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

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)

The purpose of this study was to evaluate the safety, efficacy, and pharmacokinetic of the combination M5717 plus pyronaridine in participants with acute uncomplicated Plasmodium falciparum malaria.

Study Overview

• Status: Completed
• Conditions: Acute Malaria
• Intervention / Treatment: Drug: M5717 330 mg; Drug: Pyronaridine 360 mg; Drug: Pyronaridine 360 mg; Drug: M5717 500 mg; Drug: M5717 660 mg; Drug: Pyronaridine 540 mg; Drug: Pyronaridine 720 mg

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• Burkina Faso
  • Nanoro, Burkina Faso
    • Institut de Recherche en Sciences de la Santé (IRSS)
  • Ouagadougou, Burkina Faso
    • Groupe de Recherche Action en Santé (GRAS)
• Gabon
  • Lambaréné, Gabon
    • Centre de Recherches Médicales de Lambaréné (CERMEL)
• Mozambique
  • Maputo, Mozambique
    • Centro de Investigação em saúde de Manhiça/Fundação Manhiça (CISM/FM)
• Uganda
  • Tororo, Uganda
    • Infectious Diseases Research Collaboration (IDRC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 55 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Safety Run-in Cohort M5717+Pyronaridine; 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; Participants will receive orally 330 mg granules of M5717 in combination with pyronaridine dispersed in water under fasting condition.; Drug: Pyronaridine 360 mg; Participants will receive 360 mg of pyronaridine tablets in combination with M5717 under fasting condition.; Drug: Pyronaridine 360 mg; Participants with weight >=24 to <45 kg will receive 360 mg of tablets in combination with M5717 under fasting condition.
Experimental: Part B: Dose escalation cohort; M5717+Pyronaridine; 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: Pyronaridine 360 mg; Participants will receive 360 mg of pyronaridine tablets in combination with M5717 under fasting condition.; Drug: Pyronaridine 360 mg; Participants with weight >=24 to <45 kg will receive 360 mg of tablets in combination with M5717 under fasting condition.; Drug: M5717 500 mg; 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.; Drug: M5717 660 mg; 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.; Drug: Pyronaridine 540 mg; Participants with weight >=45 to <65 kg will receive 540 mg of Pyronaridine tablets in combination with M5717 under fasting condition.; Drug: Pyronaridine 720 mg; Participants with weight >=65 kg will receive 720 mg of Pyronaridine tablets in combination with M5717 under fasting condition.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Related TEAEs	An adverse event (AE) was defined as any untoward medical occurrence in a participant. TEAEs are defined as AEs which started at or after the administration of study intervention (study treatment) or which started prior to the first administration of study intervention but worsened after the dose intake, until the last scheduled assessment will be regarded as treatment-emergent, but before established rescue antimalarial treatment is administered, if required. A serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE was considered to be "related" if a causal relationship between study treatment and the TEAE is at least reasonably possible.	Day 1 up to Day 43
Cohort A: Number of Participants With Clinically Significant Change From Baseline in Safety Laboratory Parameters	Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical Significance was decided by the investigator. Laboratory investigation included hematology, biochemistry, and coagulation.	Day 1 up to Day 29
Cohort A: Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiogram (ECG) Findings	Number of participants with clinically significant change from baseline in ECG parameters were reported. Clinical Significance was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula.	Day 1 up to Day 29
Cohort A: Number of Participants With Clinically Significant Change From Baseline in Vital Signs	Number of participants with clinically significant change from baseline in vital signs. Clinical Significance was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate.	Day 1 up to Day 29
Cohort B0: Percentage of Participants With Polymerase Chain Reaction (PCR)-Adjusted Adequate Clinical and Parasitological Response (ACPR)	PCR-adjusted ACPR 28 days after first treatment (i.e., on Day 29) was defined as absence of parasitemia (thick smear/microscopy, after adjustment for parasitemia due to new infections as determined by genotyping using PCR techniques), irrespective of axillary temperature, in participants who did not previously meet any of the criteria of Early treatment failure (ETF), Late clinical failure (LCF), or Late parasitological failure (LPF).	At Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort A and Cohort B0: Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717 and Pyronaridine	The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. Calculated as AUC0-inf = AUC0-tlast + Clast pred/ lambda z.	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Area Under Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M5717 and Pyronaridine	The AUC from time zero (dosing time) to 24 hours post dose was calculated using the mixed log linear trapezoidal rule (linear up, log down) using the nominal dosing interval.	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Area Under Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-tlast) of M5717 and Pyronaridine	The AUC from time zero (= dosing time) to the time of the last quantifiable concentration (tlast), calculated using the mixed log linear trapezoidal rule (linear up, log down)	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Apparent Total Clearance (CL/F) of M5717 and Pyronaridine	The apparent total body clearance of study intervention following extravascular administration. CL/ F was calculated by oral dose divided by Area under the plasma concentration curve 0- infinity.	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Maximum Plasma Concentration (Cmax) of M5717 and Pyronaridine	Cmax was taken directly from the observed concentration-time curve.	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Apparent Terminal Half-Life of M5717 and Pyronaridine	t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Lambda z.	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Time to Reach Maximum Plasma Concentration (Tmax) of M5717 and Pyronaridine	tmax was obtained directly from the concentration versus time curve.	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Apparent Volume of Distribution (Vz/F) of M5717 and Pyronaridine	The apparent volume of distribution during the terminal phase following extravascular administration. Vz/F = Dose/(AUC0-∞*λz) following single dose.	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Dose Normalized Area Under the Curve From Time Zero to 24 Hours Post Dose (AUC0-24h/Dose) of M5717 and Pyronaridine	The dose normalized AUC from time zero to 24 hours post dose. Normalized using the dose, using the formula AUC0-24/Dose.	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Dose Normalized Area Under the Curve From Time Zero to the Last Sampling Time (AUC0-tlast/Dose) of M5717 and Pyronaridine	The dose normalized AUC from time zero to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Normalized using the dose, using the formula AUC0-tlast /Dose.	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Dose Normalized Area Under the Curve From Time Zero Extrapolated to Infinity (AUC0-∞/Dose) of M5717 and Pyronaridine	The dose normalized AUC from time zero extrapolated to infinity. Normalized using dose, using the formula AUC0-∞ /Dose.	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Terminal Elimination Rate Constant (Lambda z) of M5717 and Pyronaridine	Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Dose Normalized Maximum Concentration (Cmax/Dose) of M5717 and Pyronaridine	The dose normalized maximum concentration. Normalized using the dose, and the formula Cmax /Dose.	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43
Cohort A and Cohort B0: Percentage of Participants With Early Treatment Failure (ETF)	Early treatment failure (ETF) was defined as meeting any of the following : 1. Danger signs or severe malaria 1, 2, or 3 days after treatment, in the presence of parasitemia2. Parasitemia 2 days after treatment higher than on day of treatment, irrespective of axillary temperature • Parasitemia 3 days after treatment with temperature ≥ 37.5°C 3. Parasitemia 3 days after treatment ≥ 25% of count on day of treatment. ETF rate will be estimated with 95% confidence intervals. Confidence intervals was derived by use of Wilson's score method.	Up to Day 3 post treatment on Day 1
Cohort A and Cohort B0: Percentage of Participants With Late Clinical Failure (LCF)	Late clinical failure (LCF) was defined as:1. Danger signs or severe malaria in the presence of parasitemia on any day between 4 and 28 days after treatment (i.e., between Days 5 and 29) in participants who did not previously meet any of the criteria of ETF. 2. Presence of parasitemia on any day between 4 and 28 days after treatment with temperature ≥ 37.5°C in participants who did not previously meet any of the criteria of ETF. LCF was estimated with 95% confidence intervals. Confidence intervals will be derived by use of Wilson's score method.	Day 1 up to Day 29
Cohort A and Cohort B0: Percentage of Participants With Late Parasitological Failure (LPF)	Late parasitological failure (LPF) was defined as: Presence of parasitemia on any day between 7 and 28 days after treatment (i.e., between Days 8 and 29) with temperature < 37.5°C in participants who did not previously meet any of the criteria of ETF or LCF. LPF was estimated with 95% confidence intervals. Confidence intervals will be derived by use of Wilson's score method.	From Day 8 to Day 29
Cohort A: Percentage of Participants With Polymerase Chain Reaction (PCR)-Adjusted Adequate Clinical and Parasitological Response (ACPR)	PCR-adjusted ACPR 28 and 42 days after treatment defined as absence of parasitemia (thick smear/microscopy, after adjustment for parasitemia due to new infections as determined by genotyping using PCR techniques), irrespective of axillary temperature, in participants who did not previously meet any of the criteria of ETF, LCF, or LPF.	Day 28 and 42
Cohort A and B0: Percentage of Participants With Crude Adequate Clinical and Parasitological Response (ACPR)	Crude ACPR 28 and 42 days after first dose is defined as absence of parasitemia (parasite count = 0) from thick smear/microscopy, irrespective of axillary temperature, in participants who did not previously meet any of the criteria of ETF, LCF, or LPF.	Day 28 and 42
Cohort A and Cohort B0: Time to Fever Clearance as Estimated by Kaplan-Meier Method	Fever clearance time was defined as the time from first dosing to the first measurement of temperature < 37.5°C for 2 consecutive temperature readings plus confirmed normal temperature 24 h after the first normal body temperature reading. This analysis was done on participants with fever.	Day 1 up to Day 29
Cohort A and Cohort B0: Parasite Clearance Time as Estimated by Kaplan-Meier Method	Parasite clearance time defined as time from dosing to the first negative (no parasites) film	Day 1 up to Day 43
Cohort B0: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Related TEAEs	An adverse event (AE) was defined as any untoward medical occurrence in a participant. TEAEs are defined as AEs which started at or after the administration of study intervention (study treatment) or which started prior to the first administration of study intervention but worsened after the dose intake, until the last scheduled assessment will be regarded as treatment-emergent, but before established rescue antimalarial treatment is administered, if required. A serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE was considered to be "related" if a causal relationship between study treatment and the TEAE is at least reasonably possible.	Day 1 up to Day 43

Collaborators and Investigators

• Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• Trial Awareness and Transparency website
• Medical Information Location Map - Med Info Contacts

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2023
• Primary Completion (Actual): May 28, 2024
• Study Completion (Actual): May 28, 2024

Study Registration Dates

• First Submitted: January 9, 2023
• First Submitted That Met QC Criteria: January 9, 2023
• First Posted (Actual): January 18, 2023

Study Record Updates

• Last Update Posted (Estimated): August 27, 2025
• Last Update Submitted That Met QC Criteria: August 26, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Plasmodium falciparum; Polymerase chain reaction; M5717; Pyronaridine; Plasmodium mutants; Acute Malaria; Adequate Clinical and Parasitological Response; Plasmodium eukaryotic translation Elongation Factor 2
• Additional Relevant MeSH Terms: Vector Borne Diseases; Mosquito-Borne Diseases; Infections; Protozoan Infections; Parasitic Diseases; Malaria; Malaria, Falciparum; Acute malaria; Anti-Infective Agents; Antineoplastic Agents; Antiviral Agents; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; pyronaridine
• Other Study ID Numbers: MS201618_0033

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21
• IPD Sharing Time Frame: Within six months after the approval of a new product or a new indication for an approved product in both the United States and the European Union
• IPD Sharing Access Criteria: Qualified scientific and medical researchers can request the data. Such requests must be submitted in writing to the company's portal and will be internally reviewed regarding criteria for researchers' qualification and legitimacy of the research proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No