficiency Virus-Acquired Immunodeficiency Syndrome (HIV-AIDS)], neurological (including auditory), endocrine, infectious, malignancy, psychiatric, history of convulsions, or other abnormality (including head trauma) Previous treatment with pyronaridine as part of a combination therapy during the last 3 months Prior antimalarial therapy or antibiotics with antimalarial activity within a minimum of their 5 plasma half-lives (or within 4 weeks of Screening if half-life is unknown) Participants taking medications prohibited by the protocol Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 55 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: Part A: Safety Run-in Cohort M5717+Pyronaridine<br>M5717 and pyronaridine once daily in a single day treatment regimen at low dose of 330 milligrams (mg) and 360 mg respectively. | Drug: M5717 330 mg<br>* Participants will receive orally 330 mg granules of M5717 in combination with pyronaridine dispersed in water under fasting condition.<br>Drug: Pyronaridine 360 mg<br>* Participants will receive 360 mg of pyronaridine tablets in combination with M5717 under fasting condition.<br>|
| Experimental: Part B: Dose escalation cohort; M5717+Pyronaridine<br>After completion of Part A, if dose will be considered safe and well tolerated, the Internal Data Monitoring Committee (IDMC) will have the option to recommend dose adjustments. M5717 and pyronaridine once daily will be administered in an escalated dose in a single day or 2-day treatment regimen. | Drug: M5717 500 mg<br>* Adolescent participants with weight less than (<) 45 kilograms (kg) will receive orally 500 mg granules of M5717 in combination with pyronaridine dispersed in water once daily under fasting condition.<br>Drug: M5717 660 mg<br>* Adult and adolescent participants with weight more than or equal to (>=) 45 kg will receive orally 660 mg granules of M5717 in combination with pyronaridine dispersed in water once daily under fasting condition.<br>Drug: Pyronaridine 360 mg<br>* Participants with weight >=24 to <45 kg will receive 360 mg of tablets in combination with M5717 under fasting condition.<br>Drug: Pyronaridine 540 mg<br>* Participants with weight >=45 to <65 kg will receive 540 mg of Pyronaridine tablets in combination with M5717 under fasting condition.<br>Drug: Pyronaridine 720 mg<br>* Participants with weight >=65 kg will receive 720 mg of Pyronaridine tablets in combination with M5717 under fasting condition.<br>|
| Active Comparator: Pyronaridine-artesunate<br>Pyronaridine-artesunate (Pyramax) once daily in a 3-day treatment regimen. | Drug: Pyronaridine-artesunate (Pyramax) 360 mg/120 mg<br>* Participants with weight >=24 to <45 kg will receive dose of 360/120 mg dose of Pyronaridine- artesunate (Pyramax) tablets under fasting condition.<br>Drug: Pyronaridine- artesunate (Pyramax) 540 mg/180 mg<br>* Participants with weight >=45 to <65 kg will receive 540/180 mg dose of Pyronaridine-artesunate (Pyramax) tablets under fasting condition.<br>Drug: Pyronaridine-artesunate (Pyramax) 720 mg/240 mg<br>* Participants with weight >=65 kg will receive 720/240 mg dose of Pyronaridine- artesunate (Pyramax) tablets under fasting condition.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Related TEAEs |  | Day 1 up to Day 43 | 
| Part A: Number of Participants With Clinically Significant Change From Baseline in Safety Laboratory Parameters, Vital Signs and 12-lead Electrocardiogram (ECG) Findings |  | Day 1 up to Day 29 | 
| Part B: Percentage of Participants with Polymerase Chain Reaction (PCR)-Adjusted Adequate Clinical and Parasitological Response (ACPR) |  | At Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A and Part B: Pharmacokinetic Plasma Concentration of M5717 and Pyronaridine |  | Day 1 up to Day 43 | 
| Part A and Part B: Percentage of Participants with Early Treatment Failure (ETF) |  | Day 1,2 and 3 | 
| Part A and Part B: Percentage of Participants with Late Clinical Failure (LCF) |  | From Day 5 to Day 29 | 
| Part A and Part B: Percentage of Participants with Late parasitological failure (LPF) |  | From Day 8 to Day 29 | 
| Part A and Part B: Percentage of Participants With Crude Adequate Clinical and Parasitological Response (ACPR) |  | Day 15, 29 and 43 | 
| Part A: Percentage of Participants with Polymerase Chain Reaction (PCR)-Adjusted Adequate Clinical and Parasitological Response (ACPR) |  | Day 15, 29 and 43 | 
| Part B: Percentage of Participants with Polymerase Chain Reaction (PCR)-Adjusted Adequate Clinical and Parasitological Response (ACPR) |  | At Day 15 and 43 | 
| Part A and Part B: Percentage of Participants with Crude (PCR-uncorrected) Efficacy |  | At Day 9 | 
| Part A and Part B: Percentage of Participants with PCR-Adjusted Efficacy |  | At Day 9 | 
| Part A and Part B: Parasite Reduction Rate |  | Upto 48 hours post-dose | 
| Part A and Part B: Time to Fever Clearance as Estimated by Kaplan-Meier Method |  | Day 1 up to Day 29 | 
| Part A and Part B: Parasite Clearance Time as Estimated by Kaplan-Meier Method |  | Day 1 up to Day 43 | 
| Part A and Part B: Time to Recrudescence as Estimated by Kaplan-Meier Method |  | Day 1 up to Day 43 | 
| Part A and Part B: Time to Re-Infection as Estimated by Kaplan-Meier Method |  | Up to Day 43 | 
| Part A and Part B: Time to Re-Emergence as Estimated by Kaplan-Meier Method |  | Up to Day 43 | 
| Part B: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Related TEAEs |  | Up to Day 43 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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M5717, Plasmodium mutants, Acute Malaria, Pyronaridine, Plasmodium falciparum, Polymerase chain reaction, Adequate Clinical and Parasitological Response, Plasmodium eukaryotic translation Elongation Factor 2