Healthy
Conditions
Keywords
Pharmacokinetic, Safety, Tolerability, Healthy Chinese subjects
Brief summary
This is a Phase I, single center, single and multiple-dose, open-label, randomised, parallel-group, pharmacokinetics, safety and tolerability study. The subjects will be randomised into two study cohorts to receive single and multiple doses of 50 mg safinamide (cohort 1), or single and multiple doses of 100 mg safinamide (cohort 2) as follows: Cohort 1: One safinamide 50 mg film-coated tablet will be administered on day 1 followed by 7 safinamide 50 mg film-coated tablets in total from day 8 to day 14 and hence administered 1 tablet orally from day 8 to day 14. Cohort 2: One safinamide 100 mg film-coated tablet will be administered on day 1 followed by 7 safinamide 100 mg film-coated tablets in total from day 8 to day 14 and hence administered 1 tablet orally from day 8 to day 14. The investigational products will be administered in the morning, at 8:00±1hour, under fasting conditions, with 240 mL (total volume) of still mineral water. A mouth-and-hand check will be performed immediately after dosing to ensure treatment compliance. The primary endpoint will assess the pharmacokinetic parameters after single and multiple dose administration of the study drug. The secondary endpoint will provide the safety and tolerability data after single and multiple dose administration of the study drug.
Interventions
DRUGSafinamide 50 mg
Safinamide 50mg film-coated tablets will be administered to subjects in Cohort 1. The subjects will receive the tablets orally in the morning, at 8:00±1hour, under fasting conditions, with 240 mL (total volume) of still mineral water. A mouth-and-hand check will be performed immediately after dosing to ensure treatment compliance.
DRUGSafinamide 100mg
Safinamide 100mg film-coated tablets will be administered to subjects in Cohort 2. The subjects will receive the tablets orally in the morning, at 8:00±1hour, under fasting conditions, with 240 mL (total volume) of still mineral water. A mouth-and-hand check will be performed immediately after dosing to ensure treatment compliance.
Sponsors
Zambon SpA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
There will be 2 treatment groups. A total of 24 subjects will be randomized to receive 50mg or 100 mg Safinamide in Period 1 (Day 1) and Period 2 (Days 8 to 14) separated by a 7 days washout period.
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Informed consent: signed written informed consent before inclusion in the study 2. Sex and Age: males and females, 18-45-year old inclusive 3. Ethnicity: Chinese 4. Weight: body weight ≥ 50 kg; 5. Body Mass Index: 19-26 kg/m2 inclusive 6. Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, heart rate 50-90 bpm, measured after 5 min at rest in the sitting/supine position 7. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study 8. No nicotine addiction (smoker subjects only): ability to abstain for smoking for the duration of the clinical study 9. Contraception and fertility (women only): women of child-bearing potential must be using at least one of the following reliable methods of contraception during the study and two weeks post-dose: 1. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit 2. A non-hormonal intrauterine device or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit 3. A male sexual partner who agrees to use a male condom with spermicide 4. A sterile sexual partner Women of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. For all women, pregnancy test result must be negative at screening and day -1.
Exclusion criteria
1. Electrocardiogram (12-lead ECG in supine position): clinically significant abnormalities 2. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study 3. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness 4. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect the outcome of the study 5. Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases that may interfere with the aim of the study; positive result on HIV, hepatitis B (HBV) (except for vaccination), hepatitis C (HCV). Retinal degeneration, uveitis, inherited retinopathy or severe progressive diabetic retinopathy. 6. Medications: medications, including over the counter medications, herbal remedies and traditional Chinese remedies for 2 weeks before the start of the study. In particular statins and β-Hydroxy β-methylglutaryl-CoA (HMG-CoA)reductase inhibitors in the 2 weeks before the screening visit; medicinal products that are Breast Cancer Resistance Protein (BCRP) substrates; treatment with morphine or other similar opioids, whose concomitant use with Monoamine oxidase B (MAO-B) inhibitors is contraindicated, Selective serotonin reuptake inhibitors (SSRIs), Serotonin-norepinephrine reuptake inhibitors (SNRIs), tri- or tetracyclic antidepressant, tramadol, pethidine, dextromethorphan, Monoamino oxidase (MAO) inhibitors (e.g. selegiline), meperidine derivatives and antiepileptic drugs in the 4 weeks before the screening visit; treatment with any known enzyme inhibiting or inducing agent within 4 weeks preceding the screening visit. Hormonal contraceptives for women will be allowed 7. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study 8. Blood donation: blood donations or blood components transfusion for 3 months before this study 9. Abuse drug, alcohol, caffeine, tobacco: history of drug, alcohol \[\>1 drink/day for females and \>2 drinks/day for males, defined according to the USDA Dietary Guidelines 2015-2020\], caffeine (\>5 cups coffee/tea/day) or tobacco abuse (≥10 cigarettes or equivalent amount of tobacco per day within 3 months prior to day-1) 10. Abuse drug test: positive result at urine drug test at screening or day-1 11. Alcohol test: positive alcohol breath test at day -1 12. Diet: abnormal diets (\<1600 or \>3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians; consumption of grapefruit or products containing grapefruit within 48 hours prior to the enrolment; consumption of beverages containing xanthines (e.g. coffee, tea, soda, coffee, milk, energy drinks) within 48 hours prior to the enrolment 13. Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Total Body Clearance at Steady-state, (CL/F_ss) | Day 14 | The CL/F\_ss was determined on Day 14 (after the multiple dose) of Safinamide. |
| Last Quantifiable Concentration (Clast/Ct) | Day 1 | The (Clast/Ct) was determined on Day 1 (after the first dose) of safinamide. |
| Area Under the Concentration-time Curve in the Tau Interval (From Single Dose Administration to 24 h Post Dose) (AUC0-24h) | Day 1 and Day 8 | The (AUC0-24h) was determined on Day 1 (after the first dose), on Day 8 (after the first multiple dose) of safinamide. |
| Maximum Safinamide Plasma Concentration (Cmax) | Day 1 and Day 8 | The Cmax was determined on Day 1 (after the first dose), on Day 8 (after the first multiple doses) of Safinamide. |
| Time Corresponding to Occurrence of Cmax (Tmax) | Day 1 and Day 8 | The tmax was determined on Day 1 (after the first dose), on Day 8 (after the first multiple dose) of Safinamide. |
| Area Under the Concentration-time Curve From Single-dose Administration to the Last Quantifiable Concentration-time t (AUC0-t) | Day 1 and Day 8 | The (AUC0-t) was determined on Day 1 (after the first dose), on Day 8 (after the first multiple doses) of Safinamide. |
| Terminal Elimination Rate Constant (Kel) | Day 1 | Apparent terminal elimination rate constant, calculated, if feasible, from the slope of a log-linear regression using at least 3 last concentration \> lower limit of quantification (LLOQ) points. The Kel was determined on Day 1 (after the first dose) of safinamide. |
| Apparent Terminal Elimination Half Life (t1/2) | Day 1 | Apparent terminal elimination half-life, calculated, if feasible, as ln2/Kel. The t1/2 will be determined on Day 1 (after the first dose) of Safinamide. |
| Percentage of AUC(0-inf) Obtained by Extrapolation (%AUCex) | Day 1 | The %AUCex was determined on Day 1 (after the first dose) of Safinamide. |
| AUC From Time Zero Extrapolated to Infinity (AUC(0-inf)) | Day 1 | Area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/Kel, where Ct is the last measurable drug concentration. The AUC(0-inf) was determined on day 1 (after the first dose) of Safinamide. |
| Apparent Volume of Distribution During Terminal Phase (Vd/F) | Day 1 | Apparent volume of distribution associated with the terminal slope, calculated, if feasible, as Dose/(AUC0-∞\*Kel). The Vd/F was determined on Day 1 (after the first dose) of safinamide. |
| Apparent Clearance Following Oral Administration (CL/F) | Day 1 | Apparent total body clearance, calculated, if feasible, as Dose/AUC0-∞. The CL/F was determined on Day 1 (after the first dose) of safinamide. |
| Mean Residence Time (MRT) | Day 1 | Mean residence time, calculated, if feasible, as AUMC0-∞/AUC0-∞, where AUMC0-∞ is area under the moment concentration-time curve extrapolated to infinity. The MRT was determined on Day 1 (after the first dose) of Safinamide. |
| Area Under the First Moment of the Concentration-time Curve (AUMC) | Day 1 | The AUMC was determined on Day 1 (after the first dose) of Safinamide. |
| Maximum Safinamide Plasma Concentration at Steady State (Cmax_ss) | Day 14 | The Cmax\_ss was determined on day 14 (after the multiple-dose) of Safinamide. |
| Time Corresponding to Occurrence of Cmax_ss at Steady State (tmax_ss) | Day 14 | The tmax\_ss was determined on day 14 (after the multiple-dose) of Safinamide. |
| Minimum Observed Concentration at Steady State (Cmin_ss) | Day 14 | The Cmin\_ss was determined on day 14 (after the multiple dose) of Safinamide. |
| Area Under the Concentration-time Curve at Steady State From the Last Dose Administration to the Last Observed Concentration Time t (AUC0-t_ss) | Day 14 | The AUC0-t\_ss was determined on Day 14 (after the multiple dose) of Safinamide. |
| AUC Over the Dosing Interval at Steady State (AUC0-τ_ss) | Day 14 | The AUC0-τ\_ss was determined on Day 14 (after the multiple dose) of Safinamide. |
| Average Safinamide Plasma Concentration at Steady State(Cave_ss) | Day 14 | Average safinamide plasma concentration at steady state, calculated as AUC0- 24h\_ss /tau (24 h). The Cave\_ss was determined on Day 14 (after the multiple dose) of Safinamide. |
| Accumulation Ratio, Based on AUC (Racc,AUC) | Day 14 | Racc,AUC was determined on Day 14 (after the multiple dose) of Safinamide. |
| Accumulation Ratio, Based on Cmax (Racc,Cmax) | Day 14 | Racc,Cmax was determined on Day 14 (after the multiple dose) of Safinamide. |
| Peak-trough Fluctuation Over One Dosing Interval at Steady-state (DF%) | Day 14 | Peak-trough fluctuation over one dosing interval at steady-state, calculated as (Cmax,ss - Cmin,ss)/Cave,ss\*100. The DF% was determined on Day 14 (after the multiple dose) of Safinamide. |
| Apparent Volume of Distribution at Steady-state Associated With the Terminal Slope (Vd/F_ss) | Day 14 | Apparent volume of distribution at steady-state associated with the terminal slope, calculated, if feasible, as Dose/( AUC0-24h\_ss\*Kel). The Vd/F\_ss was determined on Day 14 (after the multiple dose) of Safinamide. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Day 1 to18 | Safety and general tolerability were assessed for safinamide. |
Countries
China
Participant flow
Recruitment details
This single-center study was conducted on 24 Healthy Adult Chinese Volunteers in China from 21 Jun 2021 to 20 Aug 2021.
Pre-assignment details
The screening period was between Day -14 and Day -2. All the study assessments were performed as per the schedule of assessments.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (Safinamide 50mg) The subjects received 50mg single-dose of safinamide on Day 1 orally (Period 1) and later subjects received 50mg one tablet once daily orally from Days 8 to 14 (Period 2). The single-dose in Period 1 and the first dose in Period 2 were separated by a washout interval of 7 days. | 12 |
| Cohort 2 (Safinamide 100mg) The subjects received 100mg single-dose of safinamide on Day 1 orally (Period 1) and later subjects received 100mg one tablet once daily orally from Days 8 to 14 (Period 2). The single-dose in Period 1 and the first dose in Period 2 were separated by a washout interval of 7 days. | 12 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 (Safinamide 50mg) | Cohort 2 (Safinamide 100mg) | Total |
|---|---|---|---|
| Age, Continuous | 30.8 years STANDARD_DEVIATION 5.86 | 29.9 years STANDARD_DEVIATION 5.38 | 30.4 years STANDARD_DEVIATION 5.52 |
| Race/Ethnicity, Customized Chinese | 12 Participants | 12 Participants | 24 Participants |
| Race/Ethnicity, Customized Not Chinese | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 6 / 12 | 7 / 12 | 5 / 12 | 4 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Accumulation Ratio, Based on AUC (Racc,AUC)
Racc,AUC was determined on Day 14 (after the multiple dose) of Safinamide.
Time frame: Day 14
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Accumulation Ratio, Based on AUC (Racc,AUC) | 2.101 ratio | Standard Deviation 0.2525 |
| Cohort 2 (Safinamide 100mg) | Accumulation Ratio, Based on AUC (Racc,AUC) | 2.027 ratio | Standard Deviation 0.1367 |
Primary
Accumulation Ratio, Based on Cmax (Racc,Cmax)
Racc,Cmax was determined on Day 14 (after the multiple dose) of Safinamide.
Time frame: Day 14
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Accumulation Ratio, Based on Cmax (Racc,Cmax) | 1.939 ratio | Standard Deviation 0.3691 |
| Cohort 2 (Safinamide 100mg) | Accumulation Ratio, Based on Cmax (Racc,Cmax) | 1.898 ratio | Standard Deviation 0.1594 |
Primary
Apparent Clearance Following Oral Administration (CL/F)
Apparent total body clearance, calculated, if feasible, as Dose/AUC0-∞. The CL/F was determined on Day 1 (after the first dose) of safinamide.
Time frame: Day 1
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Apparent Clearance Following Oral Administration (CL/F) | 4159 milliliter/ hour (mL/h) | Standard Deviation 697.2 |
| Cohort 2 (Safinamide 100mg) | Apparent Clearance Following Oral Administration (CL/F) | 4634 milliliter/ hour (mL/h) | Standard Deviation 707.1 |
Primary
Apparent Terminal Elimination Half Life (t1/2)
Apparent terminal elimination half-life, calculated, if feasible, as ln2/Kel. The t1/2 will be determined on Day 1 (after the first dose) of Safinamide.
Time frame: Day 1
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Apparent Terminal Elimination Half Life (t1/2) | 23.79 hour (h) | Standard Deviation 3.391 |
| Cohort 2 (Safinamide 100mg) | Apparent Terminal Elimination Half Life (t1/2) | 23.08 hour (h) | Standard Deviation 1.74 |
Primary
Apparent Total Body Clearance at Steady-state, (CL/F_ss)
The CL/F\_ss was determined on Day 14 (after the multiple dose) of Safinamide.
Time frame: Day 14
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Apparent Total Body Clearance at Steady-state, (CL/F_ss) | 3933 milliliter/hour (mL/h) | Standard Deviation 705.8 |
| Cohort 2 (Safinamide 100mg) | Apparent Total Body Clearance at Steady-state, (CL/F_ss) | 4426 milliliter/hour (mL/h) | Standard Deviation 692 |
Primary
Apparent Volume of Distribution at Steady-state Associated With the Terminal Slope (Vd/F_ss)
Apparent volume of distribution at steady-state associated with the terminal slope, calculated, if feasible, as Dose/( AUC0-24h\_ss\*Kel). The Vd/F\_ss was determined on Day 14 (after the multiple dose) of Safinamide.
Time frame: Day 14
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Apparent Volume of Distribution at Steady-state Associated With the Terminal Slope (Vd/F_ss) | 134400 milliliter (mL) | Standard Deviation 28640 |
| Cohort 2 (Safinamide 100mg) | Apparent Volume of Distribution at Steady-state Associated With the Terminal Slope (Vd/F_ss) | 153100 milliliter (mL) | Standard Deviation 30250 |
Primary
Apparent Volume of Distribution During Terminal Phase (Vd/F)
Apparent volume of distribution associated with the terminal slope, calculated, if feasible, as Dose/(AUC0-∞\*Kel). The Vd/F was determined on Day 1 (after the first dose) of safinamide.
Time frame: Day 1
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Apparent Volume of Distribution During Terminal Phase (Vd/F) | 142700 milliliter (mL) | Standard Deviation 33040 |
| Cohort 2 (Safinamide 100mg) | Apparent Volume of Distribution During Terminal Phase (Vd/F) | 154800 milliliter (mL) | Standard Deviation 29600 |
Primary
Area Under the Concentration-time Curve at Steady State From the Last Dose Administration to the Last Observed Concentration Time t (AUC0-t_ss)
The AUC0-t\_ss was determined on Day 14 (after the multiple dose) of Safinamide.
Time frame: Day 14
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Area Under the Concentration-time Curve at Steady State From the Last Dose Administration to the Last Observed Concentration Time t (AUC0-t_ss) | 24170 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 6349 |
| Cohort 2 (Safinamide 100mg) | Area Under the Concentration-time Curve at Steady State From the Last Dose Administration to the Last Observed Concentration Time t (AUC0-t_ss) | 42420 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 6676 |
Primary
Area Under the Concentration-time Curve From Single-dose Administration to the Last Quantifiable Concentration-time t (AUC0-t)
The (AUC0-t) was determined on Day 1 (after the first dose), on Day 8 (after the first multiple doses) of Safinamide.
Time frame: Day 1 and Day 8
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Area Under the Concentration-time Curve From Single-dose Administration to the Last Quantifiable Concentration-time t (AUC0-t) | Day 1 | 11560 hour* nanogram/milliliter (h*ng/mL) | Standard Deviation 2170 |
| Cohort 1 (Safinamide 50mg) | Area Under the Concentration-time Curve From Single-dose Administration to the Last Quantifiable Concentration-time t (AUC0-t) | Day 8 | 6652 hour* nanogram/milliliter (h*ng/mL) | Standard Deviation 985.5 |
| Cohort 2 (Safinamide 100mg) | Area Under the Concentration-time Curve From Single-dose Administration to the Last Quantifiable Concentration-time t (AUC0-t) | Day 1 | 20790 hour* nanogram/milliliter (h*ng/mL) | Standard Deviation 3131 |
| Cohort 2 (Safinamide 100mg) | Area Under the Concentration-time Curve From Single-dose Administration to the Last Quantifiable Concentration-time t (AUC0-t) | Day 8 | 12130 hour* nanogram/milliliter (h*ng/mL) | Standard Deviation 1846 |
Primary
Area Under the Concentration-time Curve in the Tau Interval (From Single Dose Administration to 24 h Post Dose) (AUC0-24h)
The (AUC0-24h) was determined on Day 1 (after the first dose), on Day 8 (after the first multiple dose) of safinamide.
Time frame: Day 1 and Day 8
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Area Under the Concentration-time Curve in the Tau Interval (From Single Dose Administration to 24 h Post Dose) (AUC0-24h) | Day 1 | 6291 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 1158 |
| Cohort 1 (Safinamide 50mg) | Area Under the Concentration-time Curve in the Tau Interval (From Single Dose Administration to 24 h Post Dose) (AUC0-24h) | Day 8 | 6649 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 986.3 |
| Cohort 2 (Safinamide 100mg) | Area Under the Concentration-time Curve in the Tau Interval (From Single Dose Administration to 24 h Post Dose) (AUC0-24h) | Day 1 | 11420 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 1727 |
| Cohort 2 (Safinamide 100mg) | Area Under the Concentration-time Curve in the Tau Interval (From Single Dose Administration to 24 h Post Dose) (AUC0-24h) | Day 8 | 12090 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 1931 |
Primary
Area Under the First Moment of the Concentration-time Curve (AUMC)
The AUMC was determined on Day 1 (after the first dose) of Safinamide.
Time frame: Day 1
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Area Under the First Moment of the Concentration-time Curve (AUMC) | 431100 hour2* nanogram/milliliter (h2*ng/mL) | Standard Deviation 131600 |
| Cohort 2 (Safinamide 100mg) | Area Under the First Moment of the Concentration-time Curve (AUMC) | 729400 hour2* nanogram/milliliter (h2*ng/mL) | Standard Deviation 117100 |
Primary
AUC From Time Zero Extrapolated to Infinity (AUC(0-inf))
Area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/Kel, where Ct is the last measurable drug concentration. The AUC(0-inf) was determined on day 1 (after the first dose) of Safinamide.
Time frame: Day 1
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | AUC From Time Zero Extrapolated to Infinity (AUC(0-inf)) | 12380 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 2424 |
| Cohort 2 (Safinamide 100mg) | AUC From Time Zero Extrapolated to Infinity (AUC(0-inf)) | 22030 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 3290 |
Primary
AUC Over the Dosing Interval at Steady State (AUC0-τ_ss)
The AUC0-τ\_ss was determined on Day 14 (after the multiple dose) of Safinamide.
Time frame: Day 14
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | AUC Over the Dosing Interval at Steady State (AUC0-τ_ss) | 13150 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 2781 |
| Cohort 2 (Safinamide 100mg) | AUC Over the Dosing Interval at Steady State (AUC0-τ_ss) | 23100 hour*nanogram/milliliter (h*ng/mL) | Standard Deviation 3541 |
Primary
Average Safinamide Plasma Concentration at Steady State(Cave_ss)
Average safinamide plasma concentration at steady state, calculated as AUC0- 24h\_ss /tau (24 h). The Cave\_ss was determined on Day 14 (after the multiple dose) of Safinamide.
Time frame: Day 14
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Average Safinamide Plasma Concentration at Steady State(Cave_ss) | 548.0 nanogram/milliliter (ng/mL) | Standard Deviation 115.9 |
| Cohort 2 (Safinamide 100mg) | Average Safinamide Plasma Concentration at Steady State(Cave_ss) | 962.4 nanogram/milliliter (ng/mL) | Standard Deviation 147.5 |
Primary
Last Quantifiable Concentration (Clast/Ct)
The (Clast/Ct) was determined on Day 1 (after the first dose) of safinamide.
Time frame: Day 1
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Last Quantifiable Concentration (Clast/Ct) | 23.01 nanogram/milliliter (ng/mL) | Standard Deviation 9.306 |
| Cohort 2 (Safinamide 100mg) | Last Quantifiable Concentration (Clast/Ct) | 37.26 nanogram/milliliter (ng/mL) | Standard Deviation 7.483 |
Primary
Maximum Safinamide Plasma Concentration at Steady State (Cmax_ss)
The Cmax\_ss was determined on day 14 (after the multiple-dose) of Safinamide.
Time frame: Day 14
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Maximum Safinamide Plasma Concentration at Steady State (Cmax_ss) | 782.8 nnaogram/milliliter (ng/mL) | Standard Deviation 174.4 |
| Cohort 2 (Safinamide 100mg) | Maximum Safinamide Plasma Concentration at Steady State (Cmax_ss) | 1501 nnaogram/milliliter (ng/mL) | Standard Deviation 249.6 |
Primary
Maximum Safinamide Plasma Concentration (Cmax)
The Cmax was determined on Day 1 (after the first dose), on Day 8 (after the first multiple doses) of Safinamide.
Time frame: Day 1 and Day 8
Population: All randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product (IMP) intake and had evaluable pharmacokinetic (PK) data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Maximum Safinamide Plasma Concentration (Cmax) | Day 1 | 411.5 nanogram/milliliter (ng/mL) | Standard Deviation 96.58 |
| Cohort 1 (Safinamide 50mg) | Maximum Safinamide Plasma Concentration (Cmax) | Day 8 | 465.0 nanogram/milliliter (ng/mL) | Standard Deviation 86.94 |
| Cohort 2 (Safinamide 100mg) | Maximum Safinamide Plasma Concentration (Cmax) | Day 1 | 792.1 nanogram/milliliter (ng/mL) | Standard Deviation 124 |
| Cohort 2 (Safinamide 100mg) | Maximum Safinamide Plasma Concentration (Cmax) | Day 8 | 825.3 nanogram/milliliter (ng/mL) | Standard Deviation 183.5 |
Primary
Mean Residence Time (MRT)
Mean residence time, calculated, if feasible, as AUMC0-∞/AUC0-∞, where AUMC0-∞ is area under the moment concentration-time curve extrapolated to infinity. The MRT was determined on Day 1 (after the first dose) of Safinamide.
Time frame: Day 1
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Mean Residence Time (MRT) | 34.65 hour (h) | Standard Deviation 5.324 |
| Cohort 2 (Safinamide 100mg) | Mean Residence Time (MRT) | 33.12 hour (h) | Standard Deviation 1.988 |
Primary
Minimum Observed Concentration at Steady State (Cmin_ss)
The Cmin\_ss was determined on day 14 (after the multiple dose) of Safinamide.
Time frame: Day 14
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Minimum Observed Concentration at Steady State (Cmin_ss) | 358.3 nanogram/liter (ng/mL) | Standard Deviation 107.8 |
| Cohort 2 (Safinamide 100mg) | Minimum Observed Concentration at Steady State (Cmin_ss) | 583.2 nanogram/liter (ng/mL) | Standard Deviation 117.2 |
Primary
Peak-trough Fluctuation Over One Dosing Interval at Steady-state (DF%)
Peak-trough fluctuation over one dosing interval at steady-state, calculated as (Cmax,ss - Cmin,ss)/Cave,ss\*100. The DF% was determined on Day 14 (after the multiple dose) of Safinamide.
Time frame: Day 14
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Peak-trough Fluctuation Over One Dosing Interval at Steady-state (DF%) | 77.75 percentage (%) | Standard Deviation 13.42 |
| Cohort 2 (Safinamide 100mg) | Peak-trough Fluctuation Over One Dosing Interval at Steady-state (DF%) | 95.17 percentage (%) | Standard Deviation 11.9 |
Primary
Percentage of AUC(0-inf) Obtained by Extrapolation (%AUCex)
The %AUCex was determined on Day 1 (after the first dose) of Safinamide.
Time frame: Day 1
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Percentage of AUC(0-inf) Obtained by Extrapolation (%AUCex) | 6.594 percentage (%) | Standard Deviation 2.931 |
| Cohort 2 (Safinamide 100mg) | Percentage of AUC(0-inf) Obtained by Extrapolation (%AUCex) | 5.672 percentage (%) | Standard Deviation 1.077 |
Primary
Terminal Elimination Rate Constant (Kel)
Apparent terminal elimination rate constant, calculated, if feasible, from the slope of a log-linear regression using at least 3 last concentration \> lower limit of quantification (LLOQ) points. The Kel was determined on Day 1 (after the first dose) of safinamide.
Time frame: Day 1
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Terminal Elimination Rate Constant (Kel) | 0.02967 hour (h) | Standard Deviation 0.004188 |
| Cohort 2 (Safinamide 100mg) | Terminal Elimination Rate Constant (Kel) | 0.03019 hour (h) | Standard Deviation 0.002283 |
Primary
Time Corresponding to Occurrence of Cmax_ss at Steady State (tmax_ss)
The tmax\_ss was determined on day 14 (after the multiple-dose) of Safinamide.
Time frame: Day 14
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (Safinamide 50mg) | Time Corresponding to Occurrence of Cmax_ss at Steady State (tmax_ss) | 2.017 hour (h) |
| Cohort 2 (Safinamide 100mg) | Time Corresponding to Occurrence of Cmax_ss at Steady State (tmax_ss) | 1.483 hour (h) |
Primary
Time Corresponding to Occurrence of Cmax (Tmax)
The tmax was determined on Day 1 (after the first dose), on Day 8 (after the first multiple dose) of Safinamide.
Time frame: Day 1 and Day 8
Population: All randomised subjects who fulfilled the study protocol requirements in terms of IMP intake and had evaluable PK data readouts, with no major deviations that might affect the PK results. This analysis set was used for the statistical analysis of the PK summaries and analyses.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Time Corresponding to Occurrence of Cmax (Tmax) | Day 1 | 1.500 hour (h) |
| Cohort 1 (Safinamide 50mg) | Time Corresponding to Occurrence of Cmax (Tmax) | Day 8 | 2.000 hour (h) |
| Cohort 2 (Safinamide 100mg) | Time Corresponding to Occurrence of Cmax (Tmax) | Day 1 | 1.750 hour (h) |
| Cohort 2 (Safinamide 100mg) | Time Corresponding to Occurrence of Cmax (Tmax) | Day 8 | 1.508 hour (h) |
Secondary
Number of Subjects With Treatment Emergent Adverse Events (TEAEs)
Safety and general tolerability were assessed for safinamide.
Time frame: Day 1 to18
Population: All randomised subjects who receive at least one dose of the investigational medicinal product(s). This analysis set will be used for the safety analyses.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (Safinamide 50mg) | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | TEAE | 6 Participants |
| Cohort 1 (Safinamide 50mg) | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | TEAE Related to IMP | 6 Participants |
| Cohort 2 (Safinamide 100mg) | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | TEAE Related to IMP | 7 Participants |
| Cohort 2 (Safinamide 100mg) | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | TEAE | 7 Participants |
| Cohort 1 (Safinamide 50mg) Multiple Dose | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | TEAE | 5 Participants |
| Cohort 1 (Safinamide 50mg) Multiple Dose | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | TEAE Related to IMP | 5 Participants |
| Cohort 2 (Safinamide 100mg) Multiple Dose | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | TEAE | 4 Participants |
| Cohort 2 (Safinamide 100mg) Multiple Dose | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | TEAE Related to IMP | 4 Participants |