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

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ClinicalTrials.gov Identifier: NCT03261401
Recruitment Status : Completed
First Posted : August 25, 2017
Last Update Posted : June 19, 2019
Sponsor:
Information provided by (Responsible Party):
Merck KGaA, Darmstadt, Germany

Brief Summary:
The primary purpose of this study is to investigate the safety and tolerability of M5717 and to characterize the Pharmacokinetics /Pharmacodynamic relationship between M5717 PK and parasite clearance in healthy subjects following infection with Plasmodium falciparum.

Condition or disease Intervention/treatment Phase
Healthy Drug: M5717 Drug: Placebo Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 112 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Other
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
Actual Study Start Date : September 15, 2017
Actual Primary Completion Date : June 14, 2019
Actual Study Completion Date : June 14, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Experimental: Part A: M5717 Drug: M5717
Subjects will receive single ascending oral dose of M5717 after at least 8 hours of fasting together with water on Day 1, followed by a 4-hour post-dose fast

Placebo Comparator: Part A: Placebo Drug: Placebo
Subjects will receive placebo matched to M5717

Experimental: Part B: M5717 Drug: M5717
Subjects will receive multiple ascending oral doses of M5717 after an overnight fast of at least 8 hours once daily for 3 days, followed by a 4-hour post-dose fast

Placebo Comparator: Part B: Placebo Drug: Placebo
Subjects will receive placebo matched to M5717

Experimental: Part C: M5717 Drug: M5717
Subjects will receive single ascending oral dose of M5717 from Part A or as applicable multiple ascending oral doses of M5717 from Part B after at least 8 hours of fasting together with water on Day 1, followed by a 4-hour post-dose fast




Primary Outcome Measures :
  1. Part A and Part B: Occurrence and Severity of Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to end of trial visit (Week 7) ]
  2. Part A and Part B: Occurrence of Clinically Significant Changes and Abnormalities From Baseline in Vital Signs, Laboratory Parameters and 12-lead Electrocardiogram (ECG) Findings [ Time Frame: Day 1 up to end of trial visit (Week 7) ]
  3. Part C: Parasite Reduction Ratio (PRR) Assessed Through Quantitative Polymerase Chain Reaction (qPCR) Analysis [ Time Frame: Day 1 to Week 4 (Day 22) ]
  4. Part C: Maximum Observed Blood Concentration (Cmax) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  5. Part C: Time to Reach Maximum Blood Concentration of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  6. Part C: Elimination Rate Constant (λz) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  7. Part C: Apparent Terminal Half-Life (1/2) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  8. Part C: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  9. Part C: Area Under the Blood Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  10. Part C: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  11. Part C: Area Under the Concentration-Time Curve From Time Zero to 144 Hours (AUC0-144) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  12. Part C: Area Under the Concentration-Time Curve From Time tlast Extrapolated to Infinity (AUCextra%) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  13. Part C: Total Body Clearance (CL/f) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  14. Part C: Apparent Volume of Distribution (Vz/f) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  15. Part C: Dose Normalized Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  16. Part C: Dose Normalized Area Under the Blood Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  17. Part C: Dose Normalized Maximum Observed Blood Concentration (Cmax) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  18. Part C: Time Above or Equal to the Predicted M5717 Mouse Minimal Parasiticidal Concentration (MPC) of 10 nanogram per milliliter [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  19. Part C: Time Above or Equal to the Predicted M5717 Mouse Minimal Parasiticidal Concentration (MPC) of 3 nanogram per milliliter [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  20. Part C: Accumulation ratio for AUC 0-24 of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  21. Part C: Accumulation Ratio for Cmax of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  22. Part C: Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero to Last Sampling Time (AUC 0-t,overall) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  23. Part C: Area Under the Concentration-Time Curve Over Entire Dosing Time Period (From Time Zero Extrapolated to Infinity (AUC 0-inf,overall) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  24. Part C: Average Blood Concentration at Steady State (Cav) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  25. Part C: Minimum Observed Blood Concentration (Cmin) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]

Secondary Outcome Measures :
  1. Part A: Maximum Observed Blood Concentration (Cmax) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  2. Part A: Time to Reach Maximum Blood Concentration (tmax) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  3. Part A: Apparent Terminal Half-Life (t1/2) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  4. Part A: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  5. Part A: Area Under the Blood Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  6. Part A: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  7. Part A: Area Under the Concentration-Time Curve From Time Zero to 144 Hours (AUC0-144) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  8. Part A: Area Under the Concentration-Time Curve From Time tlast Extrapolated to Infinity (AUCextra%) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  9. Part A: Total Body Clearance (CL/f) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  10. Part A: Apparent Volume of Distribution (Vz/f) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  11. Part A: Dose Normalized Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  12. Part A: Dose Normalized Area Under the Blood Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  13. Part A: Dose Normalized Maximum Observed Blood Concentration (Cmax) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  14. Part A: Time Above or Equal to the Predicted M5717 Mouse Minimal Parasiticidal Concentration (MPC) of 10 nanogram per milliliter [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  15. Part A: Time Above or Equal to the Predicted M5717 Mouse Minimal Parasiticidal Concentration (MPC) of 3 nanogram per milliliter [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  16. Part B: Maximum Observed Blood Concentration (Cmax) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  17. Part B: Time to Reach Maximum Blood Concentration (tmax) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  18. Part B: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  19. Part B: Area Under the Blood Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  20. Part B: Dose Normalized Area Under the Blood Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  21. Part B: Dose Normalized Maximum Observed Blood Concentration (Cmax) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  22. Part B: Area Under the Concentration-Time Curve From Time Zero to 144 Hours (AUC0-144) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  23. Part B: Elimination Rate Constant (λz) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  24. Part B: Apparent Terminal Half-Life (t1/2) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  25. Part B: Accumulation Ratio for AUC 0-24 (R acc AUC) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  26. Part B: Accumulation ratio for C max (R acc Cmax) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  27. Part B: Area Under the Concentration-Time Curve Over Entire Dosing Time Period From Time Zero to Last Sampling Time (AUC 0-t,overall) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  28. Part B: Area Under the Concentration-Time Curve Over Entire Dosing Time Period (From Time Zero Extrapolated to Infinity (AUC 0-inf,overall) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  29. Part B: Time Above or Equal to the Predicted M5717 Mouse Minimal Parasiticidal Concentration (MPC) of 10 nanogram per milliliter [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  30. Part B: Time Above or Equal to the Predicted M5717 Mouse Minimal Parasiticidal Concentration (MPC) of 3 nanogram per milliliter [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  31. Part B: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  32. Part B: Dose Normalized Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  33. Part B: Area Under the Curve From Time tlast Extrapolated to Infinity Given as Percentage of AUC 0-infinity (AUC extra%) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  34. Part B: Total Body Clearance (CL/f) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  35. Part B: Apparent Volume of Distribution (Vz/f) of M5717 [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  36. Part B: Average Blood Concentration at Steady State (Cav) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  37. Part B: Minimum Observed Blood Concentration (Cmin) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  38. Parasite Clearance Time [ Time Frame: Day 1 up to Week 4 (Day 22) ]
  39. Minimal Inhibitory Concentration [ Time Frame: Day 1 up to Week 4 (Day 22) ]
  40. Lag Phase Assessed by Steady Exponential Decline in Parasite Count [ Time Frame: Day 1 up to Week 4 (Day 22) ]
    Lag phase is defined as the time period (measured in hours) between administration of the test drug to a parasite infected subject until first sign of parasiticidal effect in terms of steady exponential decline in the parasite count.

  41. Number of Subjects With Recrudescence [ Time Frame: Day 1 up to Week 4 (Day 22) ]
  42. Malarial Clinical Score [ Time Frame: Day 1 up to Week 4 (Day 22) ]
  43. Part C: Occurrence of Treatment-emergent Adverse Events (TEAEs) and Serious AEs (SAEs) [ Time Frame: Day 1 up to end of trial visit (Week 7) ]
  44. Part C: Occurrence of TEAEs and SAEs by Severity [ Time Frame: Day 1 up to end of trial visit (Week 7) ]
  45. Part C: Occurrence of Clinically Significant Changes and Abnormalities From Baseline in Vital Signs, Laboratory Parameters and 12-lead Electrocardiogram (ECG) Findings [ Time Frame: Day 1 up to end of trial visit (Week 7) ]
  46. Part A: Elimination Rate Constant (λz) [ Time Frame: Pre-dose up to end of trial visit (Week 7) ]
  47. Minimal Parasiticidal Concentration (MPC) [ Time Frame: Day 1 up to Week 4 (Day 22) ]
  48. Parasite Clearance Half-life (PCt½) [ Time Frame: Day 1 up to Week 4 (Day 22) ]
    The parasite clearance half-life, defined as the time needed for parasitemia to be reduced by half during the log-linear phase of parasite clearance.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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 subject safety or interfere with the trial evaluation, procedures, or completion.
  • Other protocol defined inclusion criteria could apply.

Exclusion Criteria:

  • Subjects 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.
  • Subjects 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 subject and/or outcome of the trial.
  • Subjects who have any history of malaria.
  • Subjects who have participated in a previous malaria vaccine trial.
  • Subjects who have participated in a previous human malaria challenge trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03261401


Locations
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Australia
Q-Pharm Pty Ltd
Brisbane, Australia, 4006
Sponsors and Collaborators
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: Medical Responsible Merck KGaA, Darmstadt, Germany
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Responsible Party: Merck KGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier: NCT03261401    
Other Study ID Numbers: MS201618_0013
First Posted: August 25, 2017    Key Record Dates
Last Update Posted: June 19, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck KGaA, Darmstadt, Germany:
Healthy Subjects
M5717
Malaria
Plasmodium falciparum