A Phase-I Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Escalating Oral Doses of GRT0151Y in Healthy Male and Female Subjects
Overview
- Phase
- Phase 1
- Intervention
- 100 mg GRT0151Y
- Conditions
- Acute Pain
- Sponsor
- Grünenthal GmbH
- Enrollment
- 48
- Locations
- 1
- Primary Endpoint
- Incidence of adverse events.
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
The aim of this clinical study in healthy participants is to investigate the safety and tolerability of GRT0151Y after multiple oral intake of different increasing doses and to evaluate the pharmacological effects (action of the compound) by means of pupillometry (measuring the pupil size of the eye) and Cold Presser Test (measuring the pain when immersing the hand in 2 degree Celsius cold water). An additional aim of the study is to investigate the pharmacokinetics of GRT0151Y (how it is taken up into the body and how it is excreted from the body)."
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female Caucasian.
- •Age 40-65 years.
- •Body mass index (BMI) between 18 and 30 kilograms/square meter (extremes included).
- •Extensive Cytochrome P450 2D6 (CYP2D6) metabolizer.
- •Healthy as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory parameters (haematology, Blood sedimentation rate (BSR), clotting, bio-chemistry, urinalysis and virus serology). Minor deviations of laboratory values and ECG parameters from the normal range may be accepted, if judged by the investigator as clinically not relevant and if not considered to interfere with the study objectives.
- •Adequate contraception. For females of childbearing potential (i.e. all females except surgically sterilized or at least 2 years postmenopausal) this is defined as follows: any form of hormonal contraception or intra-uterine device must be used, at least for 4 weeks prior to the first dosing AND she must give a consent to use an additional barrier contraception (condom or diaphragm) from 2 weeks prior to first dosing up to 4 weeks after the last dosing.
- •Written consent to participate in the study.
- •Negative Human immunodeficiency virus (HIV)1/2-antibodies, Hepatitis B surface (HBs)-antigen, Hepatitis B core (HBc)-antibodies, Hepatitis C virus (HCV)-antibodies determined at screening examination.
- •Negative drug abuse screening test determined at screening examination (the test will include screening for metamphetamine, opiate, cannabis, cocaine, amphetamine and benzodiazepine).
- •Negative beta-human chorion gonadotropin test for females of childbearing potential determined at screening examination (the test is not necessary in females who are in post-menopausal state for at least 2 years or in females with status after surgical sterilisation).
Exclusion Criteria
- •Pulse rate below 45 or above 100 Beats per minute (bpm). The measurement must be performed in supine position after a resting period of at least 5 minutes.
- •Systolic blood pressure below 100 or above 160 Millimeter mercury (mmHg), diastolic blood pressure below 50 or above 100 mmHg. The measurement must be performed in supine position after a resting period of at least 5 minutes.
- •History or presence of diseases or functional disorders of the Central nervous system (CNS), endocrinological system, gastrointestinal tract, hepatobiliary system, renal system, respiratory system or cardiovascular system or other conditions known to interfere with the absorption, distribution, metabolism or excretion of drugs.
- •Marked repolarisation abnormality (e.g. suspicious or definite congenital long QT syndrome) or co-medication that is known to influence cardiac repolarisation substantially.
- •History of seizures or at risk (epilepsy in family anamnesis, unclear loss of consciousness), head trauma requiring hospitalization.
- •Neurotic personality, psychiatric illness or suicide risk.
- •History of orthostatic hypotension.
- •Bronchial asthma.
- •Definite or suspected history of drug allergy or hypersensitivity.
- •History of Raynaud´s disease or phenomenon.
Arms & Interventions
Group 1 (100 mg GRT0151Y)
The dose of 100 mg will be administered twice (b.i.d.) on Day 1 (titration day). On Days 2, 3 and 4, the treatment regimen will be changed to a triple daily (t.i.d) medication with 100 mg. On Day 5 the last dose of 100 mg will be administered in the morning. Matching placebo using the same dosing regimen as defined in the treatment group.
Intervention: 100 mg GRT0151Y
Group 1 (100 mg GRT0151Y)
The dose of 100 mg will be administered twice (b.i.d.) on Day 1 (titration day). On Days 2, 3 and 4, the treatment regimen will be changed to a triple daily (t.i.d) medication with 100 mg. On Day 5 the last dose of 100 mg will be administered in the morning. Matching placebo using the same dosing regimen as defined in the treatment group.
Intervention: Matching placebo
Group 2 (125 mg GRT0151Y)
The dose of 125 mg will be administered twice (b.i.d.) on Day 1 (titration day). On Days 2, 3 and 4, the treatment regimen will be changed to a triple daily (t.i.d) medication with 125 mg. On Day 5 the last dose of 125 mg will be administered in the morning. Matching placebo using the same dosing regimen as defined in the treatment group
Intervention: 125 mg GRT0151Y
Group 2 (125 mg GRT0151Y)
The dose of 125 mg will be administered twice (b.i.d.) on Day 1 (titration day). On Days 2, 3 and 4, the treatment regimen will be changed to a triple daily (t.i.d) medication with 125 mg. On Day 5 the last dose of 125 mg will be administered in the morning. Matching placebo using the same dosing regimen as defined in the treatment group
Intervention: Matching placebo
Group 3 (150 mg GRT0151Y)
The dose of 150 mg will be administered twice (b.i.d.) on Day 1 (titration day). On Days 2, 3 and 4, the treatment regimen will be changed to a triple daily (t.i.d) medication with 150 mg. On Day 5 the last dose of 150 mg will be administered in the morning. Matching placebo using the same dosing regimen as defined in the treatment group
Intervention: 150 mg GRT0151Y
Group 3 (150 mg GRT0151Y)
The dose of 150 mg will be administered twice (b.i.d.) on Day 1 (titration day). On Days 2, 3 and 4, the treatment regimen will be changed to a triple daily (t.i.d) medication with 150 mg. On Day 5 the last dose of 150 mg will be administered in the morning. Matching placebo using the same dosing regimen as defined in the treatment group
Intervention: Matching placebo
Group 4 (225 mg GRT0151Y)
The dose of 150 mg will be administered twice (b.i.d.) on Day 1 (titration day). On Days 2, 3 and 4, the dose of 225 mg will be administered twice (b.i.d.). On Day 5 the last dose of 225 mg will be administered in the morning. Matching placebo using the same dosing regimen as defined in the treatment group
Intervention: 225 mg GRT0151Y
Group 4 (225 mg GRT0151Y)
The dose of 150 mg will be administered twice (b.i.d.) on Day 1 (titration day). On Days 2, 3 and 4, the dose of 225 mg will be administered twice (b.i.d.). On Day 5 the last dose of 225 mg will be administered in the morning. Matching placebo using the same dosing regimen as defined in the treatment group
Intervention: Matching placebo
Outcomes
Primary Outcomes
Incidence of adverse events.
Time Frame: From the first IMP administration (Day 1) to the Final Examination (Day 4 to 11 after last period).
Number of adverse events and number of participants with adverse events.
Secondary Outcomes
- Pupillometry parameter: Constriction time(Day 1 at 0 hour, 4, 11 and 23 hours, on Day 2 at 11 and 23 hours and on Day 5 at 0 hour, 1 hour, 4, 11, 23, 35 and 47 hours)
- Minimum plasma concentration during dosing interval τ at steady-state (Css,min)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Area under the concentration vs. time curve after the last dose (AUC)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Extrapolated part to infinity of AUCss at steady-state (AUCextr)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Relative total clearance (CL/F)ss(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Relative volume of distribution for the terminal log-linear phase of the concentration time data (Vz/F)ss(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Total mean time in the total volume of distribution (MRTvsys)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Peak-trough fluctuation at steady-state (PTF%)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Rate constant for the terminal log-linear phase of the concentration time data, computed as the negative slope of the regression line for the terminal linear phase of the logarithmic concentration versus time plot (λss,z)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Half-life for the terminal log-linear phase of the concentration time data (tss,1/2,z)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Apparent terminal half-life after last dose (t1/2,Z)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Apparent terminal elimination rate constant after last dose (λz)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Area under the concentration vs. time curve in dosing interval τ at steady-state (AUCss,τ)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Extrapolated part to infinity of AUCss in percent at steady-state (AUC%extr)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Area under the concentration-time data for dosing interval τ (AUC0-τ)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Cold Pressor Test (CPT) (AUC of pain assessment)(Day 1 at 0 hour, 4, 11 and 23 hours, on Day 2 at 11 and 23 hours and on Day 5 at 0 hour, 1, 4, 11, 23, 35 and 47 hours.)
- Maximum plasma concentration during dosing interval τ at steady-state (Css,max)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Average plasma concentration during dosing interval τ at steady-state (Css,ave)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)
- Pupillometry parameter: Initial pupil diameter(Day 1 at 0 hour, 4, 11 and 23 hours, on Day 2 at 11 and 23 hours and on Day 5 at 0 hour, 1 hour, 4, 11, 23, 35 and 47 hours)
- Pupillometry parameter: Amplitude of constriction(Day 1 at 0 hour, 4, 11 and 23 hours, on Day 2 at 11 and 23 hours and on Day 5 at 0 hour, 1 hour, 4, 11, 23, 35 and 47 hours)
- Pupillometry parameter: Onset latency of miosis(Day 1 at 0 hour, 4, 11 and 23 hours, on Day 2 at 11 and 23 hours and on Day 5 at 0 hour, 1 hour, 4, 11, 23, 35 and 47 hours)
- Time to reach maximum plasma concentration during dosing interval τ at steady-state (tss,max)(predose on Day 1, during 4 consecutive days of multiple dosing and up to 72 hours after the last dosing on Day 5)