HealthyPhase 1NCT03261401
First-in-Human Trial of Single Ascending Dose, Multiple Ascending Dose and Malaria Challenge Model in Healthy Participants
A Phase 1 study testing M5717 in people with Healthy, run by Merck KGaA, Darmstadt, Germany at 1 site in Australia.
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. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- M5717
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 88 participants
- Where
- 1 siteAustralia
- Study dates
- 15 Sep 2017to 14 Jun 2019
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
- Conditions
- Healthy
- Being tested
- M5717, Placebo
- Keywords
- Healthy Participants, M5717, Malaria, Plasmodium falciparum
- Medical subject headings
- Malaria, Malaria, Falciparum
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
M5717Drug
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
PlaceboDrug
Participants received placebo matched to M5717
M5717Drug
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
| Study group | Role | What they receive |
|---|---|---|
| Part A: Placebo (Pooled) | Placebo comparator | 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. Receives: Drug: Placebo |
| Part A: Cohort 1 SAD: M5717 50 mg | Experimental | 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. Receives: Drug: M5717 |
| Part A: Cohort 2 SAD: M5717 100 mg | Experimental | Participants received SAD of 100 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. Receives: Drug: M5717 |
| Part A: Cohort 3 SAD: M5717 200 mg | Experimental | Participants received SAD of 200 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. Receives: Drug: M5717 |
| Part A: Cohort 4 SAD: M5717 400 mg | Experimental | Participants received SAD of 400 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. Receives: Drug: M5717 |
| Part A: Cohort 5 SAD: M5717 600 mg | Experimental | Participants received SAD of 600 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. Receives: Drug: M5717 |
| Part A: Cohort 6 SAD: M5717 1000 mg | Experimental | Participants received SAD of 1000 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. Receives: Drug: M5717 |
| Part A: Cohort 7 SAD: M5717 1250 mg | Experimental | 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. Receives: Drug: M5717 |
| Part A: Cohort 8 SAD: M5717 1800 mg | Experimental | 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. Receives: Drug: M5717 |
| Part A: Cohort 9 SAD: M5717 2100 mg | Experimental | 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. Receives: Drug: M5717 |
| Part C: Challenge Cohort 2 M5717 150 mg | Experimental | 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. Receives: Drug: M5717 |
| Part C: Challenge Cohort 1 M5717 400 mg | Experimental | 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. Receives: Drug: M5717 |
| Part C: Challenge Cohort 3 M5717 800 mg | Experimental | 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. Receives: Drug: M5717 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline up to Day 55
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.
Measured: Baseline up to Day 55
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.
Measured: Baseline up to Day 55
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.
Measured: Baseline up to Day 55
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).
Measured: Day 1 to Day 22
Part C: Maximum Observed Plasma Concentration (Cmax) of M5717
Cmax was obtained directly from the concentration versus time curve.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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).
Measured: 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
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).
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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 outcomes (26)
Part A: Maximum Observed Plasma Concentration (Cmax) of M5717
Cmax was obtained directly from the concentration versus time curve.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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).
Measured: 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
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).
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: Day 1 up to Day 22
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).
Measured: Day 1 up to Day 22
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.
Measured: Day 1 to Day 22
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).
Measured: Day 1 to Day 22
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).
Measured: Day 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 15 and 22
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.
Measured: Day 1 up to Day 22
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.
Measured: Baseline up to Day 44
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.
Measured: Baseline up to Day 44
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.
Measured: Baseline up to Day 44
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.
Measured: Baseline up to Day 44
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Aug 2017
- Study start15 Sep 2017
- Primary completion14 Jun 2019
- Study completion14 Jun 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 88 participants (actual)
Sponsor and investigators
- Lead sponsor
- Merck KGaA, Darmstadt, Germany
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Responsible, Study director, Merck KGaA, Darmstadt, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03261401
- Sponsor's protocol ID
- MS201618_0013
- Other IDs
- 203481/Z/16/Z
- Status last verified
- Dec 2022
- First submitted
- 18 Aug 2017
- Last updated
- 16 Oct 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21
Publications
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 eukaryotic translation elongation factor 2 inhibitor M5717: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection study. Lancet Infect Dis. 2021 Dec;21(12):1713-1724. doi: 10.1016/S1473-3099(21)00252-8. Epub 2021 Oct 26.
PubMed 34715032
Study at a glance
From the registry record, last updated by the sponsor on 16 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03261401
- Acronym / sponsor ID
- MS201618_0013
- Conditions
- Healthy
- Keywords
- Healthy Participants, M5717, Malaria, Plasmodium falciparum
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 88 participants (actual)
- Lead sponsor
- Merck KGaA, Darmstadt, GermanyIndustry (pharma, biotech, devices)
- Study start
- 15 Sep 2017 (actual)
- Primary completion
- 14 Jun 2019 (actual)
- Study completion
- 14 Jun 2019 (actual)
- First posted
- 25 Aug 2017 (actual)
- Results
- Posted 16 Oct 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 13
| Arm | Type | Receives |
|---|---|---|
| Part A: Placebo (Pooled) | Placebo comparator | Drug: PlaceboParticipants 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. |
| Part A: Cohort 1 SAD: M5717 50 mg | Experimental | Drug: M5717Participants 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. |
| Part A: Cohort 2 SAD: M5717 100 mg | Experimental | Drug: M5717Participants received SAD of 100 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. |
| Part A: Cohort 3 SAD: M5717 200 mg | Experimental | Drug: M5717Participants received SAD of 200 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. |
| Part A: Cohort 4 SAD: M5717 400 mg | Experimental | Drug: M5717Participants received SAD of 400 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. |
| Part A: Cohort 5 SAD: M5717 600 mg | Experimental | Drug: M5717Participants received SAD of 600 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. |
| Part A: Cohort 6 SAD: M5717 1000 mg | Experimental | Drug: M5717Participants received SAD of 1000 mg M5717 on Day 1 after 8 hours fasting-period followed by a 4-hour post-dose fast. |
| Part A: Cohort 7 SAD: M5717 1250 mg | Experimental | Drug: M5717Participants 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. |
| Part A: Cohort 8 SAD: M5717 1800 mg | Experimental | Drug: M5717Participants 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. |
| Part A: Cohort 9 SAD: M5717 2100 mg | Experimental | Drug: M5717Participants 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. |
| Part C: Challenge Cohort 2 M5717 150 mg | Experimental | Drug: M5717Participants 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. |
| Part C: Challenge Cohort 1 M5717 400 mg | Experimental | Drug: M5717Participants 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. |
| Part C: Challenge Cohort 3 M5717 800 mg | Experimental | Drug: M5717Participants 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. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| M5717Participants 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 | Drug | Part A: Cohort 1 SAD: M5717 50 mg, Part A: Cohort 2 SAD: M5717 100 mg, 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 |
| PlaceboParticipants received placebo matched to M5717 | Drug | Part A: Placebo (Pooled) |
| M5717Participants 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 | Drug | Part C: Challenge Cohort 1 M5717 400 mg, Part C: Challenge Cohort 2 M5717 150 mg, Part C: Challenge Cohort 3 M5717 800 mg |
Primary outcome
Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
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
Cmax was obtained directly from the concentration versus time curve.
Part C: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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)
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
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)
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
Minimal parasiticidal concentration represents the lowest drug concentration value above which parasites decline at a maximal rate.
26 secondary outcomes
Part A: Maximum Observed Plasma Concentration (Cmax) of M5717
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
Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717
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
Part A: Terminal Elimination Rate Constant (Lambda z) of M5717
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
Part A: Apparent Terminal Half Life (t1/2) of M5717
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
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717
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
Part A: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717
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
Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717
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
Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717
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
Part A: Apparent Total Clearance (CL/f) of M5717
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
Part A: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717
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
Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717
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
Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717
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
Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717
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
Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717
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
Part A: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL)
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
Part A: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t=>10 ng/mL)
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
Part C: Parasite Clearance Time
Time frame: Day 1 up to Day 22
Part C: Parasite Clearance Half-life (PCT 1/2)
Time frame: Day 1 up to Day 22
Part C: Number of Participants With Lag Phase
Time frame: Day 1 to Day 22
Part C: Number of Participants With Recrudescence
Time frame: Day 1 to Day 22
Part C: Malarial Clinical Score
Time frame: Day 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 15 and 22
Part C: Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration at 90% (MPC90)
Time frame: Day 1 up to Day 22
Part C: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation of Study Treatment
Time frame: Baseline up to Day 44
Part C: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments
Time frame: Baseline up to Day 44
Part C: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings
Time frame: Baseline up to Day 44
Part C: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Time frame: Baseline up to Day 44
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Oct 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 34715032McCarthy 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 eukaryotic translation elongation factor 2 inhibitor M5717: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection study. Lancet Infect Dis. 2021 Dec;21(12):1713-1724. doi: 10.1016/S1473-3099(21)00252-8. Epub 2021 Oct 26.
- Trial Awareness and Transparency websiteLink provided by the sponsor.
- Medical Information Location Map - Med Info ContactsLink provided by the sponsor.
- Individual participant dataSharing planned: No. We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Responsible study director
Merck KGaA, Darmstadt, Germany
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing M5717 in people with Healthy, run by Merck KGaA, Darmstadt, Germany at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Oct 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment (time frame: Baseline up to Day 55). The study lists 16 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03261401, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Oct 2023.