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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/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

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

Secondary ID [1]

203481/Z/16/Z

Secondary ID [2]

MS201618_0013

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Healthy

Condition category

Condition code

Intervention/exposure

Study type

Interventional

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

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

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

Timepoint [1]

Baseline up to Day 55

Primary outcome [2]

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

Timepoint [2]

Baseline up to Day 55

Primary outcome [3]

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

Timepoint [3]

Baseline up to Day 55

Primary outcome [4]

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

Timepoint [4]

Baseline up to Day 55

Primary outcome [5]

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

Timepoint [5]

Day 1 to Day 22

Primary outcome [6]

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

Timepoint [6]

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

Primary outcome [7]

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

Timepoint [7]

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

Primary outcome [8]

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

Timepoint [8]

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

Primary outcome [9]

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

Timepoint [9]

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

Primary outcome [10]

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

Timepoint [10]

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

Primary outcome [11]

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

Timepoint [11]

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

Primary outcome [12]

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

Timepoint [12]

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

Primary outcome [13]

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

Timepoint [13]

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

Primary outcome [14]

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

Timepoint [14]

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

Primary outcome [15]

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

Timepoint [15]

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

Primary outcome [16]

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

Timepoint [16]

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 outcome [1]

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

Timepoint [1]

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 outcome [2]

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

Timepoint [2]

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 outcome [3]

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

Timepoint [3]

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 outcome [4]

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

Timepoint [4]

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 outcome [5]

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

Timepoint [5]

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 outcome [6]

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

Timepoint [6]

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 outcome [7]

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

Timepoint [7]

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

Secondary outcome [8]

Part A: Extrapolated Area Under the Plasma Concentration Curve From Time of Last Quantifiable Sample to Infinity (AUCextra%) of M5717

Timepoint [8]

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 outcome [9]

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

Timepoint [9]

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 outcome [10]

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

Timepoint [10]

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 outcome [11]

Part A: Dose Normalized AUC0-inf [AUC(0-inf/Dose)] of M5717

Timepoint [11]

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 outcome [12]

Part A: Dose Normalized AUC0-144h [AUC(0-144hour/Dose)] of M5717

Timepoint [12]

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

Secondary outcome [13]

Part A: Dose Normalized AUC0-t [AUC( 0-t/Dose)] of M5717

Timepoint [13]

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 outcome [14]

Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M5717

Timepoint [14]

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 outcome [15]

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

Timepoint [15]

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 outcome [16]

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

Timepoint [16]

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 outcome [17]

Part C: Parasite Clearance Time

Timepoint [17]

Day 1 up to Day 22

Secondary outcome [18]

Part C: Parasite Clearance Half-life (PCT 1/2)

Timepoint [18]

Day 1 up to Day 22

Secondary outcome [19]

Part C: Number of Participants With Lag Phase

Timepoint [19]

Day 1 to Day 22

Secondary outcome [20]

Part C: Number of Participants With Recrudescence

Timepoint [20]

Day 1 to Day 22

Secondary outcome [21]

Part C: Malarial Clinical Score

Timepoint [21]

Day 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 15 and 22

Secondary outcome [22]

Part C: Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration at 90% (MPC90)

Timepoint [22]

Day 1 up to Day 22

Secondary outcome [23]

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

Timepoint [23]

Baseline up to Day 44

Secondary outcome [24]

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

Timepoint [24]

Baseline up to Day 44

Secondary outcome [25]

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

Timepoint [25]

Baseline up to Day 44

Secondary outcome [26]

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

Timepoint [26]

Baseline up to Day 44

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.

Minimum age

18 Years

Maximum age

55 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

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.

Study design

Purpose of the study

Other

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 1

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Data analysis

Reason for early stopping/withdrawal

Other reasons

Date of first participant enrolment

Anticipated

Actual

15/09/2017

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

14/06/2019

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Q-Pharm Pty Ltd - Brisbane

Recruitment postcode(s) [1]

- Brisbane

Funding & Sponsors

Primary sponsor type

Commercial sector/industry

Name

Merck KGaA, Darmstadt, Germany

Address

Country

Ethics approval

Ethics application status

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.

Trial website

https://clinicaltrials.gov/study/NCT03261401

Trial related presentations / 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.

Public notes

Contacts

Principal investigator

Name

Medical Responsible

Address

Merck KGaA, Darmstadt, Germany

Country

Phone

Fax

Contact person for public queries

Name

Address

Country

Phone

Fax

Contact person for scientific queries

Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT03261401

Trial Review

Did you know?

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03261401