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

Phase 2

Completed

Conditions: Acute Malaria

Interventions: Drug: M5717 330 mg
Drug: M5717 500 mg
Drug: Pyronaridine 360 mg
Drug: M5717 660 mg
Drug: Pyronaridine 540 mg
Drug: Pyronaridine 720 mg

Registration Number: NCT05689047

Lead Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 38

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part A: Safety Run-in Cohort M5717+Pyronaridine	M5717 330 mg	M5717 and pyronaridine once daily in a single day treatment regimen at low dose of 330 milligrams (mg) and 360 mg respectively.
Part A: Safety Run-in Cohort M5717+Pyronaridine	Pyronaridine 360 mg	M5717 and pyronaridine once daily in a single day treatment regimen at low dose of 330 milligrams (mg) and 360 mg respectively.
Part B: Dose escalation cohort; M5717+Pyronaridine	M5717 500 mg	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.
Part B: Dose escalation cohort; M5717+Pyronaridine	M5717 660 mg	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.
Part B: Dose escalation cohort; M5717+Pyronaridine	Pyronaridine 360 mg	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.
Part B: Dose escalation cohort; M5717+Pyronaridine	Pyronaridine 540 mg	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.
Part B: Dose escalation cohort; M5717+Pyronaridine	Pyronaridine 720 mg	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.

Primary Outcome Measures

Name	Time	Method
Cohort A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Related TEAEs	Day 1 up to Day 43	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.
Cohort A: Number of Participants With Clinically Significant Change From Baseline in Safety Laboratory Parameters	Day 1 up to Day 29	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.
Cohort A: Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiogram (ECG) Findings	Day 1 up to Day 29	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.
Cohort A: Number of Participants With Clinically Significant Change From Baseline in Vital Signs	Day 1 up to Day 29	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.
Cohort B0: Percentage of Participants With Polymerase Chain Reaction (PCR)-Adjusted Adequate Clinical and Parasitological Response (ACPR)	At Day 29	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).

Secondary Outcome Measures

Name	Time	Method
Cohort A and Cohort B0: Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717 and Pyronaridine	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	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.
Cohort A and Cohort B0: Area Under Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M5717 and Pyronaridine	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	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.
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	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	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)
Cohort A and Cohort B0: Apparent Total Clearance (CL/F) of M5717 and Pyronaridine	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	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.
Cohort A and Cohort B0: Maximum Plasma Concentration (Cmax) of M5717 and Pyronaridine	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	Cmax was taken directly from the observed concentration-time curve.
Cohort A and Cohort B0: Apparent Terminal Half-Life of M5717 and Pyronaridine	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	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.
Cohort A and Cohort B0: Time to Reach Maximum Plasma Concentration (Tmax) of M5717 and Pyronaridine	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	tmax was obtained directly from the concentration versus time curve.
Cohort A and Cohort B0: Apparent Volume of Distribution (Vz/F) of M5717 and Pyronaridine	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	The apparent volume of distribution during the terminal phase following extravascular administration. Vz/F = Dose/(AUC0-∞\*λz) following single dose.
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	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	The dose normalized AUC from time zero to 24 hours post dose. Normalized using the dose, using the formula AUC0-24/Dose.
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	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	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.
Cohort A and Cohort B0: Dose Normalized Area Under the Curve From Time Zero Extrapolated to Infinity (AUC0-∞/Dose) of M5717 and Pyronaridine	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	The dose normalized AUC from time zero extrapolated to infinity. Normalized using dose, using the formula AUC0-∞ /Dose.
Cohort A and Cohort B0: Terminal Elimination Rate Constant (Lambda z) of M5717 and Pyronaridine	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Cohort A and Cohort B0: Dose Normalized Maximum Concentration (Cmax/Dose) of M5717 and Pyronaridine	Predose and Post dose on Day 1, Post dose on Day 2, 3, 4, 8, 15, 22, 29 and Day 43	The dose normalized maximum concentration. Normalized using the dose, and the formula Cmax /Dose.
Cohort A and Cohort B0: Percentage of Participants With Early Treatment Failure (ETF)	Up to Day 3 post treatment on Day 1	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.
Cohort A and Cohort B0: Percentage of Participants With Late Clinical Failure (LCF)	Day 1 up to Day 29	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.
Cohort A and Cohort B0: Percentage of Participants With Late Parasitological Failure (LPF)	From Day 8 to Day 29	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.
Cohort A: Percentage of Participants With Polymerase Chain Reaction (PCR)-Adjusted Adequate Clinical and Parasitological Response (ACPR)	Day 28 and 42	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.
Cohort A and B0: Percentage of Participants With Crude Adequate Clinical and Parasitological Response (ACPR)	Day 28 and 42	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.
Cohort A and Cohort B0: Time to Fever Clearance as Estimated by Kaplan-Meier Method	Day 1 up to Day 29	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.
Cohort A and Cohort B0: Parasite Clearance Time as Estimated by Kaplan-Meier Method	Day 1 up to Day 43	Parasite clearance time defined as time from dosing to the first negative (no parasites) film
Cohort B0: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Related TEAEs	Day 1 up to Day 43	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.

Trial Locations

Locations (5): Institut de Recherche en Sciences de la Santé (IRSS)
🇧🇫
Nanoro, Burkina Faso
Groupe de Recherche Action en Santé (GRAS)
🇧🇫
Ouagadougou, Burkina Faso
Centre de Recherches Médicales de Lambaréné (CERMEL)
🇬🇦
Lambaréné, Gabon
Centro de Investigação em saúde de Manhiça/Fundação Manhiça (CISM/FM)
🇲🇿
Maputo, Mozambique
Infectious Diseases Research Collaboration (IDRC)
🇺🇬
Tororo, Uganda
Institut de Recherche en Sciences de la Santé (IRSS)
🇧🇫Nanoro, Burkina Faso