Healthy
Conditions
Keywords
Healthy Participants, M5717, Malaria, Plasmodium falciparum
Brief summary
The primary purpose of this study was to investigate the safety and tolerability of M5717 and to characterize the Pharmacokinetics (PK) /Pharmacodynamic relationship between M5717 PK and parasite clearance in healthy participants following infection with Plasmodium falciparum.
Interventions
DRUGM5717
Participants received single ascending oral dose of M5717 after at least 8 hours of fasting together with water on Day 1, followed by a 4-hour post-dose fast
DRUGPlacebo
Participants received placebo matched to M5717
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Adult men and women of non-childbearing potential, with total body weight greater than or equal to 50.0 kilogram and body mass index (BMI) between 19.0 kilogram per meter square(kg/m\^2) and 29.9 kg/m\^2. * Healthy as assessed by the Investigator with no clinically significant abnormality identified on physical examination or laboratory evaluation and no active clinically significant disorder, condition, infection or disease that would pose a risk to participant safety or interfere with the trial evaluation, procedures, or completion. * Other protocol defined inclusion criteria could apply.
Exclusion criteria
* Participants with history or presence of clinically relevant respiratory, gastrointestinal, renal, hepatic, hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological dermatological, connective tissue diseases or disorders. * Participants with history of relevant drug hypersensitivity, ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or formulation ingredients; history of serious allergic reactions leading to hospitalization or any other allergic reaction in general, which the Investigator considers may affect the safety of the participant and/or outcome of the trial. * Participants who have any history of malaria. * Participants who have participated in a previous malaria vaccine trial. * Participants who have participated in a previous human malaria challenge trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | Baseline up to Day 55 | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered with study drug which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) 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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. |
| Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | Baseline up to Day 55 | Laboratory assessments included hematology, biochemistry, urinalysis, and coagulation. Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical significance was decided by the investigator. |
| Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | Baseline up to Day 55 | The 12-lead ECGs were recorded after the participants had rested for at least 5 minutes in supine position. Number of participants with clinically significant change from baseline in ECGs was reported. Clinical significance was decided by the investigator. |
| Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Baseline up to Day 55 | Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Number of participants with clinically significant change from baseline in vital signs was reported. Clinical significance was decided by the investigator. |
| Part C: Parasite Reduction Ratio (PRR) Assessed Through Quantitative Polymerase Chain Reaction (qPCR) Analysis | Day 1 to Day 22 | The parasite reduction ratio (PRR) of asexual parasites based on quantitative polymerase chain reaction (qPCR) after administration of M5717 is a mathematical representation of the ratio of the parasite density between drug administration and for a defined period of time. The PRR for asexual forms was estimated using the slope of the optimal fit of the log-linear relationship of the parasitemia decay; ie, the time point where steady exponential decay in parasitemia occurs which may happen after a lag-phase. Lag phase is defined as an initial period after dosing that precedes a steady exponential decline in the parasite count. It was observed that the decline of parasitemia had a biphasic profile, with the first phase, followed by a second phase (the main clearance phase). |
| Part C: Maximum Observed Plasma Concentration (Cmax) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Cmax was obtained directly from the concentration versus time curve. |
| Part C: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | The time to reach the maximum observed plasma concentration (tmax) was obtained directly from the concentration versus time curve. |
| Part C: Terminal Elimination Rate Constant (Lambda z) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Lambda z determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve. |
| Part C: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | 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 the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. Clastpred was the last predicted quantifiable concentration. |
| Part C: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), calculated using the mixed log-linear trapezoidal rule (linear up, log down). |
| Part C: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, and 144 hours post-dose | The area under the plasma concentration-time curve from time zero to 144 hours after dosing was reported. It is calculated using the mixed log-linear trapezoidal rule (linear up, log down). |
| Part C: Apparent Terminal Half Life (t1/2) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | T1/2 was the time measured for the concentration to decrease by one half. T1/2 was calculated as natural log2 divided by lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. |
| Part C: Apparent Total Clearance (CL/f) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for M5717, whereas AUC0-infinity is area under the plasma concentration-time curve from time zero (dosing time) extrapolated to infinity of unchanged drug calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-infinity calculated by Clastpred/lambda z, where Clastpred is the predicted plasma concentration at the last sampling time point, calculated from the log linear regression line for lambda z determination at which the measured plasma concentration is at or above lower limit of quantification. |
| Part C: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. |
| Part C: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Minimal inhibitory concentration (MIC), defined as the concentration at which the relative rate of change in parasitemia is equal to zero. |
| Part C: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t =>10 ng/mL) | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Minimal parasiticidal concentration represents the lowest drug concentration value above which parasites decline at a maximal rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part C: Parasite Clearance Time | Day 1 up to Day 22 | The parasite clearance time (PCT), defined as the time at which malaria parasite levels decline below detectable levels in blood after treatment, estimated as the time at which the linear portion of the optimal log parasitemia-versus-time relationship intersects the LLOQ concentration line. |
| Part C: Parasite Clearance Half-life (PCT 1/2) | Day 1 up to Day 22 | The parasite clearance half-life (PCt1/2), defined as the time needed for parasitemia to be reduced by half during the log-linear phase of parasite clearance, as derived using the slope of the optimal fit of the log-linear relationship of parasitemia decay. It was observed that the decline of parasitemia had a biphasic profile, with the first phase, followed by a second phase (the main clearance phase). |
| Part C: Number of Participants With Lag Phase | Day 1 to Day 22 | Lag phase is defined as an initial period after dosing that precedes a steady exponential decline in the parasite count. Lag phase is categorized in lag of 4 hours, lag of 6 hours, lag of 12 hours and lag of 24 hours. |
| Part C: Number of Participants With Recrudescence | Day 1 to Day 22 | Recrudescence is as defined as greater than and equal to 5000 blood stage parasites/milliliter (mL) and a 2-fold parasitemia increase within 48 hours, or re-occurrence of malaria symptoms with a malaria clinical score \> 6. The malaria clinical score consists of 14 signs/symptoms frequently associated with malaria and graded using a 4-point scale with minimum score is 0 (no symptoms) and the maximum score is 42 (maximum symptoms). |
| Part C: Malarial Clinical Score | Day 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 15 and 22 | The malaria clinical score consists of 14 signs/symptoms frequently associated with malaria and graded using a 4-point scale (absent: 0; mild: 1; moderate: 2; severe: 3) and summed to generate a total malaria clinical score (maximum score possible is 42): headache, myalgia (muscle ache), arthralgia (joint ache), fatigue/lethargy, malaise (general discomfort/uneasiness), chills/shivering/rigors, sweating/hot spells, anorexia, nausea, vomiting, abdominal discomfort, fever, tachycardia and hypotension. Total scores are reported here. The minimum score is 0 (no symptoms) and the maximum score is 42 (maximum symptoms). |
| Part A: Maximum Observed Plasma Concentration (Cmax) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Cmax was obtained directly from the concentration versus time curve. |
| Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment | Baseline up to Day 44 | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered with study drug which does not necessarily had a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) 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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. |
| Part C: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | Baseline up to Day 44 | Laboratory assessments included hematology, biochemistry, urinalysis, and coagulation. Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical significance was decided by the investigator. |
| Part C: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | Baseline up to Day 44 | The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. Number of participants with clinically significant change from baseline in ECG were reported. Clinical significance was decided by the investigator. |
| Part C: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Baseline up to Day 44 | Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Number of participants with clinically significant change from baseline in vital signs were reported. Clinical significance was decided by the investigator. |
| Part C: Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration at 90% (MPC90) | Day 1 up to Day 22 | MIC is defined as the minimum concentration of a drug at which parasite counts continue to decrease and is equivalent to equating the rate in the change of parasite to 0. Parasiticidal concentration required for 90% killing (MPC90) is defined as the concentration at which the parasite clearance effect is at 90% of the maximum. The estimated MIC and MPC were derived from the final pharmacodynamics (PD) model and pharmacokinetic (PK)/PD relationship. |
| Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | The time to reach the maximum observed plasma concentration (tmax) was obtained directly from the concentration versus time curve. |
| Part A: Terminal Elimination Rate Constant (Lambda z) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Lambda z determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve. |
| Part A: Apparent Terminal Half Life (t1/2) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | T1/2 was the time measured for the concentration to decrease by one half. T1/2 was calculated as natural log2 divided by lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. |
| Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | 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 the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. Clastpred was the last predicted quantifiable concentration. |
| Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), calculated using the mixed log-linear trapezoidal rule (linear up, log down). |
| Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, and 144 hours post-dose | The area under the plasma concentration-time curve from time zero to 144 hours after dosing was reported. It is calculated using the mixed log-linear trapezoidal rule (linear up, log down). |
| Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | AUCextra% was calculated as area under the curve from time tlast extrapolated to infinity given as percentage of AUC 0-infinity. Here, tlast is the last sampling time at which the concentration is at or above the lower limit of quantification. |
| Part A: Apparent Total Clearance (CL/f) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for M5717, whereas AUC0-infinity is area under the plasma concentration-time curve from time zero (dosing time) extrapolated to infinity of unchanged drug calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-infinity calculated by Clastpred/lambda z, where Clastpred is the predicted plasma concentration at the last sampling time point, calculated from the log linear regression line for lambda z determination at which the measured plasma concentration is at or above lower limit of quantification. |
| Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. |
| Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | 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 the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. Clastpred was the last predicted quantifiable concentration. Dose normalized was calculated using actual dose, using the formula AUC0-inf/Dose. |
| Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, and 144 hours post-dose | The area under the plasma concentration-time curve from time zero to 144 hours after dosing was reported. It is calculated using the mixed log-linear trapezoidal rule (linear up, log down). Dose normalized was calculated using actual dose, using the formula AUC0-144h/Dose. |
| Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), calculated using the mixed log-linear trapezoidal rule (linear up, log down). Dose normalized was calculated using actual dose, using the formula AUC0-t/Dose. |
| Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717 | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Cmax was obtained directly from the concentration versus time curve. Dose normalized was calculated using actual dose, using the formula Cmax/Dose. |
| Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Minimal inhibitory concentration (MIC), defined as the concentration at which the relative rate of change in parasitemia is equal to zero. |
| Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL) | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose | Minimal parasiticidal concentration represents the lowest drug concentration value above which parasites decline at a maximal rate. |
Countries
Australia
Participant flow
Pre-assignment details
The study was planned to be conducted in 3 parts: Part A, B and C. Part B of the study was optional and sponsor decided not to perform part B of the study. In each cohort of Part A, participants were randomized in a 6:2 ratio to receive M5717 or matching placebo.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Placebo (Pooled) Participants from each cohort of Part A received single oral dose of placebo matched with M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose. | 17 |
| Part A: Cohort 1 SAD: M5717 50 mg Participants received single ascending dose (SAD) of 50 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. | 6 |
| Part A: Cohort 2 SAD: M5717 100 mg Participants received SAD of 100 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. | 6 |
| Part A: Cohort 3 SAD: M5717 200 mg Participants received SAD of 200 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. | 6 |
| Part A: Cohort 4 SAD: M5717 400 mg Participants received SAD of 400 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. | 6 |
| Part A: Cohort 5 SAD: M5717 600 mg Participants received SAD of 600 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. | 6 |
| Part A: Cohort 6 SAD: M5717 1000 mg Participants received SAD of 1000 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. | 6 |
| Part A: Cohort 7 SAD: M5717 1250 mg Participants in SAD received an oral dose of 1250 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. | 6 |
| Part A: Cohort 8 SAD: M5717 1800 mg Participants in SAD received an oral dose of 1800 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. | 6 |
| Part A: Cohort 9 SAD: M5717 2100 mg Participants in SAD received an oral dose of 2100 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. | 1 |
| Part C: M5717 150 mg Participants received single oral dose of 150 mg M5717 (eight days after the administration of intravenous malaria inoculum) on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. | 6 |
| Part C: M5717 400 mg Participants received single oral dose of 400 mg M5717 (eight days after the administration of intravenous malaria inoculum) on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. | 8 |
| Part C: M5717 800 mg Participants received single oral dose of 800 mg M5717 (eight days after the administration of intravenous malaria inoculum) on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. | 8 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Participant Unable To Attend Final Visit | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Part A: Cohort 1 SAD: M5717 50 mg | Part A: Cohort 2 SAD: M5717 100 mg | Part A: Placebo (Pooled) | Part A: Cohort 3 SAD: M5717 200 mg | Part A: Cohort 4 SAD: M5717 400 mg | Part A: Cohort 5 SAD: M5717 600 mg | Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Cohort 9 SAD: M5717 2100 mg | Part C: M5717 150 mg | Part C: M5717 400 mg | Part C: M5717 800 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 83 Participants | 6 Participants | 6 Participants | 17 Participants | 6 Participants | 6 Participants | 4 Participants | 6 Participants | 6 Participants | 6 Participants | 1 Participants | 5 Participants | 6 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 76 Participants | 5 Participants | 5 Participants | 16 Participants | 6 Participants | 5 Participants | 5 Participants | 4 Participants | 5 Participants | 5 Participants | 1 Participants | 5 Participants | 6 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 6 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 66 Participants | 4 Participants | 4 Participants | 13 Participants | 6 Participants | 5 Participants | 6 Participants | 2 Participants | 5 Participants | 4 Participants | 1 Participants | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 88 Participants | 6 Participants | 6 Participants | 17 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 1 Participants | 6 Participants | 8 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 1 | 0 / 6 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 13 / 17 | 6 / 6 | 5 / 6 | 3 / 6 | 4 / 6 | 3 / 6 | 4 / 6 | 5 / 6 | 6 / 6 | 1 / 1 | 6 / 6 | 8 / 8 | 7 / 8 |
| serious Total, serious adverse events | 0 / 17 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 1 | 0 / 6 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings
The 12-lead ECGs were recorded after the participants had rested for at least 5 minutes in supine position. Number of participants with clinically significant change from baseline in ECGs was reported. Clinical significance was decided by the investigator.
Time frame: Baseline up to Day 55
Population: Safety Analysis Set included all participants who received investigational medicinal product (M5717 or placebo for Part A).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo (Pooled) | Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 0 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 0 Participants |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 0 Participants |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 0 Participants |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 0 Participants |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 0 Participants |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 0 Participants |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 0 Participants |
| Part A: Cohort 9 SAD: M5717 2100 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 0 Participants |
Primary
Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments
Laboratory assessments included hematology, biochemistry, urinalysis, and coagulation. Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical significance was decided by the investigator.
Time frame: Baseline up to Day 55
Population: Safety Analysis Set included all participants who received investigational medicinal product (M5717 or placebo for Part A).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo (Pooled) | Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
| Part A: Cohort 9 SAD: M5717 2100 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
Primary
Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Number of participants with clinically significant change from baseline in vital signs was reported. Clinical significance was decided by the investigator.
Time frame: Baseline up to Day 55
Population: Safety Analysis Set included all participants who received investigational medicinal product (M5717 or placebo for Part A).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo (Pooled) | Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 1 Participants |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part A: Cohort 9 SAD: M5717 2100 mg | Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
Primary
Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered with study drug which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) 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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs.
Time frame: Baseline up to Day 55
Population: Safety Analysis Set included all participants who received investigational medicinal product (M5717 or placebo for Part A).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 13 Participants |
| Part A: Placebo (Pooled) | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs Leading to Discontinuation | 0 Participants |
| Part A: Placebo (Pooled) | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs Leading to Discontinuation | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 6 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs Leading to Discontinuation | 0 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 5 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs Leading to Discontinuation | 0 Participants |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 3 Participants |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 4 Participants |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs Leading to Discontinuation | 0 Participants |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 3 Participants |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs Leading to Discontinuation | 0 Participants |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 4 Participants |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs Leading to Discontinuation | 0 Participants |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 5 Participants |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs Leading to Discontinuation | 0 Participants |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 6 Participants |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs Leading to Discontinuation | 0 Participants |
| Part A: Cohort 9 SAD: M5717 2100 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 1 Participants |
| Part A: Cohort 9 SAD: M5717 2100 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | TEAEs Leading to Discontinuation | 0 Participants |
| Part A: Cohort 9 SAD: M5717 2100 mg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
Primary
Part C: Apparent Terminal Half Life (t1/2) of M5717
T1/2 was the time measured for the concentration to decrease by one half. T1/2 was calculated as natural log2 divided by lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Apparent Terminal Half Life (t1/2) of M5717 | 106 Hours | Geometric Coefficient of Variation 19.4 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Apparent Terminal Half Life (t1/2) of M5717 | 146 Hours | Geometric Coefficient of Variation 14.9 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Apparent Terminal Half Life (t1/2) of M5717 | 193 Hours | Geometric Coefficient of Variation 20.1 |
Primary
Part C: Apparent Total Clearance (CL/f) of M5717
Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for M5717, whereas AUC0-infinity is area under the plasma concentration-time curve from time zero (dosing time) extrapolated to infinity of unchanged drug calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-infinity calculated by Clastpred/lambda z, where Clastpred is the predicted plasma concentration at the last sampling time point, calculated from the log linear regression line for lambda z determination at which the measured plasma concentration is at or above lower limit of quantification.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Apparent Total Clearance (CL/f) of M5717 | 38.4 Liter per hour | Geometric Coefficient of Variation 41 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Apparent Total Clearance (CL/f) of M5717 | 31.1 Liter per hour | Geometric Coefficient of Variation 40.4 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Apparent Total Clearance (CL/f) of M5717 | 31.9 Liter per hour | Geometric Coefficient of Variation 37.6 |
Primary
Part C: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | 5880 Liter | Geometric Coefficient of Variation 30.1 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | 6530 Liter | Geometric Coefficient of Variation 28.7 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | 8890 Liter | Geometric Coefficient of Variation 26.8 |
Primary
Part C: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717
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 the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. Clastpred was the last predicted quantifiable concentration.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | 3100 Nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 41 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | 10300 Nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 40.4 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | 20000 Nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 37.6 |
Primary
Part C: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717
The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), calculated using the mixed log-linear trapezoidal rule (linear up, log down).
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | 2680 ng*h/mL | Geometric Coefficient of Variation 44.9 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | 9470 ng*h/mL | Geometric Coefficient of Variation 42.9 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | 19200 ng*h/mL | Geometric Coefficient of Variation 38.9 |
Primary
Part C: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717
The area under the plasma concentration-time curve from time zero to 144 hours after dosing was reported. It is calculated using the mixed log-linear trapezoidal rule (linear up, log down).
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, and 144 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | 1930 ng*h/mL | Geometric Coefficient of Variation 34.7 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | 6260 ng*h/mL | Geometric Coefficient of Variation 35.1 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | 10000 ng*h/mL | Geometric Coefficient of Variation 28.4 |
Primary
Part C: Maximum Observed Plasma Concentration (Cmax) of M5717
Cmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717,had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Maximum Observed Plasma Concentration (Cmax) of M5717 | 36.3 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 37 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Maximum Observed Plasma Concentration (Cmax) of M5717 | 174 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 28.7 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Maximum Observed Plasma Concentration (Cmax) of M5717 | 269 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 48.2 |
Primary
Part C: Parasite Reduction Ratio (PRR) Assessed Through Quantitative Polymerase Chain Reaction (qPCR) Analysis
The parasite reduction ratio (PRR) of asexual parasites based on quantitative polymerase chain reaction (qPCR) after administration of M5717 is a mathematical representation of the ratio of the parasite density between drug administration and for a defined period of time. The PRR for asexual forms was estimated using the slope of the optimal fit of the log-linear relationship of the parasitemia decay; ie, the time point where steady exponential decay in parasitemia occurs which may happen after a lag-phase. Lag phase is defined as an initial period after dosing that precedes a steady exponential decline in the parasite count. It was observed that the decline of parasitemia had a biphasic profile, with the first phase, followed by a second phase (the main clearance phase).
Time frame: Day 1 to Day 22
Population: Pharmacodynamic (PD) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PD and provided at least one (measurable) post-dose PD data. Here 'Number of Participants Analyzed' =number of participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Parasite Reduction Ratio (PRR) Assessed Through Quantitative Polymerase Chain Reaction (qPCR) Analysis | First Phase | 1.15 Ratio |
| Part A: Placebo (Pooled) | Part C: Parasite Reduction Ratio (PRR) Assessed Through Quantitative Polymerase Chain Reaction (qPCR) Analysis | Second Phase | 12892 Ratio |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Parasite Reduction Ratio (PRR) Assessed Through Quantitative Polymerase Chain Reaction (qPCR) Analysis | First Phase | 1.73 Ratio |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Parasite Reduction Ratio (PRR) Assessed Through Quantitative Polymerase Chain Reaction (qPCR) Analysis | Second Phase | 5127 Ratio |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Parasite Reduction Ratio (PRR) Assessed Through Quantitative Polymerase Chain Reaction (qPCR) Analysis | First Phase | 3.86 Ratio |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Parasite Reduction Ratio (PRR) Assessed Through Quantitative Polymerase Chain Reaction (qPCR) Analysis | Second Phase | 436 Ratio |
Primary
Part C: Terminal Elimination Rate Constant (Lambda z) of M5717
Lambda z determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Terminal Elimination Rate Constant (Lambda z) of M5717 | 0.00653 one per hour (1/hour) | Geometric Coefficient of Variation 19.4 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Terminal Elimination Rate Constant (Lambda z) of M5717 | 0.00476 one per hour (1/hour) | Geometric Coefficient of Variation 14.9 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Terminal Elimination Rate Constant (Lambda z) of M5717 | 0.00358 one per hour (1/hour) | Geometric Coefficient of Variation 20.1 |
Primary
Part C: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL)
Minimal inhibitory concentration (MIC), defined as the concentration at which the relative rate of change in parasitemia is equal to zero.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo (Pooled) | Part C: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | 314.55 Hours |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | 518.50 Hours |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | 809.12 Hours |
Primary
Part C: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t =>10 ng/mL)
Minimal parasiticidal concentration represents the lowest drug concentration value above which parasites decline at a maximal rate.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo (Pooled) | Part C: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t =>10 ng/mL) | 107.47 Hours |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t =>10 ng/mL) | 281.15 Hours |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t =>10 ng/mL) | 500.26 Hours |
Primary
Part C: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717
The time to reach the maximum observed plasma concentration (tmax) was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo (Pooled) | Part C: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | 3.75 Hours |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | 2.01 Hours |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | 2.00 Hours |
Secondary
Part A: Apparent Terminal Half Life (t1/2) of M5717
T1/2 was the time measured for the concentration to decrease by one half. T1/2 was calculated as natural log2 divided by lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Apparent Terminal Half Life (t1/2) of M5717 | 133 Hours | Geometric Coefficient of Variation 39.7 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Apparent Terminal Half Life (t1/2) of M5717 | 133 Hours | Geometric Coefficient of Variation 29.5 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Apparent Terminal Half Life (t1/2) of M5717 | 145 Hours | Geometric Coefficient of Variation 28.4 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Apparent Terminal Half Life (t1/2) of M5717 | 155 Hours | Geometric Coefficient of Variation 17.3 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Apparent Terminal Half Life (t1/2) of M5717 | 181 Hours | Geometric Coefficient of Variation 25.6 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Apparent Terminal Half Life (t1/2) of M5717 | 169 Hours | Geometric Coefficient of Variation 38 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Apparent Terminal Half Life (t1/2) of M5717 | 180 Hours | Geometric Coefficient of Variation 16.7 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Apparent Terminal Half Life (t1/2) of M5717 | 181 Hours | Geometric Coefficient of Variation 31.4 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Apparent Terminal Half Life (t1/2) of M5717 | 140 Hours | — |
Secondary
Part A: Apparent Total Clearance (CL/f) of M5717
Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for M5717, whereas AUC0-infinity is area under the plasma concentration-time curve from time zero (dosing time) extrapolated to infinity of unchanged drug calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-infinity calculated by Clastpred/lambda z, where Clastpred is the predicted plasma concentration at the last sampling time point, calculated from the log linear regression line for lambda z determination at which the measured plasma concentration is at or above lower limit of quantification.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Apparent Total Clearance (CL/f) of M5717 | 39.9 Liter per hour | Geometric Coefficient of Variation 23.9 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Apparent Total Clearance (CL/f) of M5717 | 46.5 Liter per hour | Geometric Coefficient of Variation 44.3 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Apparent Total Clearance (CL/f) of M5717 | 45.5 Liter per hour | Geometric Coefficient of Variation 28.1 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Apparent Total Clearance (CL/f) of M5717 | 31.7 Liter per hour | Geometric Coefficient of Variation 24.9 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Apparent Total Clearance (CL/f) of M5717 | 27.4 Liter per hour | Geometric Coefficient of Variation 29.7 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Apparent Total Clearance (CL/f) of M5717 | 27.9 Liter per hour | Geometric Coefficient of Variation 29.8 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Apparent Total Clearance (CL/f) of M5717 | 26.3 Liter per hour | Geometric Coefficient of Variation 28.2 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Apparent Total Clearance (CL/f) of M5717 | 27.1 Liter per hour | Geometric Coefficient of Variation 32.4 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Apparent Total Clearance (CL/f) of M5717 | 38.8 Liter per hour | — |
Secondary
Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | 7640 Liters | Geometric Coefficient of Variation 45.6 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | 8890 Liters | Geometric Coefficient of Variation 18.3 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | 9510 Liters | Geometric Coefficient of Variation 32.9 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | 7100 Liters | Geometric Coefficient of Variation 24.3 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | 7160 Liters | Geometric Coefficient of Variation 24.1 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | 6770 Liters | Geometric Coefficient of Variation 38.7 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | 6830 Liters | Geometric Coefficient of Variation 22.5 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | 7060 Liters | Geometric Coefficient of Variation 24.8 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717 | 7870 Liters | — |
Secondary
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717
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 the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. Clastpred was the last predicted quantifiable concentration.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | 997 ng*h/mL | Geometric Coefficient of Variation 23.9 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | 1710 ng*h/mL | Geometric Coefficient of Variation 44.3 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | 3500 ng*h/mL | Geometric Coefficient of Variation 28.1 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | 10100 ng*h/mL | Geometric Coefficient of Variation 24.9 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | 17500 ng*h/mL | Geometric Coefficient of Variation 29.7 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | 28600 ng*h/mL | Geometric Coefficient of Variation 29.8 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | 37800 ng*h/mL | Geometric Coefficient of Variation 28.2 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | 52800 ng*h/mL | Geometric Coefficient of Variation 32.4 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717 | 43000 ng*h/mL | — |
Secondary
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717
The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), calculated using the mixed log-linear trapezoidal rule (linear up, log down).
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | 492 ng*h/mL | Geometric Coefficient of Variation 53.7 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | 1250 ng*h/mL | Geometric Coefficient of Variation 50 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | 2630 ng*h/mL | Geometric Coefficient of Variation 32.6 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | 9290 ng*h/mL | Geometric Coefficient of Variation 25.5 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | 15800 ng*h/mL | Geometric Coefficient of Variation 40.9 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | 27900 ng*h/mL | Geometric Coefficient of Variation 29.7 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | 37000 ng*h/mL | Geometric Coefficient of Variation 28.6 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | 51300 ng*h/mL | Geometric Coefficient of Variation 33 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717 | 42200 ng*h/mL | — |
Secondary
Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717
The area under the plasma concentration-time curve from time zero to 144 hours after dosing was reported. It is calculated using the mixed log-linear trapezoidal rule (linear up, log down).
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, and 144 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | 475 ng*h/mL | Geometric Coefficient of Variation 44 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | 949 ng*h/mL | Geometric Coefficient of Variation 30.3 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | 1940 ng*h/mL | Geometric Coefficient of Variation 28.9 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | 5830 ng*h/mL | Geometric Coefficient of Variation 29.6 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | 9510 ng*h/mL | Geometric Coefficient of Variation 22.4 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | 18400 ng*h/mL | Geometric Coefficient of Variation 28.8 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | 24200 ng*h/mL | Geometric Coefficient of Variation 24 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | 32200 ng*h/mL | Geometric Coefficient of Variation 24.8 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717 | 27200 ng*h/mL | — |
Secondary
Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717
The area under the plasma concentration-time curve from time zero to 144 hours after dosing was reported. It is calculated using the mixed log-linear trapezoidal rule (linear up, log down). Dose normalized was calculated using actual dose, using the formula AUC0-144h/Dose.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, and 144 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717 | 11.9 ng*h/mL/mg | Geometric Coefficient of Variation 44 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717 | 11.9 ng*h/mL/mg | Geometric Coefficient of Variation 30.3 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717 | 12.2 ng*h/mL/mg | Geometric Coefficient of Variation 28.9 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717 | 18.3 ng*h/mL/mg | Geometric Coefficient of Variation 29.6 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717 | 19.9 ng*h/mL/mg | Geometric Coefficient of Variation 22.4 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717 | 23.1 ng*h/mL/mg | Geometric Coefficient of Variation 28.8 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717 | 24.3 ng*h/mL/mg | Geometric Coefficient of Variation 24 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717 | 22.5 ng*h/mL/mg | Geometric Coefficient of Variation 24.8 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717 | 16.3 ng*h/mL/mg | — |
Secondary
Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717
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 the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. Clastpred was the last predicted quantifiable concentration. Dose normalized was calculated using actual dose, using the formula AUC0-inf/Dose.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717 | 25.1 ng*h/mL/mg | Geometric Coefficient of Variation 23.9 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717 | 21.5 ng*h/mL/mg | Geometric Coefficient of Variation 44.3 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717 | 22.0 ng*h/mL/mg | Geometric Coefficient of Variation 28.1 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717 | 31.5 ng*h/mL/mg | Geometric Coefficient of Variation 24.9 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717 | 36.5 ng*h/mL/mg | Geometric Coefficient of Variation 29.7 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717 | 35.9 ng*h/mL/mg | Geometric Coefficient of Variation 29.8 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717 | 38.0 ng*h/mL/mg | Geometric Coefficient of Variation 28.2 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717 | 36.9 ng*h/mL/mg | Geometric Coefficient of Variation 32.4 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717 | 25.8 ng*h/mL/mg | — |
Secondary
Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717
The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), calculated using the mixed log-linear trapezoidal rule (linear up, log down). Dose normalized was calculated using actual dose, using the formula AUC0-t/Dose.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717 | 12.4 ng*h/mL/mg | Geometric Coefficient of Variation 53.7 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717 | 15.7 ng*h/mL/mg | Geometric Coefficient of Variation 50 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717 | 16.5 ng*h/mL/mg | Geometric Coefficient of Variation 32.6 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717 | 29.1 ng*h/mL/mg | Geometric Coefficient of Variation 25.5 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717 | 33.1 ng*h/mL/mg | Geometric Coefficient of Variation 40.9 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717 | 35.0 ng*h/mL/mg | Geometric Coefficient of Variation 29.7 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717 | 37.1 ng*h/mL/mg | Geometric Coefficient of Variation 28.6 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717 | 35.9 ng*h/mL/mg | Geometric Coefficient of Variation 33 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717 | 25.3 ng*h/mL/mg | — |
Secondary
Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717
Cmax was obtained directly from the concentration versus time curve. Dose normalized was calculated using actual dose, using the formula Cmax/Dose.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717 | 0.189 ng/mL/mg | Geometric Coefficient of Variation 54.3 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717 | 0.187 ng/mL/mg | Geometric Coefficient of Variation 19.7 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717 | 0.224 ng/mL/mg | Geometric Coefficient of Variation 41.3 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717 | 0.459 ng/mL/mg | Geometric Coefficient of Variation 37.9 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717 | 0.559 ng/mL/mg | Geometric Coefficient of Variation 25.4 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717 | 0.805 ng/mL/mg | Geometric Coefficient of Variation 53.2 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717 | 0.992 ng/mL/mg | Geometric Coefficient of Variation 40.3 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717 | 0.815 ng/mL/mg | Geometric Coefficient of Variation 22.7 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717 | 0.743 ng/mL/mg | — |
Secondary
Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717
AUCextra% was calculated as area under the curve from time tlast extrapolated to infinity given as percentage of AUC 0-infinity. Here, tlast is the last sampling time at which the concentration is at or above the lower limit of quantification.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717 | 45.2 percentage of AUC0-inf | Geometric Coefficient of Variation 40.5 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717 | 26.2 percentage of AUC0-inf | Geometric Coefficient of Variation 24.3 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717 | 24.0 percentage of AUC0-inf | Geometric Coefficient of Variation 25.8 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717 | 6.98 percentage of AUC0-inf | Geometric Coefficient of Variation 47.1 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717 | 5.89 percentage of AUC0-inf | Geometric Coefficient of Variation 106.5 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717 | 2.36 percentage of AUC0-inf | Geometric Coefficient of Variation 33.2 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717 | 2.09 percentage of AUC0-inf | Geometric Coefficient of Variation 41.9 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717 | 2.12 percentage of AUC0-inf | Geometric Coefficient of Variation 88.7 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717 | 1.78 percentage of AUC0-inf | — |
Secondary
Part A: Maximum Observed Plasma Concentration (Cmax) of M5717
Cmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Maximum Observed Plasma Concentration (Cmax) of M5717 | 7.50 ng/mL | Geometric Coefficient of Variation 54.3 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Maximum Observed Plasma Concentration (Cmax) of M5717 | 14.9 ng/mL | Geometric Coefficient of Variation 19.7 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Maximum Observed Plasma Concentration (Cmax) of M5717 | 35.7 ng/mL | Geometric Coefficient of Variation 41.3 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Maximum Observed Plasma Concentration (Cmax) of M5717 | 146 ng/mL | Geometric Coefficient of Variation 37.9 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Maximum Observed Plasma Concentration (Cmax) of M5717 | 267 ng/mL | Geometric Coefficient of Variation 25.4 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Maximum Observed Plasma Concentration (Cmax) of M5717 | 642 ng/mL | Geometric Coefficient of Variation 53.2 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Maximum Observed Plasma Concentration (Cmax) of M5717 | 988 ng/mL | Geometric Coefficient of Variation 40.3 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Maximum Observed Plasma Concentration (Cmax) of M5717 | 1160 ng/mL | Geometric Coefficient of Variation 22.7 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Maximum Observed Plasma Concentration (Cmax) of M5717 | 1240 ng/mL | — |
Secondary
Part A: Terminal Elimination Rate Constant (Lambda z) of M5717
Lambda z determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part A: Terminal Elimination Rate Constant (Lambda z) of M5717 | 0.00523 one per hour (1/hour) | Geometric Coefficient of Variation 39.7 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Terminal Elimination Rate Constant (Lambda z) of M5717 | 0.00523 one per hour (1/hour) | Geometric Coefficient of Variation 29.5 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Terminal Elimination Rate Constant (Lambda z) of M5717 | 0.00478 one per hour (1/hour) | Geometric Coefficient of Variation 28.4 |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Terminal Elimination Rate Constant (Lambda z) of M5717 | 0.00447 one per hour (1/hour) | Geometric Coefficient of Variation 17.3 |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Terminal Elimination Rate Constant (Lambda z) of M5717 | 0.00382 one per hour (1/hour) | Geometric Coefficient of Variation 25.6 |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Terminal Elimination Rate Constant (Lambda z) of M5717 | 0.00411 one per hour (1/hour) | Geometric Coefficient of Variation 38 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Terminal Elimination Rate Constant (Lambda z) of M5717 | 0.00386 one per hour (1/hour) | Geometric Coefficient of Variation 16.7 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Terminal Elimination Rate Constant (Lambda z) of M5717 | 0.00383 one per hour (1/hour) | Geometric Coefficient of Variation 31.4 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Terminal Elimination Rate Constant (Lambda z) of M5717 | 0.00493 one per hour (1/hour) | — |
Secondary
Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL)
Minimal inhibitory concentration (MIC), defined as the concentration at which the relative rate of change in parasitemia is equal to zero.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo (Pooled) | Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | 84.97 Hours |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | 190.36 Hours |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | 318.49 Hours |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | 551.05 Hours |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | 765.01 Hours |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | 868.99 Hours |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | 832.05 Hours |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | 1031.17 Hours |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL) | 867.02 Hours |
Secondary
Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL)
Minimal parasiticidal concentration represents the lowest drug concentration value above which parasites decline at a maximal rate.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo (Pooled) | Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL) | 0.00 Hours |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL) | 12.43 Hours |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL) | 88.02 Hours |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL) | 272.00 Hours |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL) | 436.47 Hours |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL) | 506.34 Hours |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL) | 531.75 Hours |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL) | 708.93 Hours |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL) | 495.96 Hours |
Secondary
Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717
The time to reach the maximum observed plasma concentration (tmax) was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose
Population: Pharmacokinetic (PK) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PK, and provide at least one (measurable) post-dose concentration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo (Pooled) | Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | 1.00 Hours |
| Part A: Cohort 1 SAD: M5717 50 mg | Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | 7.00 Hours |
| Part A: Cohort 2 SAD: M5717 100 mg | Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | 4.00 Hours |
| Part A: Cohort 3 SAD: M5717 200 mg | Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | 3.00 Hours |
| Part A: Cohort 4 SAD: M5717 400 mg | Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | 2.00 Hours |
| Part A: Cohort 5 SAD: M5717 600 mg | Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | 1.75 Hours |
| Part A: Cohort 6 SAD: M5717 1000 mg | Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | 1.75 Hours |
| Part A: Cohort 7 SAD: M5717 1250 mg | Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | 2.00 Hours |
| Part A: Cohort 8 SAD: M5717 1800 mg | Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717 | 1.50 Hours |
Secondary
Part C: Malarial Clinical Score
The malaria clinical score consists of 14 signs/symptoms frequently associated with malaria and graded using a 4-point scale (absent: 0; mild: 1; moderate: 2; severe: 3) and summed to generate a total malaria clinical score (maximum score possible is 42): headache, myalgia (muscle ache), arthralgia (joint ache), fatigue/lethargy, malaise (general discomfort/uneasiness), chills/shivering/rigors, sweating/hot spells, anorexia, nausea, vomiting, abdominal discomfort, fever, tachycardia and hypotension. Total scores are reported here. The minimum score is 0 (no symptoms) and the maximum score is 42 (maximum symptoms).
Time frame: Day 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 15 and 22
Population: Safety Analysis Set included all participants who received investigational medicinal product (M5717 for Part C). Here, Number Analyzed signified those participants who were evaluable for the specified category at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Malarial Clinical Score | Day 1 | 0 Units on a Scale | Standard Deviation 0.4 |
| Part A: Placebo (Pooled) | Part C: Malarial Clinical Score | Day 2 | 0 Units on a Scale | Standard Deviation 0.4 |
| Part A: Placebo (Pooled) | Part C: Malarial Clinical Score | Day 3 | 1 Units on a Scale | Standard Deviation 0.8 |
| Part A: Placebo (Pooled) | Part C: Malarial Clinical Score | Day 4 | 0 Units on a Scale | Standard Deviation 0.4 |
| Part A: Placebo (Pooled) | Part C: Malarial Clinical Score | Day 5 | 0 Units on a Scale | Standard Deviation 0.4 |
| Part A: Placebo (Pooled) | Part C: Malarial Clinical Score | Day 6 | 0 Units on a Scale | Standard Deviation 0.8 |
| Part A: Placebo (Pooled) | Part C: Malarial Clinical Score | Day 7 | 1 Units on a Scale | Standard Deviation 0.5 |
| Part A: Placebo (Pooled) | Part C: Malarial Clinical Score | Day 9 | 0 Units on a Scale | Standard Deviation 0 |
| Part A: Placebo (Pooled) | Part C: Malarial Clinical Score | Day 11 | 0 Units on a Scale | Standard Deviation 0 |
| Part A: Placebo (Pooled) | Part C: Malarial Clinical Score | Day 15 | 0 Units on a Scale | Standard Deviation 0.4 |
| Part A: Placebo (Pooled) | Part C: Malarial Clinical Score | Day 22 | 0 Units on a Scale | Standard Deviation 0 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Malarial Clinical Score | Day 4 | 1 Units on a Scale | Standard Deviation 0.9 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Malarial Clinical Score | Day 11 | 0 Units on a Scale | Standard Deviation 0 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Malarial Clinical Score | Day 5 | 0 Units on a Scale | Standard Deviation 0.4 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Malarial Clinical Score | Day 6 | 2 Units on a Scale | Standard Deviation 0.7 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Malarial Clinical Score | Day 22 | 0 Units on a Scale | Standard Deviation 0 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Malarial Clinical Score | Day 7 | 0 Units on a Scale | Standard Deviation 0.5 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Malarial Clinical Score | Day 1 | 0 Units on a Scale | Standard Deviation 0 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Malarial Clinical Score | Day 15 | 0 Units on a Scale | Standard Deviation 0.4 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Malarial Clinical Score | Day 2 | 1 Units on a Scale | Standard Deviation 0.9 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Malarial Clinical Score | Day 9 | 0 Units on a Scale | Standard Deviation 0 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Malarial Clinical Score | Day 3 | 0 Units on a Scale | Standard Deviation 0.5 |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Malarial Clinical Score | Day 13 | 0 Units on a Scale | Standard Deviation 0 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Malarial Clinical Score | Day 5 | 0 Units on a Scale | Standard Deviation 0.4 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Malarial Clinical Score | Day 1 | 1 Units on a Scale | Standard Deviation 0.8 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Malarial Clinical Score | Day 4 | 0 Units on a Scale | Standard Deviation 0.7 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Malarial Clinical Score | Day 6 | 0 Units on a Scale | Standard Deviation 0 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Malarial Clinical Score | Day 3 | 0 Units on a Scale | Standard Deviation 0.5 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Malarial Clinical Score | Day 2 | 0 Units on a Scale | Standard Deviation 0.5 |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Malarial Clinical Score | Day 7 | 0 Units on a Scale | — |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Malarial Clinical Score | Day 22 | 0 Units on a Scale | Standard Deviation 0 |
Secondary
Part C: Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration at 90% (MPC90)
MIC is defined as the minimum concentration of a drug at which parasite counts continue to decrease and is equivalent to equating the rate in the change of parasite to 0. Parasiticidal concentration required for 90% killing (MPC90) is defined as the concentration at which the parasite clearance effect is at 90% of the maximum. The estimated MIC and MPC were derived from the final pharmacodynamics (PD) model and pharmacokinetic (PK)/PD relationship.
Time frame: Day 1 up to Day 22
Population: Pharmacodynamic (PD) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PD and provided at least one (measurable) post-dose PD data.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration at 90% (MPC90) | MIC | 7.59 ng/mL |
| Part A: Placebo (Pooled) | Part C: Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration at 90% (MPC90) | MPC90 | 9.21 ng/mL |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration at 90% (MPC90) | MIC | 7.59 ng/mL |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration at 90% (MPC90) | MPC90 | 9.21 ng/mL |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration at 90% (MPC90) | MIC | 7.59 ng/mL |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration at 90% (MPC90) | MPC90 | 9.21 ng/mL |
Secondary
Part C: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings
The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. Number of participants with clinically significant change from baseline in ECG were reported. Clinical significance was decided by the investigator.
Time frame: Baseline up to Day 44
Population: Safety Analysis Set included all participants who received investigational medicinal product (M5717 for Part C).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo (Pooled) | Part C: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 1 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings | 1 Participants |
Secondary
Part C: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments
Laboratory assessments included hematology, biochemistry, urinalysis, and coagulation. Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical significance was decided by the investigator.
Time frame: Baseline up to Day 44
Population: Safety Analysis Set included all participants who received investigational medicinal product (M5717 for Part C).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo (Pooled) | Part C: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments | 0 Participants |
Secondary
Part C: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Number of participants with clinically significant change from baseline in vital signs were reported. Clinical significance was decided by the investigator.
Time frame: Baseline up to Day 44
Population: Safety Analysis Set included all participants who received investigational medicinal product (M5717 for Part C).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo (Pooled) | Part C: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
Secondary
Part C: Number of Participants With Lag Phase
Lag phase is defined as an initial period after dosing that precedes a steady exponential decline in the parasite count. Lag phase is categorized in lag of 4 hours, lag of 6 hours, lag of 12 hours and lag of 24 hours.
Time frame: Day 1 to Day 22
Population: Pharmacodynamic (PD) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PD and provided at least one (measurable) post-dose PD data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Number of Participants With Lag Phase | Lag of 4 hours | 0 Participants |
| Part A: Placebo (Pooled) | Part C: Number of Participants With Lag Phase | Lag of 6 hours | 3 Participants |
| Part A: Placebo (Pooled) | Part C: Number of Participants With Lag Phase | Lag of 12 hours | 1 Participants |
| Part A: Placebo (Pooled) | Part C: Number of Participants With Lag Phase | Lag of 24 hours | 1 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Number of Participants With Lag Phase | Lag of 24 hours | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Number of Participants With Lag Phase | Lag of 4 hours | 6 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Number of Participants With Lag Phase | Lag of 12 hours | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Number of Participants With Lag Phase | Lag of 6 hours | 0 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Number of Participants With Lag Phase | Lag of 24 hours | 0 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Number of Participants With Lag Phase | Lag of 6 hours | 7 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Number of Participants With Lag Phase | Lag of 12 hours | 0 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Number of Participants With Lag Phase | Lag of 4 hours | 0 Participants |
Secondary
Part C: Number of Participants With Recrudescence
Recrudescence is as defined as greater than and equal to 5000 blood stage parasites/milliliter (mL) and a 2-fold parasitemia increase within 48 hours, or re-occurrence of malaria symptoms with a malaria clinical score \> 6. The malaria clinical score consists of 14 signs/symptoms frequently associated with malaria and graded using a 4-point scale with minimum score is 0 (no symptoms) and the maximum score is 42 (maximum symptoms).
Time frame: Day 1 to Day 22
Population: Pharmacodynamic (PD) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PD and provided at least one (measurable) post-dose PD data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo (Pooled) | Part C: Number of Participants With Recrudescence | 3 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Number of Participants With Recrudescence | 2 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Number of Participants With Recrudescence | 0 Participants |
Secondary
Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered with study drug which does not necessarily had a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) 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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs.
Time frame: Baseline up to Day 44
Population: Safety Analysis Set included all participants who received investigational medicinal product (M5717 for Part C).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
| Part A: Placebo (Pooled) | Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 6 Participants |
| Part A: Placebo (Pooled) | Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment | TEAE leading to Discontinuation | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 8 Participants |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment | TEAE leading to Discontinuation | 0 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment | TEAEs | 7 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment | TEAE leading to Discontinuation | 0 Participants |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment | Serious TEAEs | 0 Participants |
Secondary
Part C: Parasite Clearance Half-life (PCT 1/2)
The parasite clearance half-life (PCt1/2), defined as the time needed for parasitemia to be reduced by half during the log-linear phase of parasite clearance, as derived using the slope of the optimal fit of the log-linear relationship of parasitemia decay. It was observed that the decline of parasitemia had a biphasic profile, with the first phase, followed by a second phase (the main clearance phase).
Time frame: Day 1 up to Day 22
Population: Pharmacodynamic (PD) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PD and provided at least one (measurable) post-dose PD data. Here 'Number of Participants Analyzed' =number of participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Part A: Placebo (Pooled) | Part C: Parasite Clearance Half-life (PCT 1/2) | First Phase | 231.06 Hours |
| Part A: Placebo (Pooled) | Part C: Parasite Clearance Half-life (PCT 1/2) | Second Phase | 3.52 Hours |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Parasite Clearance Half-life (PCT 1/2) | First Phase | 60.42 Hours |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Parasite Clearance Half-life (PCT 1/2) | Second Phase | 3.89 Hours |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Parasite Clearance Half-life (PCT 1/2) | First Phase | 24.66 Hours |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Parasite Clearance Half-life (PCT 1/2) | Second Phase | 5.47 Hours |
Secondary
Part C: Parasite Clearance Time
The parasite clearance time (PCT), defined as the time at which malaria parasite levels decline below detectable levels in blood after treatment, estimated as the time at which the linear portion of the optimal log parasitemia-versus-time relationship intersects the LLOQ concentration line.
Time frame: Day 1 up to Day 22
Population: Pharmacodynamic (PD) analysis set included all participants who received M5717, had no clinically important protocol deviations or important events affecting PD and provided at least one (measurable) post-dose PD data. Here 'Number of Participants Analyzed' =number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Placebo (Pooled) | Part C: Parasite Clearance Time | 35.8 Hours |
| Part A: Cohort 1 SAD: M5717 50 mg | Part C: Parasite Clearance Time | 54.4 Hours |
| Part A: Cohort 2 SAD: M5717 100 mg | Part C: Parasite Clearance Time | 55.7 Hours |