Healthy Volunteers
Conditions
Brief summary
This is a phase I PK study in healthy males.
Detailed description
This is a phase I, open, repeated dose, randomised PK study in healthy males. The study will consist of 4 parallel groups (Groups 1-4). All groups will have a crossover design with 4 treatment periods, each lasting for 7 days.
Interventions
DRUGLevodopa
Levodopa 50 mg or 100 mg or 150 mg
DRUGCarbidopa
Carbidopa 12.5 mg or 25 mg or 65 mg
DRUGODM-104
ODM-104 50 mg or 100 mg
Sponsors
Orion Corporation, Orion Pharma
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Written informed consent (IC) obtained. * Good general health ascertained by detailed medical history and physical examinations. * Males between 18-65 years of age inclusive at screening. * Body mass index (BMI) between 19-30 kg/m2 (BMI = weight/height2) inclusive at screening. * Weight at least 55 kg inclusive at screening. * Regular intestinal transit (no recent history of recurrent constipation, diarrhoea, or other intestinal problems, and no history of major gastrointestinal surgery). * Subject with a partner of childbearing potential agrees to use adequate contraception from the first dose of study treatment until 90 days after the last dose of study treatment. Adequate methods of contraception include: Hormonal contraceptives, barrier methods (condom, diaphragm, cervical cap, etc.) in combination with a spermicide, intrauterine device and sexual abstinence. * Subject agrees to not donate sperm from the first dose of study treatment until 90 days after the last dose of study treatment.
Exclusion criteria
* Evidence of clinically significant cardiovascular, renal, hepatic, haematological, gastrointestinal, pulmonary, metabolic, endocrine, neurological or psychiatric disease or cancer (except local non-melanoma skin cancer) within the previous 2 years. * Any condition requiring regular concomitant treatment (including vitamins and herbal products) or likely to need any concomitant treatment during the study. As an exception, paracetamol for occasional pain is allowed. * Any clinically significant abnormal laboratory value or ECG (such as prolonged QTcF \>450 ms or QRS \>120 ms) that in the opinion of the investigator could interfere with the interpretation of study results or cause a health risk for the subject if he takes part in the study. * Known hypersensitivity to the active substances or the excipients of the drugs. * History of vasovagal collapses or vagal reactions with unexplained reason within the previous 2 years or a tendency for vasovagal reactions during blood sampling. * HR \< 50 bpm or \> 90 bpm in the supine position after 5 min rest at the screening visit. * At the screening visit: * systolic BP \< 100 mmHg or \> 140 mmHg in the supine position after 5 min rest * diastolic BP \< 50 mmHg or \> 90 mmHg in the supine position after 5 min rest. * Creatinine \> 1.5 x upper limit of normal (ULN) and alanine aminotransferase or aspartate aminotransferase \>1.25 x ULN at screening. * History of anaphylactic/anaphylactoid reactions. * Strong tendency to motion sickness. * Recent or current (suspected) drug abuse. * Recent or current alcohol abuse; regular drinking of more than 21 units per week (1 unit = 4 cl spirits or equivalent). * Current use of nicotine-containing products more than 5 cigarettes (or equivalent)/day and/or inability to refrain from the use of nicotine-containing products for 48 h before the first dose in each period until collection of the 24 h PK sample in the morning of day 8. * Use of caffeine-containing beverages more than 600 mg of caffeine/day and/or inability to refrain from using caffeine-containing beverages 24 h before the first levodopa administration on the PK day (day 7) until collection of the 24 h PK sample in the morning of day 8. * Blood donation or loss of a significant amount of blood (\> 500 ml) within 90 days before the first study treatment administration. * Participation in another investigational drug study or administration of another investigational drug within 60 days before the first study treatment administration. * Veins unsuitable for repeated venipuncture or cannulation. * Predictable poor compliance or inability to communicate well with the study centre personnel. * Inability to participate in all treatment periods.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | During 24 hours | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fluctuation of Levodopa Cmax/Cmin, Tau | 16 hours | Explore fluctuation of levodopa Cmax/Cmin, tau. Figures given are per performed statistical analysis. |
| Levodopa Peak Plasma Concentration (Cmax) | 24 hours | Levodopa peak plasma concentration (Cmax) |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 A1 levodopa 50 mg, carbidopa 12.5 mg; B1 levodopa 50 mg, carbidopa 65 mg; C1 levodopa 50 mg, carbidopa 65 mg, ODM-104 50 mg; D1 levodopa 50 mg, carbidopa 65 mg, ODM-104 100 mg | 14 |
| Group 2 A2 levodopa 100 mg, carbidopa 25 mg; B2 levodopa 100 mg, carbidopa 65 mg; C2 levodopa 100 mg, carbidopa 65 mg, ODM-104 50 mg; D2 levodopa 100 mg, carbidopa 65 mg, ODM-104 100 mg | 14 |
| Group 3 A3 levodopa 150 mg, carbidopa 37.5 mg; B3 levodopa 150 mg, carbidopa 65 mg; C3 levodopa 150 mg, carbidopa 65 mg, ODM-104 50 mg; D3 levodopa 150 mg, carbidopa 65 mg, ODM-104 100 mg | 14 |
| Group 4 A4 (Sinemet): levodopa IR 100 mg, carbidopa 25 mg; B4 levodopa 100 mg, carbidopa 65 mg; C4 levodopa 100 mg, carbidopa 25 mg, ODM-104 100 mg; D4 levodopa 100 mg, carbidopa 65 mg, ODM-104 100 mg | 14 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 | 1 |
| Overall Study | Personal reason | 2 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Group 1 | Group 2 | Group 3 | Group 4 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 14 Participants | 14 Participants | 14 Participants | 56 Participants |
| Age, Continuous | 42.4 years STANDARD_DEVIATION 13.7 | 49.5 years STANDARD_DEVIATION 10.9 | 48.0 years STANDARD_DEVIATION 13.5 | 46.0 years STANDARD_DEVIATION 10.6 | 46.4 years STANDARD_DEVIATION 12.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 13 Participants | 13 Participants | 13 Participants | 52 Participants |
| Region of Enrollment Germany | 14 participants | 14 participants | 14 participants | 14 participants | 14 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 14 Participants | 14 Participants | 14 Participants | 14 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 6 / 14 | 8 / 14 | 7 / 14 | 7 / 14 | 6 / 14 | 7 / 14 | 8 / 14 | 7 / 14 | 7 / 14 | 4 / 14 | 9 / 14 | 10 / 14 | 6 / 14 | 5 / 14 | 5 / 14 | 9 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 2 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24)
Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24)
Time frame: During 24 hours
Population: PP (Per Protocol population)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| A1 50 mg LD + 12.5 mg CD | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 4300 h*ng/ml |
| B1 50 mg LD + 65 mg CD | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 5423 h*ng/ml |
| C1 50 mg LD + 65 mg CD + 50 mg ODM-104 | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 7439 h*ng/ml |
| D1 50 mg LD + 65 mg CD + 100 mg ODM-104 | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 9046 h*ng/ml |
| A2 100 mg LD + 25 mg CD | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 9643 h*ng/ml |
| B2 100 mg LD + 65 mg CD | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 10709 h*ng/ml |
| C2 100 mg of LD + 65 mg CD + 50 mg ODM-104 | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 15257 h*ng/ml |
| D2 100 mg LD + 65 mg CD + 100 mg of ODM-104 | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 17896 h*ng/ml |
| A3 150 mg LD + 37.5 mg CD | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 14285 h*ng/ml |
| B3 150 mg LD + 65 mg CD | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 15805 h*ng/ml |
| C3 150 mg LD + 65 mg CD + 50 mg ODM-104 | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 22473 h*ng/ml |
| D3 150 mg LD + 65 mg CD + 100 mg ODM-104 | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 25672 h*ng/ml |
| A4 (Sinemet) 100 mg IR LD + 25 mg CD | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 7965 h*ng/ml |
| B4 100 mg LD + 65 mg CD | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 8994 h*ng/ml |
| C4 100 mg LD + 25 mg CD + 100 mg ODM-104 | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 13866 h*ng/ml |
| D4 100 mg LD + 65 mg CD + 100 mg ODM-104 | Levodopa Area Under the Concentration-time Curve From Time 0 to the 24 h PK Sample (AUC0-24) Time 0 to the 24 h PK Sample (AUC0-24) | 16310 h*ng/ml |
Secondary
Fluctuation of Levodopa Cmax/Cmin, Tau
Explore fluctuation of levodopa Cmax/Cmin, tau. Figures given are per performed statistical analysis.
Time frame: 16 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A1 50 mg LD + 12.5 mg CD | Fluctuation of Levodopa Cmax/Cmin, Tau | 12.24 (ng/ml)/(ng/ml) | Standard Deviation 5.73 |
| B1 50 mg LD + 65 mg CD | Fluctuation of Levodopa Cmax/Cmin, Tau | 7.49 (ng/ml)/(ng/ml) | Standard Deviation 2.23 |
| C1 50 mg LD + 65 mg CD + 50 mg ODM-104 | Fluctuation of Levodopa Cmax/Cmin, Tau | 4.16 (ng/ml)/(ng/ml) | Standard Deviation 0.77 |
| D1 50 mg LD + 65 mg CD + 100 mg ODM-104 | Fluctuation of Levodopa Cmax/Cmin, Tau | 3.02 (ng/ml)/(ng/ml) | Standard Deviation 1 |
| A2 100 mg LD + 25 mg CD | Fluctuation of Levodopa Cmax/Cmin, Tau | 11.00 (ng/ml)/(ng/ml) | Standard Deviation 3.3 |
| B2 100 mg LD + 65 mg CD | Fluctuation of Levodopa Cmax/Cmin, Tau | 8.32 (ng/ml)/(ng/ml) | Standard Deviation 2.23 |
| C2 100 mg of LD + 65 mg CD + 50 mg ODM-104 | Fluctuation of Levodopa Cmax/Cmin, Tau | 4.46 (ng/ml)/(ng/ml) | Standard Deviation 1.09 |
| D2 100 mg LD + 65 mg CD + 100 mg of ODM-104 | Fluctuation of Levodopa Cmax/Cmin, Tau | 3.35 (ng/ml)/(ng/ml) | Standard Deviation 0.74 |
| A3 150 mg LD + 37.5 mg CD | Fluctuation of Levodopa Cmax/Cmin, Tau | 8.45 (ng/ml)/(ng/ml) | Standard Deviation 3.16 |
| B3 150 mg LD + 65 mg CD | Fluctuation of Levodopa Cmax/Cmin, Tau | 7.16 (ng/ml)/(ng/ml) | Standard Deviation 3.87 |
| C3 150 mg LD + 65 mg CD + 50 mg ODM-104 | Fluctuation of Levodopa Cmax/Cmin, Tau | 3.67 (ng/ml)/(ng/ml) | Standard Deviation 1.29 |
| D3 150 mg LD + 65 mg CD + 100 mg ODM-104 | Fluctuation of Levodopa Cmax/Cmin, Tau | 2.82 (ng/ml)/(ng/ml) | Standard Deviation 0.99 |
| A4 (Sinemet) 100 mg IR LD + 25 mg CD | Fluctuation of Levodopa Cmax/Cmin, Tau | 19.52 (ng/ml)/(ng/ml) | Standard Deviation 14.13 |
| B4 100 mg LD + 65 mg CD | Fluctuation of Levodopa Cmax/Cmin, Tau | 9.18 (ng/ml)/(ng/ml) | Standard Deviation 6.23 |
| C4 100 mg LD + 25 mg CD + 100 mg ODM-104 | Fluctuation of Levodopa Cmax/Cmin, Tau | 7.63 (ng/ml)/(ng/ml) | Standard Deviation 12.96 |
| D4 100 mg LD + 65 mg CD + 100 mg ODM-104 | Fluctuation of Levodopa Cmax/Cmin, Tau | 3.04 (ng/ml)/(ng/ml) | Standard Deviation 0.76 |
Secondary
Levodopa Peak Plasma Concentration (Cmax)
Levodopa peak plasma concentration (Cmax)
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A1 50 mg LD + 12.5 mg CD | Levodopa Peak Plasma Concentration (Cmax) | 685.92 ng/ml | Standard Deviation 193.08 |
| B1 50 mg LD + 65 mg CD | Levodopa Peak Plasma Concentration (Cmax) | 775.36 ng/ml | Standard Deviation 186.29 |
| C1 50 mg LD + 65 mg CD + 50 mg ODM-104 | Levodopa Peak Plasma Concentration (Cmax) | 908.86 ng/ml | Standard Deviation 230.23 |
| D1 50 mg LD + 65 mg CD + 100 mg ODM-104 | Levodopa Peak Plasma Concentration (Cmax) | 950.38 ng/ml | Standard Deviation 241.6 |
| A2 100 mg LD + 25 mg CD | Levodopa Peak Plasma Concentration (Cmax) | 1519.92 ng/ml | Standard Deviation 294.51 |
| B2 100 mg LD + 65 mg CD | Levodopa Peak Plasma Concentration (Cmax) | 1593.85 ng/ml | Standard Deviation 288.95 |
| C2 100 mg of LD + 65 mg CD + 50 mg ODM-104 | Levodopa Peak Plasma Concentration (Cmax) | 1855.38 ng/ml | Standard Deviation 240.58 |
| D2 100 mg LD + 65 mg CD + 100 mg of ODM-104 | Levodopa Peak Plasma Concentration (Cmax) | 1955.38 ng/ml | Standard Deviation 278.62 |
| A3 150 mg LD + 37.5 mg CD | Levodopa Peak Plasma Concentration (Cmax) | 2105.45 ng/ml | Standard Deviation 422.05 |
| B3 150 mg LD + 65 mg CD | Levodopa Peak Plasma Concentration (Cmax) | 2072.73 ng/ml | Standard Deviation 403.78 |
| C3 150 mg LD + 65 mg CD + 50 mg ODM-104 | Levodopa Peak Plasma Concentration (Cmax) | 2545.45 ng/ml | Standard Deviation 424.3 |
| D3 150 mg LD + 65 mg CD + 100 mg ODM-104 | Levodopa Peak Plasma Concentration (Cmax) | 2616.67 ng/ml | Standard Deviation 388.76 |
| A4 (Sinemet) 100 mg IR LD + 25 mg CD | Levodopa Peak Plasma Concentration (Cmax) | 1634.62 ng/ml | Standard Deviation 361.7 |
| B4 100 mg LD + 65 mg CD | Levodopa Peak Plasma Concentration (Cmax) | 1367.36 ng/ml | Standard Deviation 352.26 |
| C4 100 mg LD + 25 mg CD + 100 mg ODM-104 | Levodopa Peak Plasma Concentration (Cmax) | 1711.43 ng/ml | Standard Deviation 316.1 |
| D4 100 mg LD + 65 mg CD + 100 mg ODM-104 | Levodopa Peak Plasma Concentration (Cmax) | 1717.69 ng/ml | Standard Deviation 641.6 |