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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Healthy

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ODM-108 Part I<br>Oral capsules dosage 0.2 - 240 mg once daily for one day | Drug: ODM-108 Part I<br>* Single oral escalating dose of ODM-108. Each volunteer will receive either one dose of ODM-108 or placebo<br>|
| Placebo Comparator: Placebo Part I<br>Oral capsules given once daily for one day | Drug: Placebo Part I<br>* Single oral escalating dose of ODM-108. Each volunteer will receive either one dose of ODM-108 or placebo<br>|
| Experimental: ODM-108 Part II<br>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<br>* Multiple escalating doses based on the results of Part 1. Either ODM-108 or placebo 1 - 4 times a day for 7 days<br>|
| Placebo Comparator: Placebo Part II<br>Oral capsules 1 - 4 times per day for 7 days | Drug: Placebo Part II<br>* Multiple escalating doses based on the results of Part 1. Either ODM-108 or placebo 1 - 4 times a day for 7 days<br>|
| Experimental: ODM-108 Part III<br>Oral capsules 1-4 times daily for 7 to 10 days | Drug: ODM-108 Part III<br>* Oral capsules 1 - 4 times daily for 7 to 10 days<br>|
| Active Comparator: Midazolam<br>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<br>* 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<br>|

What is the study measuring?
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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. |