Clinical trial NCT02432664: Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Effects of ODM-108: in Healthy Male Volunteers
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Orion Corporation, Orion Pharma
Sponsor class: INDUSTRY
Collaborators: name: PRA Health Sciences
First posted: 2015-05-04
Enrollment: 85
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief 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).

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Number of participants with adverse events in Part I and Part II.
timeFrame: From screening up to 8 weeks
Secondary outcomes:
measure: Part III (optional) Effect of ODM-108 on the activity of CYP3A4 (cytochrome P450 3A4) isoenzymes
timeFrame: Day 1 up to Day 11
measure: Part I Peak plasma concentration Cmax of ODM-108
timeFrame: 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.
measure: Part I Metabolite screening in plasma and urine
timeFrame: 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.
measure: Part I Sedation scores on Visual Analogue Scales
timeFrame: Pre-dose, 2 h 30 min and 10 h post dose at each dose level
measure: Part I Cognitive function - Digital Symbol Substitution Test
timeFrame: Pre-dose, 2 h 30 min and 10 h post dose at each dose level
measure: Part I Intensity of spontaneous pain
timeFrame: Screening and day 1 at 1, 5, 15, 30, 60 and 120 min after capsaicin injection.
measure: Part I Area of hyperalgesia
timeFrame: Screening and day 1 at 15, 30, 60 and 120 min after capsaicin injection.
measure: Part I area of flare response
timeFrame: Screening and day 1 at baseline and 15, 30, 60 and 120 min after capsaicin injection.
measure: Part II Peak plasma concentration Cmax of ODM-108
timeFrame: 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
measure: Part II Peak plasma concentration Cmax of ODM-108 fed day 5 period 1
timeFrame: 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
measure: Part II Time to peak plasma concentration (tmax) of ODM-108
timeFrame: 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
measure: Part II Time to peak plasma concentration (tmax) of ODM-108 fed day 5 period 1
timeFrame: 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
measure: Part II Area under the plasma concentration versus time curve (AUC) of ODM-108.
timeFrame: 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
measure: Part II Area under the plasma concentration versus time curve (AUC) of ODM-108 fed day 5 period 1
timeFrame: 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
measure: Part II Elimination half-life of ODM-108
timeFrame: 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
measure: Part II Elimination half-life of ODM-108- fed day 5 period 1
timeFrame: 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
measure: Part II Binding of ODM-108 to proteins in plasma
timeFrame: Days 1 and 7 -1 h 30 min post dose
measure: Part II Metabolite screening in plasma and urine
timeFrame: 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.
measure: Part II Sedation scores on Visual Analogue Scales
timeFrame: Day 1 and day 6 pre-dose, 2 h 30 min, and 10 h post dose
measure: Part II Computerised psychomotor test battery measuring: attention, concentration, vigilance, memory, visual motor coordination and body sway.
timeFrame: Days 1 and 6: pre-dose, approx. 2 h 30 min and 10 h after first daily ODM-108 dose
measure: Part II Intensity of spontaneous pain
timeFrame: Screening and day 5 at 1, 5, 15, 30, 60 and 120 min after capsaicin injection.
measure: Part II Area of hyperalgesia
timeFrame: Screening and day 5 at 5, 15, 30, 60 and 120 min after capsaicin injection.
measure: Part II Cutaneous blood flow and area of flare response
timeFrame: Screening and day 5 pre -dose and 5, 15, 30, 60 and 120 min after capsaicin injection.
measure: Part II Intensity of spontaneous pain
timeFrame: Screening and day 7 at 1, 5, 15, 30, 60 and 120 min after mustard oil challenge.
measure: Part II Area of hyperalgesia
timeFrame: Screening and day 7 at 5, 15, 30, 60 and 120 min after mustard oil challenge.
measure: Part II Area of flare response
timeFrame: Screening and day 7 baseline and 5, 15, 30, 60 and 120 min after mustard oil challenge.
measure: Part III (optional) Peak plasma concentration Cmax of midazolam
timeFrame: day 1 and day 10 or 13
measure: Part III (optional) Time to peak plasma concentration (tmax) of midazolam
timeFrame: day 1 and day 10 or 13
measure: Part III (optional) Area under the plasma concentration versus time curve (AUC) of midazolam.
timeFrame: day 1 and day 10 or 13 (
measure: Part III (optional) ODM-108 levels in cerebrospinal fluid
timeFrame: day 9
measure: Part I Time to peak plasma concentration (tmax) of ODM-108
timeFrame: 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.
measure: Part I Area under the plasma concentration versus time curve (AUC) of ODM-108.
timeFrame: 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.
measure: Part I Elimination half-life of ODM-108
timeFrame: 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.
Other outcomes:
Locations:
city: Zuidlaren
country: Netherlands
facility: PRA Health Sciences
Study officials:
affiliation: PRA Health Sciences
name: Sjoerd van Marle, M.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Orion Corporation, Orion Pharma
name: Sara Haworth
role: STUDY_DIRECTOR
References: