A Randomized, Single-center, Double-blind, Placebo-controlled, First-in-human Trial With Single and Multiple Ascending Doses to Determine Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GRT7041 in Healthy Participants.
Overview
- Phase
- Phase 1
- Intervention
- GRT7041 SAD
- Conditions
- Not specified
- Sponsor
- Grünenthal GmbH
- Enrollment
- 70
- Locations
- 1
- Primary Endpoint
- Number of participants with Adverse Events
- Status
- Recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
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.
Detailed Description
The trial will consist of two parts: * Part 1: SAD with up to five cohorts SAD1 to SAD5 (n = 40). To be conducted in adult males and women of non-childbearing potential (WONCBP). * Part 2: MAD 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. 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Main Inclusion Criteria:
- •The participant must be able to give signed informed consent, including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
- •Participants must sign the ICF before any trial-related assessments.
- •The participant is in good health as judged by the Investigator including medical history, physical examination, 12-lead ECG, vital signs (pulse rate, respiratory rate, systolic and diastolic BP), body temperature, and clinical laboratory parameters (clinical chemistry, hematology, coagulation and urinalysis) without clinically relevant deviations from reference ranges, unless further specified in the
Exclusion Criteria
- •Main Exclusion Criteria:
- •History of any of the following: cardiac impairment, renal impairment, pancreatitis, coagulation abnormalities.
- •Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk for treatment complications/ participation in the trial unsafe.
- •Any disease or conditions known to interfere with the absorption, distribution, metabolism, or excretion of the IMP.
- •Evidence or medical history of clinically significant and relevant psychiatric issues as assessed by the Investigator.
- •Confirmed or suspected history of clinically relevant drug allergy.
- •Major surgical procedure, within 30 days prior to ICF signing, or anticipation of need for a major surgical procedure during the trial.
- •Blood loss of 500 mL or more (eg, owing to blood donation) within 90 days before Screening Visit.
- •The participant has used any medication, including herbal remedies or over-the-counter medication within 2 weeks (or 5 half-lives, whichever is longer) before the start of the trial intervention or anticipated use during the trial, unless, in the opinion of the Investigator and Sponsor, the medication will not interfere with the trial.
- •The participant is enrolled in another clinical trial unless it is an observational (non-interventional) clinical trial or during the follow-up period of an interventional trial) or has received an IMP in another clinical trial within 30 days before Day 1 or within 5 times the elimination half-life of the IMP, whichever is longer.
Arms & Interventions
Part 1: SAD
With up to five cohorts SAD1 to SAD5 (n = 40). To be conducted in adult males and WONCBP
Intervention: GRT7041 SAD
Part 1: SAD
With up to five cohorts SAD1 to SAD5 (n = 40). To be conducted in adult males and WONCBP
Intervention: Placebo
Part 2: MAD
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.
Intervention: Placebo
Part 2: MAD
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.
Intervention: Midazolam
Part 2: MAD
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.
Intervention: GRT7041 MAD
Outcomes
Primary Outcomes
Number of participants with Adverse Events
Time Frame: Through study completion, an average of 8 Weeks
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
Number of participants with Serious Adverse Events
Time Frame: Through study completion, an average of 8 Weeks
A Serious Adverse Event (SAE) is any untoward medical occurrence that, at any dose: * Results in death, is life-threatening, or requires (or prolongs) hospitalization; * Results in persistent or significant disability/incapacity; * Is a congenital anomaly or birth defect; or * Is considered medically significant, requiring intervention to prevent one of the outcomes above. * Investigator judgment applies to other clinically important events that may not be immediately life-threatening but could jeopardize participant safety. Assessment of the safety and tolerability of GRT7041 after oral single and multiple-dose escalation
Secondary Outcomes
- Area Under the Concentration-Time Curve from 0 to 24 hours [(AUC)0-24] [SAD](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](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](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](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](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](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))
- Average Observed Plasma Concentration at Steady State (Cav.ss) [MAD](Day 1, Day 2, Day 4, Day 6, Day 8, Day 10, and Day 12 to Day 17 and Day 21)
- Lag Time Before First Measurable Concentration (tlag) [SAD](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))
- Renal Clearance of Study Drug (CLr) [SAD](Day 1 to Day 4 (from 0 hours to 72 hours))
- Time to Reach Maximum Observed Plasma Concentration (Tmax) at Steady State (tmax,ss) [MAD](Day 14 - Day 17 (0 hours to 72 hours after last dose) and Day 21)
- Terminal Elimination Rate Constant (λz) [SAD](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](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](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](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](Day 1 to Day 4 (from 0 hours to 72 hours))
- Cumulative Amount of Study Drug Excreted in Urine (Cumulative Ae) [SAD](Day 1 to Day 4 (from 0 hours to 72 hours))
- Percentage of Dose Excreted in Urine (Ae%) [SAD].(Day 1 to Day 4 (from 0 hours to 72 hours))
- Cumulative Percentage of Dose Excreted in Urine (Cumulative Ae%) [SAD](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](Day 1 (0 hours - 24 hours))
- Maximum Observed Plasma Concentration (Cmax) [MAD](Day 1 (0 hours - 24 hours))
- Time to Reach Maximum Observed Plasma Concentration (Tmax) [MAD](Day 1 (0 hours - 24 hours))
- Area Under the Plasma Concentration-time Curve Over a Dose Interval at Steady State (AUCτ,ss) [MAD](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](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](Day 1, Day 2, Day 4, Day 6, Day 8, Day 10, and Day 12 to Day 17 and Day 21)
- Terminal Elimination Half-Life (t₁/₂) [MAD](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](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](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](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](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(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(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(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(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(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(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(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(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))