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

NCT03261401 | Completed Phase 1 Results

• 2 other identifiers: MS201618_0013203481/Z/16/Z
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy

Keywords

Healthy Participants; M5717; Malaria; Plasmodium falciparum

Outcome Measures

Primary Outcomes (16)

• Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation of Study Treatment

  An adverse event (AE) was defined as any untoward medical occurrence in a participant administered with study drug which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs.

  Baseline up to Day 55

• Part A: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Assessments

  Laboratory assessments included hematology, biochemistry, urinalysis, and coagulation. Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical significance was decided by the investigator.

  Baseline up to Day 55

• Part A: Number of Participants With Clinically Significant Changes From Baseline in 12-lead Electrocardiograms (ECGs) Findings

  The 12-lead ECGs were recorded after the participants had rested for at least 5 minutes in supine position. Number of participants with clinically significant change from baseline in ECGs was reported. Clinical significance was decided by the investigator.

  Baseline up to Day 55

• Part A: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs

  Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Number of participants with clinically significant change from baseline in vital signs was reported. Clinical significance was decided by the investigator.

  Baseline up to Day 55

• Part C: Parasite Reduction Ratio (PRR) Assessed Through Quantitative Polymerase Chain Reaction (qPCR) Analysis

  The parasite reduction ratio (PRR) of asexual parasites based on quantitative polymerase chain reaction (qPCR) after administration of M5717 is a mathematical representation of the ratio of the parasite density between drug administration and for a defined period of time. The PRR for asexual forms was estimated using the slope of the optimal fit of the log-linear relationship of the parasitemia decay; ie, the time point where steady exponential decay in parasitemia occurs which may happen after a lag-phase. Lag phase is defined as an initial period after dosing that precedes a steady exponential decline in the parasite count. It was observed that the decline of parasitemia had a biphasic profile, with the first phase, followed by a second phase (the main clearance phase).

  Day 1 to Day 22

• Part C: Maximum Observed Plasma Concentration (Cmax) of M5717

  Cmax was obtained directly from the concentration versus time curve.

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part C: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717

  The time to reach the maximum observed plasma concentration (tmax) was obtained directly from the concentration versus time curve.

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part C: Terminal Elimination Rate Constant (Lambda z) of M5717

  Lambda z determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve.

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part C: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717

  The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. Clastpred was the last predicted quantifiable concentration.

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part C: Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M5717

  The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), calculated using the mixed log-linear trapezoidal rule (linear up, log down).

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part C: Area Under the Plasma Concentration-Time Curve From Time Zero to Time 144 Hours After Drug Administration (AUC0-144h) of M5717

  The area under the plasma concentration-time curve from time zero to 144 hours after dosing was reported. It is calculated using the mixed log-linear trapezoidal rule (linear up, log down).

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, and 144 hours post-dose

• Part C: Apparent Terminal Half Life (t1/2) of M5717

  T1/2 was the time measured for the concentration to decrease by one half. T1/2 was calculated as natural log2 divided by lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve.

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part C: Apparent Total Clearance (CL/f) of M5717

  Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for M5717, whereas AUC0-infinity is area under the plasma concentration-time curve from time zero (dosing time) extrapolated to infinity of unchanged drug calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-infinity calculated by Clastpred/lambda z, where Clastpred is the predicted plasma concentration at the last sampling time point, calculated from the log linear regression line for lambda z determination at which the measured plasma concentration is at or above lower limit of quantification.

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part C: Apparent Volume of Distribution During Terminal Phase (VZ/f) of M5717

  Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose.

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part C: Time Above or Equal to the Predicted M5717 Minimum Inhibitory Concentration (MIC) of 3 ng/mL (t =>3 ng/mL)

  Minimal inhibitory concentration (MIC), defined as the concentration at which the relative rate of change in parasitemia is equal to zero.

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part C: Time Above or Equal to the Predicted M5717 Minimum Parasiticidal Concentration (MPC) of 10 ng/mL (t =>10 ng/mL)

  Minimal parasiticidal concentration represents the lowest drug concentration value above which parasites decline at a maximal rate.

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

Secondary Outcomes (26)

• Part A: Maximum Observed Plasma Concentration (Cmax) of M5717

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of M5717

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part A: Terminal Elimination Rate Constant (Lambda z) of M5717

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part A: Apparent Terminal Half Life (t1/2) of M5717

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

• Part A: Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M5717

  Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 72, 96, 120, 144, 192, 240, 384, 504, 768 and 1032 hours post-dose

Study Arms (13)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Drug: M5717

Interventions

M5717 DRUG

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

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

Placebo DRUG

Participants received placebo matched to M5717

Part A: Placebo (Pooled)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead

Study Sites (1)

Q-Pharm Pty Ltd

Brisbane, Australia

Location

Related Publications (1)

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

  PMID: 34715032 RESULT

Related Links

• Trial Awareness and Transparency website
• Medical Information Location Map - Med Info Contacts

MeSH Terms

Conditions

Malaria; Malaria, Falciparum

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Results Point of Contact

• Title: Communication Center
• Organization: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 18, 2017
• First Posted: August 25, 2017
• Study Start: September 15, 2017
• Primary Completion: June 14, 2019
• Study Completion: June 14, 2019
• Last Updated: October 16, 2023
• Results First Posted: October 16, 2023

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)