First-in-Human Trial of Single Ascending Dose, Multiple Ascending Dose and Malaria Challenge Model in Healthy Participants

Healthy Clinical Trial

Official title:

A Phase I, First-in-Human, Randomized, Double-Blind, Placebo-Controlled Trial of Single and Multiple Ascending Doses of M5717 to Assess the Safety, Tolerability and Pharmacokinetic Profile of Oral Doses, and to Assess the Antimalarial Activity of M5717 Against Plasmodium Falciparum in Healthy Male and Female Adult Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03261401
• Other study ID #: MS201618_0013
• Secondary ID: 203481/Z/16/Z
• Status: Completed
• Phase: Phase 1
• Start date: September 15, 2017
• Est. completion date: June 14, 2019

Study information

• Verified date: December 2022
• Source: Merck KGaA, Darmstadt, Germany
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 88
• Est. completion date: June 14, 2019
• Est. primary completion date: June 14, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• M5717
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
• Placebo
Participants received placebo matched to M5717
• M5717
Participants received single ascending oral dose of M5717 from Part A after at least 8 hours of fasting together with water on Day 1, followed by a 4-hour post-dose fast

Locations

Country	Name	City	State
Australia	Q-Pharm Pty Ltd	Brisbane

Sponsors (1)

Lead Sponsor	Collaborator
Merck KGaA, Darmstadt, Germany

Country where clinical trial is conducted

Australia, 

References & Publications (1)

McCarthy JS, Yalkinoglu O, Odedra A, Webster R, Oeuvray C, Tappert A, Bezuidenhout D, Giddins MJ, Dhingra SK, Fidock DA, Marquart L, Webb L, Yin X, Khandelwal A, Bagchus WM. Safety, pharmacokinetics, and antimalarial activity of the novel plasmodium eukar — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline up to Day 55
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.	Baseline up to Day 55
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.	Baseline up to Day 55
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.	Baseline up to Day 55
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).	Day 1 to Day 22
Primary	Part C: Maximum Observed Plasma Concentration (Cmax) of M5717	Cmax was obtained directly from the concentration versus time curve.	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
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.	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
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.	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
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.	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
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).	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
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).	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
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.	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
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.	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
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.	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
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.	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
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.	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
Secondary	Part A: Maximum Observed Plasma Concentration (Cmax) of M5717	Cmax was obtained directly from the concentration versus time curve.	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
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.	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
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.	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
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.	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
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.	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
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).	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
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).	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	Day 1 up to Day 22
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).	Day 1 up to Day 22
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.	Day 1 to Day 22
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).	Day 1 to Day 22
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).	Day 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 15 and 22
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.	Day 1 up to Day 22
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.	Baseline up to Day 44
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.	Baseline up to Day 44
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.	Baseline up to Day 44
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.	Baseline up to Day 44

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