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

Healthy Clinical Trial

— FIMTRIP  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02432664
• Other study ID #: 3118001
• Status: Terminated
• Phase: Phase 1
• First received: April 2, 2015
• Last updated: June 30, 2017
• Start date: April 14, 2015
• Est. completion date: April 22, 2016

Study information

• Verified date: June 2017
• Source: Orion Corporation, Orion Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 85
• Est. completion date: April 22, 2016
• Est. primary completion date: April 22, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 55 Years

Eligibility

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).

Related Conditions & MeSH terms

• Healthy

Intervention

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 Part I
Single oral escalating dose of ODM-108. Each volunteer will receive either one dose of ODM-108 or placebo
• 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 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
• ODM-108 Part III
Oral capsules 1 - 4 times daily for 7 to 10 days
• 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

Locations

Country	Name	City	State
Netherlands	PRA Health Sciences	Zuidlaren

Sponsors (2)

Lead Sponsor	Collaborator
Orion Corporation, Orion Pharma	PRA Health Sciences

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Part III (optional) Peak plasma concentration Cmax of midazolam	Cmax of midazolam	day 1 and day 10 or 13
Secondary	Part III (optional) Time to peak plasma concentration (tmax) of midazolam	tmax of midazolam	day 1 and day 10 or 13
Secondary	Part III (optional) Area under the plasma concentration versus time curve (AUC) of midazolam.	AUC of midazolam	day 1 and day 10 or 13 (
Secondary	Part III (optional) ODM-108 levels in cerebrospinal fluid	Assessment of levels of ODM 108 in cerebrospinal fluid	day 9
Secondary	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.
Secondary	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.
Secondary	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.