Clinical trial NCT03887221: 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
Official title: A Phase I, Pharmacokinetics, Safety and Tolerability Study of Single and Multiple Oral Doses of Safinamide in Healthy Adult Chinese Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Pharmacokinetic
Safety
Tolerability
Healthy Chinese subjects
Lead sponsor: Zambon SpA
Sponsor class: INDUSTRY
First posted: 2019-03-22
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Maximum Safinamide Plasma Concentration (Cmax)
timeFrame: Day 1 and Day 8
measure: Time Corresponding to Occurrence of Cmax (Tmax)
timeFrame: Day 1 and Day 8
measure: Area Under the Concentration-time Curve From Single-dose Administration to the Last Quantifiable Concentration-time t (AUC0-t)
timeFrame: Day 1 and Day 8
measure: Area Under the Concentration-time Curve in the Tau Interval (From Single Dose Administration to 24 h Post Dose) (AUC0-24h)
timeFrame: Day 1 and Day 8
measure: Last Quantifiable Concentration (Clast/Ct)
timeFrame: Day 1
measure: Terminal Elimination Rate Constant (Kel)
timeFrame: Day 1
measure: Apparent Terminal Elimination Half Life (t1/2)
timeFrame: Day 1
measure: Percentage of AUC(0-inf) Obtained by Extrapolation (%AUCex)
timeFrame: Day 1
measure: AUC From Time Zero Extrapolated to Infinity (AUC(0-inf))
timeFrame: Day 1
measure: Apparent Volume of Distribution During Terminal Phase (Vd/F)
timeFrame: Day 1
measure: Apparent Clearance Following Oral Administration (CL/F)
timeFrame: Day 1
measure: Mean Residence Time (MRT)
timeFrame: Day 1
measure: Area Under the First Moment of the Concentration-time Curve (AUMC)
timeFrame: Day 1
measure: Maximum Safinamide Plasma Concentration at Steady State (Cmax_ss)
timeFrame: Day 14
measure: Time Corresponding to Occurrence of Cmax_ss at Steady State (tmax_ss)
timeFrame: Day 14
measure: Minimum Observed Concentration at Steady State (Cmin_ss)
timeFrame: Day 14
measure: Area Under the Concentration-time Curve at Steady State From the Last Dose Administration to the Last Observed Concentration Time t (AUC0-t_ss)
timeFrame: Day 14
measure: AUC Over the Dosing Interval at Steady State (AUC0-τ_ss)
timeFrame: Day 14
measure: Average Safinamide Plasma Concentration at Steady State(Cave_ss)
timeFrame: Day 14
measure: Accumulation Ratio, Based on AUC (Racc,AUC)
timeFrame: Day 14
measure: Accumulation Ratio, Based on Cmax (Racc,Cmax)
timeFrame: Day 14
measure: Peak-trough Fluctuation Over One Dosing Interval at Steady-state (DF%)
timeFrame: Day 14
measure: Apparent Volume of Distribution at Steady-state Associated With the Terminal Slope (Vd/F_ss)
timeFrame: Day 14
measure: Apparent Total Body Clearance at Steady-state, (CL/F_ss)
timeFrame: Day 14
Secondary outcomes:
measure: Number of Subjects With Treatment Emergent Adverse Events (TEAEs)
timeFrame: Day 1 to18
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Ruijin Hospital, Shanghai Jiao Tong University School of Med
state: Shanghai
Study officials:
References: