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The purpose of this trial is to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of GRT7041 in healthy male and female (Women of non-childbearing potential) participants.
The trial duration will be up to approximately 6 weeks for participants in Part 1 (Single ascending dose [SAD]), except for participants taking part in the food effect cohort SAD3 where the trial duration will be up to approximately 8 weeks. The trial duration will be up to approximately 7 weeks in Part 2 (Multiple ascending dose [MAD]), and the Treatment Period will be up to 14 days (for Part 2).
The trial will include a Screening Visit, an in-house stay period and Follow-up (FU) Visit/End-of-Trial (EoT) Visit.
The trial will consist of two parts:
The trial design also evaluate the potential interaction of GRT7041 with a CYP3A4 index substrate that will be assessed separately in all cohorts in Part 2 (MAD) of the trial.
Dosing in Parts 1 and 2 will be conducted under fasted conditions, except for the SAD3 cohort in Part 1 (SAD), where participants will also receive a standardized breakfast (SAD3b treatment) to assess the effect of food.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part 1: SAD | Experimental | With up to five cohorts SAD1 to SAD5 (n = 40). To be conducted in adult males and WONCBP |
|
| Part 2: MAD | Experimental | With up to three cohorts, MAD1 to MAD3 (n = 30) dosed once daily (QD) for a period of 14 days. To be conducted in adult males only. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GRT7041 SAD | Drug | Single ascending doses |
| |
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Number of participants with Adverse Events | An AE is defined as any unfavorable medical occurrence in a trial participant administered the investigational product. Assessment of the safety and tolerability of GRT7041 after oral single and multiple-dose escalation | Through study completion, an average of 8 Weeks |
| Number of participants with Serious Adverse Events | A Serious Adverse Event (SAE) is any untoward medical occurrence that, at any dose:
Assessment of the safety and tolerability of GRT7041 after oral single and multiple-dose escalation | Through study completion, an average of 8 Weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Concentration-Time Curve from 0 to 24 hours [(AUC)0-24] [SAD] | The total amount of the study drug (and metabolite) in the blood during the first 24 hours after it is taken. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
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Main Inclusion Criteria:
Main Exclusion Criteria:
The participant is biologically male (both Part 1 and Part 2) or biological female of non-childbearing potential (Part 1 only).
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Grünenthal Clinical Trial Helpdesk | Contact | +49 241 569 | 3223 | clinical-trials@grunenthal.com |
| Director Clinical Trials | Contact | clinical-trials@grunenthal.com |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| New Zealand Clinical Research (NZCR) | Recruiting | Christchurch | 8011 | New Zealand |
Information available on the Grünenthal Group Web Site (see URL below for details); according to the European Federation of Pharmaceutical Industries and Associations (EFPIA) Data Sharing Principles.
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| ID | Term |
|---|---|
| D008874 | Midazolam |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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| Drug |
Placebo to match GRT7041 dose strength |
|
| Midazolam | Drug | Solution |
|
| GRT7041 MAD | Drug | Multiple ascending doses |
|
| Area Under the Plasma Concentration-Time Curve from Time 0 to the last measurable concentration (t) [AUC0-t] [SAD] | The total amount of the study drug (and metabolite) in the blood from the time it is taken until the last time a measurable level of the drug is found. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Area Under the Plasma Concentration-Time Curve from Time 0 extrapolated to infinity (AUC0-inf ) [SAD] | The total amount of the study drug (and metabolite) in the blood from the time it is taken until it has completely left the body. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Maximum Observed Plasma Concentration (Cmax) [SAD] | The maximum amount of the study drug (and metabolite) measured in the blood after taking the dose. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) [SAD] | The time it takes to reach the highest concentration of the study drug (and metabolite) in the blood after dosing. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Terminal Elimination Half-Life (t₁/₂) [SAD] | The time it takes for the amount of study drug (and metabolite) in the blood to reduce by half after reaching its peak level. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Terminal Elimination Rate Constant (λz) [SAD] | The rate at which the study drug (and metabolite) is eliminated from the blood during the final phase after dosing. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Apparent Total Clearance of Drug From Plasma After Extravascular Administration (CL/F) [SAD] | The amount of blood completely cleared of thestudy drug (and metabolite) per unit of time, taking into account how much of the drug is absorbed into the body. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) [SAD] | An estimate of how widely the study drug spreads through the body's tissues after it is absorbed. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Lag Time Before First Measurable Concentration (tlag) [SAD] | The time between when the study drug (and metabolite) is taken and when it first becomes measurable in the blood. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Time of Last Measurable Concentration (tlast) [SAD] | The last time point when a measurable amount of the study drug (and metabolite) is found in the blood. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Amount of Study Drug Excreted in Urine (Ae) [SAD] | The total amount of the study drug (and metabolite) that is passed out of the body through urine during a specific collection period. Collected only for one cohort in Part 1: SAD. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (from 0 hours to 72 hours) |
| Cumulative Amount of Study Drug Excreted in Urine (Cumulative Ae) [SAD] | The total amount of the study drug (and metabolite) eliminated in urine from the time of dosing up to the end of each collection period, showing how much of the drug has been removed from the body over time. Collected only for one cohort in Part 1: SAD. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (from 0 hours to 72 hours) |
| Percentage of Dose Excreted in Urine (Ae%) [SAD]. | The percentage of the total amount of the study drug (and metabolite) dose that is passed out in urine during each collection period. Collected only for one cohort in Part 1: SAD. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (from 0 hours to 72 hours) |
| Cumulative Percentage of Dose Excreted in Urine (Cumulative Ae%) [SAD] | The total percentage of the study drug dose excreted in urine from dosing until the end of each collection period, showing how much of the drug has been eliminated over time. Collected only for one cohort in Part 1: SAD. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (from 0 hours to 72 hours) |
| Renal Clearance of Study Drug (CLr) [SAD] | The rate at which the study drug (and metabolite) is removed from the blood by the kidneys and excreted in the urine. Collected only for one cohort in Part 1: SAD. Assessment of the PK of GRT7041 and its metabolite, GRT1093025, for single-dosing. | Day 1 to Day 4 (from 0 hours to 72 hours) |
| Area Under the Concentration-Time Curve from 0 to 24 hours [(AUC)0-24] [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing. | Day 1 (0 hours - 24 hours) |
| Maximum Observed Plasma Concentration (Cmax) [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing. | Day 1 (0 hours - 24 hours) |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing. | Day 1 (0 hours - 24 hours) |
| Area Under the Plasma Concentration-time Curve Over a Dose Interval at Steady State (AUCτ,ss) [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing | Day 14 - Day 17 (0 hours to 72 hours after last dose) and Day 21 |
| Maximum Observed Plasma Concentration at Steady State (Cmax,ss) [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing | Day 14 - Day 17 (0 hours to 72 hours after last dose) and Day 21 |
| Minimum Observed Plasma Concentration at Steady State (Cmin,ss) [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing | Day 1, Day 2, Day 4, Day 6, Day 8, Day 10, and Day 12 to Day 17 and Day 21 |
| Average Observed Plasma Concentration at Steady State (Cav.ss) [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing | Day 1, Day 2, Day 4, Day 6, Day 8, Day 10, and Day 12 to Day 17 and Day 21 |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady State (tmax,ss) [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing | Day 14 - Day 17 (0 hours to 72 hours after last dose) and Day 21 |
| Terminal Elimination Half-Life (t₁/₂) [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing | Day 1, Day 2, Day 4, Day 6, Day 8, Day 10, and Day 12 to Day 17 and Day 21 |
| Terminal Elimination Rate Constant (λz) [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing | Day 1, Day 2, Day 4, Day 6, Day 8, Day 10, and Day 12 to Day 17 and Day 21 |
| Apparent Total Clearance of Drug From Plasma After Extravascular Administration (CL/F) [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing | Day 1, Day 2, Day 4, Day 6, Day 8, Day 10, and Day 12 to Day 17 and Day 21 |
| Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing | Day 1, Day 2, Day 4, Day 6, Day 8, Day 10, and Day 12 to Day 17 and Day 21 |
| Time of Last Measurable Concentration (tlast) [MAD] | Assessment of the pharmacokinetics (PK) of GRT7041 and its metabolite, GRT1093025, for multiple-dosing | Day 14 - Day 17 (0 hours to 72 hours after last dose) and Day 21 |
| Maximum Observed Plasma Concentration (Cmax) [SAD] for fed and fasted state | Assessment of the effect of food on the PK of GRT7041 following single-dosing | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Area Under the Plasma Concentration-Time Curve from Time 0 to the last measurable concentration (t) [AUC0-t] [SAD] for fed and fasted state | Assessment of the effect of food on the PK of GRT7041 following single-dosing | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Area Under the Plasma Concentration-Time Curve from Time 0 extrapolated to infinity (AUC0-inf ) [SAD] for fed and fasted state | Assessment of the effect of food on the PK of GRT7041 following single-dosing | Day 1 to Day 4 (Pre-dose, 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours) and Day 10 (240 hours) |
| Area Under the Plasma Concentration-Time Curve from Time 0 to the last measurable concentration (t) [AUC0-t] of midazolam | PK parameters (AUC0-t, AUC0-inf, Cmax, tmax and t1/2) of midazolam (index substrate) before and after treatment with GRT7041 over 14 days, and when administered alone and after single day and 14 days of treatment with GRT7041 | Day -1, Day 1 and Day 14 (pre-dose, 0.25 hours, 0.5 hours, 1 hours, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours and 18 hours) |
| Area Under the Plasma Concentration-Time Curve from Time 0 extrapolated to infinity (AUC0-inf ) of midazolam | PK parameters (AUC0-t, AUC0-inf, Cmax, tmax and t1/2) of midazolam (index substrate) before and after treatment with GRT7041 over 14 days, and when administered alone and after single day and 14 days of treatment with GRT7041 | Day -1, Day 1 and Day 14 (pre-dose, 0.25 hours, 0.5 hours, 1 hours, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours and 18 hours) |
| Maximum Observed Plasma Concentration (Cmax) of midazolam | PK parameters (AUC0-t, AUC0-inf, Cmax, tmax and t1/2) of midazolam (index substrate) before and after treatment with GRT7041 over 14 days, and when administered alone and after single day and 14 days of treatment with GRT7041 | Day -1, Day 1 and Day 14 (pre-dose, 0.25 hours, 0.5 hours, 1 hours, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours and 18 hours) |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of midazolam | PK parameters (AUC0-t, AUC0-inf, Cmax, tmax and t1/2) of midazolam (index substrate) before and after treatment with GRT7041 over 14 days | Day -1, Day 1 and Day 14 (pre-dose, 0.25 hours, 0.5 hours, 1 hours, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours and 18 hours) |
| Terminal Elimination Half-Life (t₁/₂) of midazolam | PK parameters (AUC0-t, AUC0-inf, Cmax, tmax and t1/2) of midazolam (index substrate) before and after treatment with GRT7041 over 14 days | Day -1, Day 1 and Day 14 (pre-dose, 0.25 hours, 0.5 hours, 1 hours, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours and 18 hours) |
| D006571 | Heterocyclic Compounds |