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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03261401
Registration number
NCT03261401
Ethics application status
Date submitted
18/08/2017
Date registered
25/08/2017
Date last updated
16/10/2023
Titles & IDs
Public title
First-in-Human Trial of Single Ascending Dose, Multiple Ascending Dose and Malaria Challenge Model in Healthy Participants
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Scientific 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
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Secondary ID [1]
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203481/Z/16/Z
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Secondary ID [2]
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MS201618_0013
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Healthy
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Condition category
Condition code
Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - M5717
Treatment: Drugs - Placebo
Treatment: Drugs - M5717
Placebo Comparator: Part A: Placebo (Pooled) - Participants received capsules containing 50 milligram (mg) of placebo matched similar to M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose.
Experimental: 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.
Experimental: 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.
Experimental: 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.
Experimental: 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.
Experimental: 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.
Experimental: 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.
Experimental: 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.
Experimental: 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.
Experimental: 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.
Experimental: Part C: Challenge Cohort 2 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.
Experimental: Part C: Challenge Cohort 1 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.
Experimental: Part C: Challenge Cohort 3 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.
Treatment: Drugs: 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
Treatment: Drugs: Placebo
Participants received placebo matched to M5717
Treatment: Drugs: 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
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline up to Day 55
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Primary outcome [2]
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Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments
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Assessment method [2]
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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.
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Timepoint [2]
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Baseline up to Day 55
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Primary outcome [3]
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Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings
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Assessment method [3]
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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.
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Timepoint [3]
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Baseline up to Day 55
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Primary outcome [4]
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Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
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Assessment method [4]
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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.
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Timepoint [4]
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Baseline up to Day 55
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Primary outcome [5]
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Part C: Parasite Reduction Ratio (PRR) Assessed Through Quantitative Polymerase Chain Reaction (qPCR) Analysis
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Assessment method [5]
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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).
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Timepoint [5]
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Day 1 to Day 22
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Primary outcome [6]
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Part C: Maximum Observed Plasma Concentration (Cmax) of M5717
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Assessment method [6]
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Cmax was obtained directly from the concentration versus time curve.
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Timepoint [6]
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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
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Primary outcome [7]
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Part C: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717
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Assessment method [7]
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The time to reach the maximum observed plasma concentration (tmax) was obtained directly from the concentration versus time curve.
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Timepoint [7]
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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
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Primary outcome [8]
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Part C: Terminal Elimination Rate Constant (Lambda z) of M5717
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Assessment method [8]
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Lambda z determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve.
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Timepoint [8]
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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
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Primary outcome [9]
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Part C: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717
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Assessment method [9]
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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.
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Timepoint [9]
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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
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Primary outcome [10]
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Part C: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717
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Assessment method [10]
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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).
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Timepoint [10]
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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
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Primary outcome [11]
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Part C: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717
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Assessment method [11]
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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).
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Timepoint [11]
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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
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Primary outcome [12]
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Part C: Apparent Terminal Half Life (t1/2) of M5717
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Assessment method [12]
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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.
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Timepoint [12]
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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
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Primary outcome [13]
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Part C: Apparent Total Clearance (CL/f) of M5717
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Assessment method [13]
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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.
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Timepoint [13]
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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
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Primary outcome [14]
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Part C: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717
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Assessment method [14]
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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.
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Timepoint [14]
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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
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Primary outcome [15]
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Part C: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL)
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Assessment method [15]
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Minimal inhibitory concentration (MIC), defined as the concentration at which the relative rate of change in parasitemia is equal to zero.
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Timepoint [15]
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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
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Primary outcome [16]
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Part C: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t =>10 ng/mL)
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Assessment method [16]
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Minimal parasiticidal concentration represents the lowest drug concentration value above which parasites decline at a maximal rate.
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Timepoint [16]
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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
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Secondary outcome [1]
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Part A: Maximum Observed Plasma Concentration (Cmax) of M5717
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Assessment method [1]
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Cmax was obtained directly from the concentration versus time curve.
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Timepoint [1]
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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
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Secondary outcome [2]
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Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717
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Assessment method [2]
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The time to reach the maximum observed plasma concentration (tmax) was obtained directly from the concentration versus time curve.
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Timepoint [2]
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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
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Secondary outcome [3]
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Part A: Terminal Elimination Rate Constant (Lambda z) of M5717
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Assessment method [3]
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Lambda z determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve.
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Timepoint [3]
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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
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Secondary outcome [4]
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Part A: Apparent Terminal Half Life (t1/2) of M5717
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Assessment method [4]
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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.
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Timepoint [4]
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0
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
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Secondary outcome [5]
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Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717
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Assessment method [5]
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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.
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Timepoint [5]
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0
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
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Secondary outcome [6]
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Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717
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Assessment method [6]
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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).
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Timepoint [6]
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0
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
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Secondary outcome [7]
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Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717
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Assessment method [7]
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0
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).
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Timepoint [7]
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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
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Secondary outcome [8]
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Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717
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Assessment method [8]
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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.
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Timepoint [8]
0
0
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
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Secondary outcome [9]
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Part A: Apparent Total Clearance (CL/f) of M5717
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Assessment method [9]
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0
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.
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Timepoint [9]
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0
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
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Secondary outcome [10]
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0
Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717
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Assessment method [10]
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0
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.
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Timepoint [10]
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0
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
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Secondary outcome [11]
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0
Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717
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Assessment method [11]
0
0
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.
Query!
Timepoint [11]
0
0
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
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Secondary outcome [12]
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0
Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717
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Assessment method [12]
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0
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.
Query!
Timepoint [12]
0
0
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
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Secondary outcome [13]
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0
Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717
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Assessment method [13]
0
0
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.
Query!
Timepoint [13]
0
0
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
Query!
Secondary outcome [14]
0
0
Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717
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Assessment method [14]
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0
Cmax was obtained directly from the concentration versus time curve. Dose normalized was calculated using actual dose, using the formula Cmax/Dose.
Query!
Timepoint [14]
0
0
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
Query!
Secondary outcome [15]
0
0
Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL)
Query!
Assessment method [15]
0
0
Minimal inhibitory concentration (MIC), defined as the concentration at which the relative rate of change in parasitemia is equal to zero.
Query!
Timepoint [15]
0
0
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
Query!
Secondary outcome [16]
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0
Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL)
Query!
Assessment method [16]
0
0
Minimal parasiticidal concentration represents the lowest drug concentration value above which parasites decline at a maximal rate.
Query!
Timepoint [16]
0
0
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
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Secondary outcome [17]
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0
Part C: Parasite Clearance Time
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Assessment method [17]
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0
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.
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Timepoint [17]
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0
Day 1 up to Day 22
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Secondary outcome [18]
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0
Part C: Parasite Clearance Half-life (PCT 1/2)
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Assessment method [18]
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0
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).
Query!
Timepoint [18]
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0
Day 1 up to Day 22
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Secondary outcome [19]
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0
Part C: Number of Participants With Lag Phase
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Assessment method [19]
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0
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.
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Timepoint [19]
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0
Day 1 to Day 22
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Secondary outcome [20]
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0
Part C: Number of Participants With Recrudescence
Query!
Assessment method [20]
0
0
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).
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Timepoint [20]
0
0
Day 1 to Day 22
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Secondary outcome [21]
0
0
Part C: Malarial Clinical Score
Query!
Assessment method [21]
0
0
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).
Query!
Timepoint [21]
0
0
Day 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 15 and 22
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Secondary outcome [22]
0
0
Part C: Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration at 90% (MPC90)
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Assessment method [22]
0
0
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.
Query!
Timepoint [22]
0
0
Day 1 up to Day 22
Query!
Secondary outcome [23]
0
0
Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment
Query!
Assessment method [23]
0
0
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.
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Timepoint [23]
0
0
Baseline up to Day 44
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Secondary outcome [24]
0
0
Part C: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments
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Assessment method [24]
0
0
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.
Query!
Timepoint [24]
0
0
Baseline up to Day 44
Query!
Secondary outcome [25]
0
0
Part C: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings
Query!
Assessment method [25]
0
0
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.
Query!
Timepoint [25]
0
0
Baseline up to Day 44
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Secondary outcome [26]
0
0
Part C: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Query!
Assessment method [26]
0
0
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.
Query!
Timepoint [26]
0
0
Baseline up to Day 44
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Eligibility
Key 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.
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Minimum age
18
Years
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Maximum age
55
Years
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Sex
Both males and females
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Can healthy volunteers participate?
Yes
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Key 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.
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Study design
Purpose of the study
Other
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people analysing the results/data
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Query!
Query!
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
Query!
Data analysis
Query!
Reason for early stopping/withdrawal
Query!
Other reasons
Query!
Date of first participant enrolment
Anticipated
Query!
Actual
15/09/2017
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Date of last participant enrolment
Anticipated
Query!
Actual
Query!
Date of last data collection
Anticipated
Query!
Actual
14/06/2019
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Sample size
Target
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Accrual to date
Query!
Final
88
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Recruitment in Australia
Recruitment state(s)
Query!
Recruitment hospital [1]
0
0
Q-Pharm Pty Ltd - Brisbane
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Recruitment postcode(s) [1]
0
0
- Brisbane
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Merck KGaA, Darmstadt, Germany
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03261401
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
0
0
Medical Responsible
Query!
Address
0
0
Merck KGaA, Darmstadt, Germany
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Country
0
0
Query!
Phone
0
0
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Fax
0
0
Query!
Email
0
0
Query!
Contact person for public queries
Name
0
0
Query!
Address
0
0
Query!
Country
0
0
Query!
Phone
0
0
Query!
Fax
0
0
Query!
Email
0
0
Query!
Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03261401
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