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)
Overview
- Phase
- Phase 2
- Intervention
- M5717 330 mg
- Conditions
- Acute Malaria
- Sponsor
- Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
- Enrollment
- 38
- Locations
- 5
- Primary Endpoint
- Cohort A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Related TEAEs
- Status
- Completed
- Last Updated
- 8 months ago
Overview
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.
Investigators
Eligibility Criteria
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
Arms & Interventions
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.
Intervention: M5717 330 mg
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.
Intervention: Pyronaridine 360 mg
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.
Intervention: M5717 500 mg
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.
Intervention: M5717 660 mg
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.
Intervention: Pyronaridine 360 mg
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.
Intervention: Pyronaridine 540 mg
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.
Intervention: Pyronaridine 720 mg
Outcomes
Primary Outcomes
Cohort A: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Related TEAEs
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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)
Time Frame: 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 Outcomes
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Cohort A and Cohort B0: Percentage of Participants With Early Treatment Failure (ETF)(Up to Day 3 post treatment on Day 1)
- Cohort A and Cohort B0: Percentage of Participants With Late Clinical Failure (LCF)(Day 1 up to Day 29)
- Cohort A and Cohort B0: Percentage of Participants With Late Parasitological Failure (LPF)(From Day 8 to Day 29)
- Cohort A: Percentage of Participants With Polymerase Chain Reaction (PCR)-Adjusted Adequate Clinical and Parasitological Response (ACPR)(Day 28 and 42)
- Cohort A and B0: Percentage of Participants With Crude Adequate Clinical and Parasitological Response (ACPR)(Day 28 and 42)
- Cohort A and Cohort B0: Time to Fever Clearance as Estimated by Kaplan-Meier Method(Day 1 up to Day 29)
- Cohort A and Cohort B0: Parasite Clearance Time as Estimated by Kaplan-Meier Method(Day 1 up to Day 43)
- Cohort B0: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Related TEAEs(Day 1 up to Day 43)