A Single and Multiple Dose Study to Assess How the Drug Enters, Moves Through and Exits the Body, Safety and Tolerability of Safinamide in Healthy Adult Chinese Volunteers

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I, Pharmacokinetics, Safety and Tolerability Study of Single and Multiple Oral Doses of Safinamide in Healthy Adult Chinese Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Safinamide 50 mg
* Drug: Safinamide 100mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent: signed written informed consent before inclusion in the study Sex and Age: males and females, 18-45-year old inclusive Ethnicity: Chinese Weight: body weight ≥ 50 kg; Body Mass Index: 19-26 kg/m2 inclusive 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 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 No nicotine addiction (smoker subjects only): ability to abstain for smoking for the duration of the clinical study 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: Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit 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 A male sexual partner who agrees to use a male condom with spermicide 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: Electrocardiogram (12-lead ECG in supine position): clinically significant abnormalities Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness 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 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. 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 Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study Blood donation: blood donations or blood components transfusion for 3 months before this study 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) Abuse drug test: positive result at urine drug test at screening or day-1 Alcohol test: positive alcohol breath test at day -1 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 Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safinamide 50mg<br>The subjects will receive 50mg safinamide on Day 1 of Period 1 and on Days 8 to 14 in period 2. | Drug: Safinamide 50 mg<br>* 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.<br>|
| Experimental: Safinamide 100mg<br>The subjects will receive 100mg safinamide on Day 1 of Period 1 and on Days 8 to 14 in period 2. | Drug: Safinamide 100mg<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 1 and Day 8 | 
| 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. | Day 1 and Day 8 | 
| 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. | Day 1 and Day 8 | 
| 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. | Day 1 and Day 8 | 
| Last Quantifiable Concentration (Clast/Ct) | The (Clast/Ct) was determined on Day 1 (after the first dose) of safinamide. | Day 1 | 
| 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. | Day 1 | 
| 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. | Day 1 | 
| Percentage of AUC(0-inf) Obtained by Extrapolation (%AUCex) | The %AUCex was determined on Day 1 (after the first dose) of Safinamide. | Day 1 | 
| 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. | Day 1 | 
| 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. | Day 1 | 
| 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. | Day 1 | 
| 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. | Day 1 | 
| Area Under the First Moment of the Concentration-time Curve (AUMC) | The AUMC was determined on Day 1 (after the first dose) of Safinamide. | Day 1 | 
| Maximum Safinamide Plasma Concentration at Steady State (Cmax_ss) | The Cmax_ss was determined on day 14 (after the multiple-dose) of Safinamide. | Day 14 | 
| 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. | Day 14 | 
| Minimum Observed Concentration at Steady State (Cmin_ss) | The Cmin_ss was determined on day 14 (after the multiple dose) of Safinamide. | Day 14 | 
| 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. | Day 14 | 
| 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. | Day 14 | 
| 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. | Day 14 | 
| Accumulation Ratio, Based on AUC (Racc,AUC) | Racc,AUC was determined on Day 14 (after the multiple dose) of Safinamide. | Day 14 | 
| Accumulation Ratio, Based on Cmax (Racc,Cmax) | Racc,Cmax was determined on Day 14 (after the multiple dose) of Safinamide. | Day 14 | 
| 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. | Day 14 | 
| 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. | Day 14 | 
| 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. | Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs) | Safety and general tolerability were assessed for safinamide. | Day 1 to18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetic, Safety, Tolerability, Healthy Chinese subjects