Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Effects of ODM-108: in Healthy Male Volunteers (FIMTRIP)

Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Effects of Single and Multiple Escalating Doses of ODM-108: A Single Centre Study in Healthy Male Volunteers

The purpose of the study is to investigate to what extent this new study drug is tolerated in humans.

The study is divided into 3 parts (Part III is optional and may go ahead depending on the results of Parts I and II). The volunteers will only be enrolled to one part of the study. In parts I and II the volunteer will receive active study drug or placebo. In part I the volunteers will receive a single dose of one of the eight planned escalating dose levels.

In part II volunteers will receive 4 planned dose levels based on the results obtained in Part 1 of the study, with the option to include an additional dosing group.

In optional part III the volunteer will receive ODM-108 and an already registered drug so that interactions with other drugs can be studied.

It will be investigated how quickly and to what extent the study drug is absorbed and eliminated from the body (this is called pharmacokinetics). In addition, in parts I and II the effect of the compound on the sensation of pain and on cognition (activities of thinking, understanding, learning, and remembering) will be investigated (this is called pharmacodynamics).

Study Overview

• Status: Terminated
• Conditions: Healthy
• Intervention / Treatment: Drug: ODM-108 Part I; Drug: Placebo Part I; Drug: ODM-108-Part II; Drug: Placebo Part II; Drug: ODM-108 Part III; Drug: Midazolam

Detailed Description

This is the first time that this compound is being given to humans.

The study will only take place after it has been approved by the Independent Ethics Committee.

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Zuidlaren, Netherlands, 9471GP
    • PRA Health Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria applicable to Parts I - III:

• Written informed consent.
• Good general health
• Males between 18 and 55 years (inclusive).
• Body mass index (BMI) between 18-30 kg/m2 inclusive
• Weight 55-95 kg (inclusive).
• Participants with female partners of child-bearing potential must adhere to a proper form of contraception.
• Subjects with light coloured skin.

Exclusion Criteria:

• A predictable poor compliance or inability to understand and comply with the protocol , instructions and protocol restrictions or communicate well with the investigator.
• Vulnerable subjects.
• Veins unsuitable for repeated venipuncture.
• Evidence of clinically relevant cardiovascular, renal, hepatic, haematological, gastrointestinal, pulmonary, metabolic-endocrine, neurological, urogenital or psychiatric disease as judged by the investigator.
• Medical history of relevant psychiatric disorders or evidence of clinically relevant neuropsychiatric disease.
• Suicidal ideation in the 6 months before screening or current risk of suicide based on the investigators judgement.
• History of hypersensitivity to drugs or excipients.
• Any condition requiring regular concomitant medication.
• Intake of any medication that could affect the outcome of the study.
• History of Alcoholism.
• Inability to refrain from using nicotine-containing products for 48 h before and during the stay in the study centre.
• History of drug abuse or positive drug screen.
• Blood donation or loss of a clinically relevant amount of blood within 2 months before the screening visit.
• Abnormal 12-lead ECG
• Heart rate < 40 bpm or > 100 bpm at screening.
• Systolic BP < 90 mmHg or > 140 mmHg, diastolic BP< 45 mmHg or > 90 mmHg, orthostatic hypotension - decrease of more than or equal to 20 mmHg for systolic BP, decrease of more than or equal to 10 mmHg for diastolic BP at screening.
• Abnormal 24-h Holter of clinical relevance at screening.
• Positive serology for HIV antibodies (HIVAb), hepatitis B surface antigen (HBsAg) or hepatitis C virus antibodies (HCVAb).
• Thrombocytes and neutrophils count is < the lower limit of normal range.
• alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin > upper limit of normal (ULN).
• Any abnormal value of laboratory, vital signs, or physical examination, which may, in the opinion of the investigator interfere with the interpretation of the test results or cause a health risk for the subject.
• Participation in an investigational drug study within 2 months before entry into this study.
• An employee or direct relative of the employee of the CRO or sponsor.
• Any other condition that in the opinion of the investigator would interfere with the evaluation of the results or constitute a health risk for the subject.

Additional exclusion criteria for Part I and II:

• An abnormal screening EEG.
• A history of skin conditions or bad reactions after exposure to capsaicin or mustard oil.
• Following intradermal injection of capsaicin (100 μg) at screening visit, the area of hyperalgesia was < 10 cm2, or if the area of flare < 10 cm2 at 15 min.

Additional exclusion criterion for Part II:

• Use of nicotine-containing products within the previous 3 months.

The following additional exclusion criterion will be checked in Part I and II:

• Inability to complete either Digital Symbol Substitution Test (DSST) (for Part I) or psychomotor test battery (for Part II).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ODM-108 Part I; Oral capsules dosage 0.2 - 240 mg once daily for one day	Drug: ODM-108 Part I; Single oral escalating dose of ODM-108. Each volunteer will receive either one dose of ODM-108 or placebo
PLACEBO_COMPARATOR: Placebo Part I; Oral capsules given once daily for one day	Drug: Placebo Part I; Single oral escalating dose of ODM-108. Each volunteer will receive either one dose of ODM-108 or placebo
EXPERIMENTAL: ODM-108 Part II; Oral capsules 4 dose levels to be decided after Part 1 of the study. 1 - 4 times a day for 7 days	Drug: ODM-108-Part II; Multiple escalating doses based on the results of Part 1. Either ODM-108 or placebo 1 - 4 times a day for 7 days
PLACEBO_COMPARATOR: Placebo Part II; Oral capsules 1 - 4 times per day for 7 days	Drug: Placebo Part II; Multiple escalating doses based on the results of Part 1. Either ODM-108 or placebo 1 - 4 times a day for 7 days
EXPERIMENTAL: ODM-108 Part III; Oral capsules 1-4 times daily for 7 to 10 days	Drug: ODM-108 Part III; Oral capsules 1 - 4 times daily for 7 to 10 days
ACTIVE_COMPARATOR: Midazolam; Single dose as a solution 3 days prior to the first dose of ODM-108 and on the last day of dosing with ODM-108	Drug: Midazolam; Single dose as a solution 3 days prior to the first dose of ODM-108 and on the last day of dosing with ODM-108

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with adverse events in Part I and Part II.	Clinically relevant changes from baseline of safety assessment	From screening up to 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part III (optional) Effect of ODM-108 on the activity of CYP3A4 (cytochrome P450 3A4) isoenzymes	Measurement of biomarkers	Day 1 up to Day 11
Part I Peak plasma concentration Cmax of ODM-108	Cmax of ODM-108 after single dosing	Pre dose,15, 30, 45 mins, 1 h, 1 h 15, 1 h 30, 2 h, 2 h 30, 3 h, 4 h, 6 h, 8 h, 12h, 24 h, 48 h, 72 h, 96 h post dose at each dose level.
Part I Metabolite screening in plasma and urine	Metabolite screening in plasma and urine after single dosing	Pre-dose and 30 min, 1 h, 2 h, 4 h, 6 h, 12 h, 24 h and 48 h post dose at each dose level. Urine samples pre-dose and for 24 hours post dose at each dose level.
Part I Sedation scores on Visual Analogue Scales	Assessment of sedation by subject	Pre-dose, 2 h 30 min and 10 h post dose at each dose level
Part I Cognitive function - Digital Symbol Substitution Test	Assessment of cognitive function	Pre-dose, 2 h 30 min and 10 h post dose at each dose level
Part I Intensity of spontaneous pain	Intensity of spontaneous pain as assessed by a visual analogue scale	Screening and day 1 at 1, 5, 15, 30, 60 and 120 min after capsaicin injection.
Part I Area of hyperalgesia	Area of hyperalgesia quantified by a Von Frey monofilament	Screening and day 1 at 15, 30, 60 and 120 min after capsaicin injection.
Part I area of flare response	Area of flare response measured by Doppler blood flow scan	Screening and day 1 at baseline and 15, 30, 60 and 120 min after capsaicin injection.
Part II Peak plasma concentration Cmax of ODM-108	Cmax of ODM-108 after multiple dosing	Days 1 and 7: Pre-dose and 0.25, 0.5, 0.75,1,1.25,1.5, 2, 2.5, 3,4,6,8,12h post dose. Day 2-6 pre-dose, Day 7: 24, 48, 72 and 96h post dose
Part II Peak plasma concentration Cmax of ODM-108 fed day 5 period 1	Cmax of ODM-108 after multiple dosing	Days 1,5 and 7: Pre-dose and 0.25, 0.5, 0.75,1,1.25,1.5, 2, 2.5, 3,4,6,8,12h post dose. Day 2-6 pre-dose, Day 7: 24, 48, 72 and 96h post dose
Part II Time to peak plasma concentration (tmax) of ODM-108	tmax of ODM-108 after multiple dosing	Days 1 and 7: Pre-dose and 0.25, 0.5, 0.75,1,1.25,1.5, 2, 2.5, 3,4,6,8,12h post dose. Day 2-6 pre-dose, Day 7: 24, 48, 72 and 96h post dose
Part II Time to peak plasma concentration (tmax) of ODM-108 fed day 5 period 1	tmax of ODM-108 after multiple dosing	Days 1,5 and 7: Pre-dose and 0.25, 0.5, 0.75,1,1.25,1.5, 2, 2.5, 3,4,6,8,12h post dose. Day 2-6 pre-dose, Day 7: 24, 48, 72 and 96h post dose
Part II Area under the plasma concentration versus time curve (AUC) of ODM-108.	AUC of ODM-108 after multiple dosing	Days 1 and 7: Pre-dose and 0.25, 0.5, 0.75,1,1.25,1.5, 2, 2.5, 3,4,6,8,12h post dose. Day 2-6 pre-dose, Day 7: 24, 48, 72 and 96h post dose
Part II Area under the plasma concentration versus time curve (AUC) of ODM-108 fed day 5 period 1	AUC of ODM-108 after multiple dosing	Days 1,5 and 7: Pre-dose and 0.25, 0.5, 0.75,1,1.25,1.5, 2, 2.5, 3,4,6,8,12h post dose. Day 2-6 pre-dose, Day 7: 24, 48, 72 and 96h post dose
Part II Elimination half-life of ODM-108	Elimination half-life of ODM-108 after multiple dosing	Days 1 and 7: Pre-dose and 0.25, 0.5, 0.75,1,1.25,1.5, 2, 2.5, 3,4,6,8,12h post dose. Day 2-6 pre-dose, Day 7: 24, 48, 72 and 96h post dose
Part II Elimination half-life of ODM-108- fed day 5 period 1	Elimination half-life of ODM-108 after multiple dosing	Days 1,5 and 7: Pre-dose and 0.25, 0.5, 0.75,1,1.25,1.5, 2, 2.5, 3,4,6,8,12h post dose. Day 2-6 pre-dose, Day 7: 24, 48, 72 and 96h post dose
Part II Binding of ODM-108 to proteins in plasma	Assessment of binding of ODM-108 to proteins in plasma	Days 1 and 7 -1 h 30 min post dose
Part II Metabolite screening in plasma and urine	Metabolite screening in plasma and urine	Day 1 and 7 pre-dose and 30 min, 1 h, 2 h, 4 h, 6 h, 12 h, 24 h and 48 h post dose. Urine samples pre-dose and for 24 hours post dose at each dose level on days 1 and 7.
Part II Sedation scores on Visual Analogue Scales	Assessment of sedation by subject	Day 1 and day 6 pre-dose, 2 h 30 min, and 10 h post dose
Part II Computerised psychomotor test battery measuring: attention, concentration, vigilance, memory, visual motor coordination and body sway.	Assessment of psychomotor function	Days 1 and 6: pre-dose, approx. 2 h 30 min and 10 h after first daily ODM-108 dose
Part II Intensity of spontaneous pain	Assessed by numerical rating scale	Screening and day 5 at 1, 5, 15, 30, 60 and 120 min after capsaicin injection.
Part II Area of hyperalgesia	Area of hyperalgesia quantified by a Von Frey monofilament	Screening and day 5 at 5, 15, 30, 60 and 120 min after capsaicin injection.
Part II Cutaneous blood flow and area of flare response	Pain assessments	Screening and day 5 pre -dose and 5, 15, 30, 60 and 120 min after capsaicin injection.
Part II Intensity of spontaneous pain	Intensity of spontaneous pain as assessed by a visual analogue scale	Screening and day 7 at 1, 5, 15, 30, 60 and 120 min after mustard oil challenge.
Part II Area of hyperalgesia	Area of hyperalgesia quantified by a Von Frey monofilament	Screening and day 7 at 5, 15, 30, 60 and 120 min after mustard oil challenge.
Part II Area of flare response	Area of flare response measured by Doppler blood flow scan	Screening and day 7 baseline and 5, 15, 30, 60 and 120 min after mustard oil challenge.
Part III (optional) Peak plasma concentration Cmax of midazolam	Cmax of midazolam	day 1 and day 10 or 13
Part III (optional) Time to peak plasma concentration (tmax) of midazolam	tmax of midazolam	day 1 and day 10 or 13
Part III (optional) Area under the plasma concentration versus time curve (AUC) of midazolam.	AUC of midazolam	day 1 and day 10 or 13 (
Part III (optional) ODM-108 levels in cerebrospinal fluid	Assessment of levels of ODM 108 in cerebrospinal fluid	day 9
Part I Time to peak plasma concentration (tmax) of ODM-108	tmax of ODM-108 after single dosing	Pre dose,15, 30, 45 mins, 1 h, 1 h 15,1 h 30, 2 h, 2 h 30, 3 h, 4 h, 6 h, 8 h, 12h, 24 h, 48 h, 72 h, 96 h post dose at each dose level.
Part I Area under the plasma concentration versus time curve (AUC) of ODM-108.	AUC of ODM-108 after single dosing	Pre dose,15, 30, 45 mins, 1 h, 1 h 15,1 h 30, 2 h, 2 h 30, 3 h, 4 h, 6 h, 8 h, 12h, 24 h, 48 h, 72 h, 96 h post dose at each dose level.
Part I Elimination half-life of ODM-108	Elimination half-life of ODM-108 after single dosing	Pre dose,15, 30, 45 mins, 1 h, 1 h 15,1 h 30, 2 h, 2 h 30, 3 h, 4 h, 6 h, 8 h, 12h, 24 h, 48 h, 72 h, 96 h post dose at each dose level.

Collaborators and Investigators

• Sponsor: Orion Corporation, Orion Pharma
• Collaborators: PRA Health Sciences
• Investigators: Principal Investigator: Sjoerd van Marle, M.D, PRA Health Sciences; Study Director: Sara Haworth, Orion Corporation, Orion Pharma

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 14, 2015
• Primary Completion (ACTUAL): April 22, 2016
• Study Completion (ACTUAL): April 22, 2016

Study Registration Dates

• First Submitted: April 2, 2015
• First Submitted That Met QC Criteria: May 1, 2015
• First Posted (ESTIMATE): May 4, 2015

Study Record Updates

• Last Update Posted (ACTUAL): July 2, 2017
• Last Update Submitted That Met QC Criteria: June 30, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: 3118001