Clinical trial NCT03887221
Conditions: Healthy
Keywords: Pharmacokinetic Safety Tolerability Healthy Chinese subjects
Sponsor: Zambon SpA
Start date: 2021-06-21; Completion date: 2021-08-20
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: The subjects will receive 50mg safinamide on Day 1 of Period 1 and on Days 8 to 14 in period 2. arm 2: The subjects will receive 100mg safinamide on Day 1 of Period 1 and on Days 8 to 14 in period 2.
Interventions: intervention 1: Safinamide 50 mg intervention 2: Safinamide 100mg
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_000.pdf: 
 
 
 
A PHASE I, PHARMACOKINETICS, SAFETY AND TOLERABILITY 
STUDY OF SINGLE AND MULTIPLE ORAL DOSES OF SAFINAMIDE 
IN HEALTHY ADULT CHINESE VOLUNTEERS 
 
 
 
ClinicalTrials.gov Identifier: NCT03887221 
 
 
 
 
 
Original Protocol: 10-December-2018 
Amendment 1: 18 April 2019 
Amendment 2: 07 July 2020 


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                                                                                          Page 1 of 61 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
 
A PHASE I, PHARMACOKINETICS, SAFETY AND TOLERABILITY 
STUDY OF SINGLE AND MULTIPLE ORAL DOSES OF SAFINAMIDE 
IN HEALTHY ADULT CHINESE VOLUNTEERS  
 
Phase I, single centre, single and multiple-dose, open-label, randomised, 
parallel-group, pharmacokinetics, safety and tolerability study 
 
 
 
Protocol Code: Z7219J03 
 
Date: 10-December-2018 
 
Version: Final 1.0 
 
 
 
 
Zambon SpA 
Via Lillo del Duca 10 
20091 Bresso - Milan - Italy 
 
 
 
 
 
 
THIS DOCUMENT IS ZAMBON'S SOLE PROPERTY AND OWNERSHIP. THIS DOCUMENT, AND ALL 
INFORMATION AND DATA CONTAINED HEREIN HAS TO BE CONSIDERED AND TREATED AS 
STRICTLY CONFIDENTIAL. THIS DOCUMENT SHALL BE USED ONLY FOR THE PURPOSE OF THE 
DISCLOSURE HEREIN PROVIDED. NO DISCLOSURE OR PUBLICATION SHALL BE MADE WITHOUT 
THE PRIOR WRITTEN CONSENT OF ZAMBON.  
 
 
 


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                                                                                          Page 2 of 61 
 
APPROVAL PAGE 
 
Clinical Trial Title: 
 
A phase I, pharmacokinetics, safety and 
tolerability study of single and multiple oral 
doses of safinamide in Chinese adult healthy 
volunteers.  
 
 
Protocol Code  
 
Date:  
 
Z7219J03 
 
10-December-2018 
 
Author: 
  
 
Sponsor Name and 
Address: 
Zambon SpA 
Via Lillo del Duca 10 
20091 Bresso, Milan, Italy 
 
 
 
As agreed and approved: 
 
 
 
______/______/_____      _____________________    ___________________ 
Date (dd/Mmm/yyyy)
      Principal Investigator
          SIGNATURE
 
 
 
 
 
 
Accepted for the Sponsor 
 
 
 
______/______/_____      _______________________    ___________________ 
Date (dd/Mmm/yyyy) 
Global Chief Medical Officer 
and Patient’s Access Head
         SIGNATURE 
 
 
 
 
PPD




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STUDY SYNOPSIS (cont.) 
 
Study variables, continued: Primary variables - Pharmacokinetics, continued: 
After single dose only (day 1): 
 Kel: terminal elimination rate constant, calculated, if feasible, by log-linear regression using at least 3 points 
 t1/2: apparent terminal elimination half-life, calculated, if feasible, as ln2/Kel 
 AUC0-: 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 
 Vd/F: apparent volume of distribution associated with the terminal slope, calculated, if feasible, as 
Dose/(AUC0-∞*Kel) 
 Cl/F: apparent total body clearance, calculated, if feasible, as Dose/AUC0-∞ 
 MRT: Mean residence time calculated, if feasible, as AUMC0-∞/AUC0-∞, were AUMC0-∞ is area under the 
moment concentration-time curve extrapolated to infinity 
After multiple dose (day 14): 
 Cmax_ss: maximum safinamide plasma concentration at steady-state 
 tmax_ss: time to achieve Cmax,ss 
 Cmin_ss: trough safinamide plasma concentration at steady-state, measured as concentration at 24h 
 AUCss0-t: area under the concentration-time curve at steady-state from the last dose administration to the last 
observed concentration time t, calculated with the linear up/log down trapezoidal method 
 AUCss0-24: area under the concentration-time curve at steady-state in the tau interval (from the last dose 
administration to 24 h post dose), calculated with the linear up/log down trapezoidal method 
 Cave_ss: average safinamide plasma concentration at steady-state, calculated as AUCss0-24 /tau  
 R: accumulation ratio, calculated as AUCss0-24/ Day 8 AUC0-24 
 DF%: peak-trough fluctuation over one dosing interval at steady-state, calculated as (Cmax,ss - 
Cmin,ss)/Cave,ss*100 
 Vd,ss/F: apparent volume of distribution at steady-state associated with the terminal slope, calculated, if 
feasible, as Dose/( AUCss0-24*Kel) 
 Cl,ss/F: apparent total body clearance at steady-state, calculated, if feasible, as Dose/ AUCss0-24 
Secondary variables - Safety and tolerability:  
 Treatment emergent adverse events, vital signs (blood pressure, heart rate), body weight, physical 
examinations, clinical laboratory parameters, ECG. 
 
Analytics: Plasma samples for safinamide determination will be collected at: 
 pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 36, 48, 72 and 96 h post-dose after the first single dose (day 1) 
and the last multiple dose (day 14);  
 pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose after the first multiple dose (day 8) 
 pre-dose on days 10, 11, 12, 13. 
Analyses will be performed at a certified bioanalytical laboratory (to be designated). The analytical method will 
be detailed in the study analytical plan. Analytical facilities and procedures will be in compliance with the general 
principles of GLP regulations.  
Safety evaluation: Safety of the study treatments will be evaluated on the basis of treatment-emergent adverse 
events, clinical safety laboratory tests, vital signs, ECGs, and physical examinations.  
Adverse events will be collected throughout the study. Vital signs will be measured at screening, during the study 
and at final visit or early termination visit (ETV) in case of discontinuation. Physical examinations, ECGs and 
clinical laboratory tests will be performed at screening and final visit/ETV.  
 
Sample size: Twelve (12) healthy male and female Chinese volunteers per cohort (24 in total) will be included in 
the study in order to have at least 8 completers / cohort. Drop-out subjects will not be replaced. 
Since no hypothesis will be tested, no formal sample size calculation has been performed. The sample size of this 
study has been determined in agreement with the guidance issued by the Chinese Food and Drug Administration 
(CFDA) for clinical pharmacokinetic studies (1). 
 
Main selection 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
 


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STUDY SYNOPSIS (cont.) 
 
Main selection criteria, continued: Inclusion criteria, continued: 
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: 
a. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the 
screening visit 
b. 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 
c. A male sexual partner who agrees to use a male condom with spermicide 
d. 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 HMG-CoA reductase inhibitors in 
the 2 weeks before the screening visit; medicinal products that are BCRP substrates; treatment with morphine 
or other similar opioids, whose concomitant use with MAO-B inhibitors is contraindicated, SSRIs, SNRIs, 
tri- or tetracyclic antidepressant, tramadol, pethidine, dextromethorphan, 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


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STUDY SYNOPSIS (cont.) 
 
Schedule: 
Procedures and assessments during study visits are listed in the table below: 
 
 
Day 
Procedures/Assessments 
Notes 
Screening – Visit 1 
From  
day -14 
to day -2 
 Explanation to the subject of study aims, procedures 
and possible risks 
 Informed consent signature 
 Subjects' screening number assignment 
 Demographic data and life style recording 
 Medical/surgical history 
 Previous/concomitant medications check 
 Full physical examination (body weight, height, vital 
signs, physical abnormalities) 
 ECG recording 
 Clinical laboratory analyses: haematology, blood 
chemistry, urinalysis, serum virology and serum 
pregnancy test (women) 
 Urine multi-drug kit test 
 Adverse events check 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 
Period 1 
Cohorts 1 and 2 - Visit 2 
Day -1 
 Alcohol breath test 
 Urine multi-drug kit test 
 Urine pregnancy test (women) 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment 
 Subjects' randomisation number assignment 
 Adverse events and concomitant medications check 
Day -1 
Arrival at the clinical 
centre in the evening.  
Confinement until the 
morning 
of 
day 
3. 
Standardised dinner 
Fasting for at least 10 h 
(overnight) 
Period 1 
Cohorts 1 and 2 - Visit 3 
Days 1 - 
3 
Day 1 
 Investigational product administration at 08:00 ± 1 h; 
 Vital signs measurement at pre-dose and 2 h post-dose 
 
Day 1 - Day 3 
 Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 
and 48 h post-dose 
 AEs and concomitant medications check 
Day 1 
Standardised lunch at 
approximately 5 h post-
dose.  
Standardised dinner at 
approximately 13 h post-
dose.  
Day 2 
Standardised breakfast, 
lunch and dinner 
Day 3 
Discharge 
from 
the 
clinical centre in the 
morning after the 48-h 
blood sampling for PK 
analysis
 
 


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STUDY SYNOPSIS (cont.) 
 
Study schedule, continued: 
Period 1 
Cohorts 1 and 2 - Visit 4 
Days 4 - 5 
Ambulatory 
visits 
Days 4 - 5 
 Blood sample collection for pharmacokinetic analysis 
at 72 h (day 4) and 96 h (day 5) post-dose  
 Vital signs measurement at 96 h (day 5) post-dose 
 AEs and concomitant medications check 
Days 4 - 5 
The subjects will return 
to the clinical centre 
each day in the morning 
for ambulatory blood 
sampling 
and 
safety 
checks 
Day 5  
Subjects 
will 
be 
reminded to return to the 
clinical centre in the 
morning of day 8 for 
study Period 2.
A wash-out of 7 days will elapse between the single dose administered on day 1 and the first multiple dose 
administered on day 8 
Period 2 
Cohorts 1 and 2 - Visit 5 
Days 8 -9 
Day 8 - Day 9 
 Investigational product administration at 08:00 ± 1 h; 
 Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 
h post-dose 
 AEs and concomitant medications check 
 
Day 8 only 
 Vital signs measurement at pre-dose and 2 h post-dose  
 
Days 8-9 
Subjects 
will 
be 
confined 
from 
the 
morning of day 8 (before 
investigational product 
administration) up to the 
morning 
of 
day 
9. 
Subjects 
will 
be 
discharged after the 24-h 
blood sampling for PK 
analysis 
Day 8 
Standardised lunch at 
approximately 5 h post-
dose; 
Standardised 
dinner at approximately 
13 h post-dose 
Period 2 
Cohorts 1 and 2 - Visit 6 
Days 10 - 13 
Ambulatory 
visits 
Days 10 - 13 
 Investigational product administration at 08:00 ± 1 h; 
 Blood sample collection for pharmacokinetic analysis 
at pre-dose on each day 
 Vital signs measurement before blood sampling and 
investigational product administration 
 AEs and concomitant medications check 
Days 10 - 13 
The subjects will return 
to the clinical centre 
each day in the morning 
for ambulatory pre-dose 
blood sampling for PK 
analysis, investigational 
product 
administration 
and safety checks 
 
 
 


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STUDY SYNOPSIS (cont.) 
 
Period 2 
Cohorts 1 and 2 - Visit 7 
Days 14 - 
17 
Day 14 
 Investigational product administration at 08:00 ± 1 h; 
 Vital signs measurement at pre-dose and 2 h post-dose 
 
Day 14 - Day 17 
 Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48 
and 72 h post-dose 
 AEs and concomitant medications check 
Day 14 
Standardised lunch at 
approximately 5 h post-
dose. 
Standardised 
dinner at approximately 
13 h post-dose  
Days 15-16 
Standardised breakfast, 
lunch and dinner. 
Day 17 
Discharge 
from 
the 
clinical centre in the 
morning after the 72-h 
blood sampling for PK 
analysis
Period 1 
Cohorts 1 and 2 - Visit 8 
Day 18 
Ambulator
y visit 
Day 18 
 Blood sample collection for pharmacokinetic analysis 
at 96 h post-dose  
 Vital signs measurement at 96 h post-dose 
 AEs and concomitant medications check 
 
Final visit assessments (see below) and discharge 
Day 18 
The subjects will return 
to the clinical centre in 
the 
morning 
for 
ambulatory 
blood 
sampling 
and 
safety 
checks 
 
Subjects 
will 
be 
discharged after final 
visit assessments (see 
Final visit/ETV below)
Final Visit/ETV 
Day 18. At 
ETV in 
case of 
early 
terminatio
n 
The following final assessments will be performed after 
the 96-h time-point assessments  (day 18) or at ETV in 
case of early discontinuation: 
 Physical examination (body weight, physical 
abnormalities)  
 ECG recording  
 Laboratory analyses: haematology, blood chemistry, 
urinalysis 
Vital signs assessments performed at 96 h post-dose on day 
18 will be considered as the final assessment. Vital signs 
will also be measured at ETV, in case of early 
discontinuation. 
AEs and concomitant medications will also be checked at 
final visit/ETV. AEs will be captured up to the end of study 
visit. 
 
In case of clinically significant results at the final visit, the 
subjects will be followed-up by the investigator until the 
normalisation of the concerned clinical parameter(s) 
Upon 
leaving, 
the 
subjects will be instructed 
to contact immediately 
the investigator in case of 
occurrence of any adverse 
reactions 
 
 


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STUDY SYNOPSIS (cont.) 
 
Life style and constraints: 
During the study, the subjects will be confined as follows: 
 from the evening preceding the first administration (study day -1) until the morning of day 3.  
 from the morning of day 8 to the morning of day 9.  
 from the morning of day 14 to the morning of day 17.  
Subjects will be discharged from the study after final assessments, as specified above (Final visit/ETV). 
The subjects will not take any food or drinks (except water) for at least 10 h (i.e. overnight) before investigational 
product administration. On days 1, 8 and 14, subjects will remain fasted up to 5 h post-dose. Standardised meals 
will be served at the clinical centre according to the schedule above. Water will be allowed as desired, except for 
one hour before and one hour after investigational product administration. Coffee, tea or food containing 
xanthines (i.e. coke, chocolate, etc.), alcohol and grapefruit will be forbidden during confinement starting 48 h 
before the first administration until the end of the study. Smoking is not allowed for the whole study duration. 
Routine ambulant daily activities will be strongly recommended. Hazardous, strenuous or athletic activities will 
not be permitted. 
 
Data analysis:  
The data documented in this trial and the clinical parameters measured will be analysed using classic descriptive 
statistics for quantitative variables and frequencies for qualitative variables. 
Analysis set:  
Enrolled set: all enrolled subjects. This analysis set will be used for demographic, baseline and background 
characteristics 
Safety set: all subjects who receive at least one dose of investigational medicinal product. This analysis set will be 
used for the safety analyses 
PK set: all randomised subjects who fulfil the study protocol requirements in terms of investigational medicinal 
products intake and have evaluable PK data readouts, with no major deviations that may affect the PK results. This 
analysis set will be used for the PK analysis 
Safety Assessments: 
The statistical analysis of demographic and safety data will be performed using SAS®. 
The safety and tolerability of the investigational products will be evaluated on the basis of treatment-emergent 
adverse events occurrence, laboratory tests and other safety assessments (see section above). 
All adverse events, adverse drug reactions (ADR) and serious adverse events (SAEs), if applicable, will be coded 
using the Medical Dictionary for regulatory Activities and summarized by system organ class and preferred term, 
incidence, severity and relationship to study drug. 
Pharmacokinetics: 
The pharmacokinetic parameters will be calculated with a Non-Compartmental Analysis (NCA) using Phoenix 
WinNonlin v6.3 (or higher). Pharmacokinetic data will be listed and summarised by descriptive statistics.
 
Study duration: 
Maximum study duration for both cohort 1 and 2 will be 32 days including screening period, study Period 1, 
washout and study Period 2.
 
 
 




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3 
TABLE OF CONTENTS 
 
Page 
CLINICAL TRIAL PROTOCOL 
1 
APPROVAL PAGE 
2 
1 
STUDY SYNOPSIS 
3 
2 
STUDY SCHEDULE (a more detailed table is shown in appendix 1) 
10 
3 
TABLE OF CONTENTS 
11 
4 
INTRODUCTION 
16 
4.1 
Safinamide 
16 
4.1.1 
Background 
16 
4.1.2 
Clinical pharmacology and pharmacokinetics 
16 
4.1.3 
Safety 
16 
4.2 
Study rationale 
17 
4.3 
Risks and benefits 
17 
5 
STUDY OBJECTIVES 
18 
5.1 
Primary end-point 
18 
5.2 
Secondary end-point 
18 
6 
CLINICAL SUPPLIES 
19 
6.1 
Treatment 
19 
6.1.1 
Description of investigational products 
19 
6.1.2 
Dose regimen 
19 
6.1.3 
Route and method of administration 
20 
6.1.4 
Investigational product distribution 
20 
6.2 
Packaging and labelling 
20 
6.3 
Storage conditions 
21 
6.4 
Drug accountability 
21 
7 
INVESTIGATIONAL PLAN 
22 
7.1 
Overall study design 
22 
7.2 
Discussion of design 
22 
8 
STUDY POPULATION 
23 
8.1 
Target population 
23 
8.2 
Inclusion criteria 
23 
8.3 
Exclusion criteria 
23 
8.3.1 
Not allowed treatments 
24 
9 
STUDY SCHEDULE 
26 
9.1 
Study visits and procedures 
26 
9.2 
Diet, lifestyle and study restrictions 
30 
10 
DESCRIPTION OF SPECIFIC PROCEDURES 
31 
10.1 
Physical examination 
31 
10.1.1 
Body weight 
31 
10.1.2 
Vital signs 
31 
10.1.3 
ECGs 
31 
10.2 
Clinical laboratory assays 
31 
10.3 
Sampling for pharmacokinetic analysis 
32 
10.3.1 
Venous blood sampling 
32 
10.3.2 
Analytics 
33 
10.3.3 
Labelling, storage and transport of samples 
33 
10.3.3.1 Samples labelling 
33 
10.3.3.2 Samples storage and transport 
33 
11 
ASSIGNMENT OF STUDY TREATMENT 
34 
11.1 
Randomisation 
34 
11.2 
Treatment allocation 
34 
11.3 
Blinding 
34 
12 
EVALUATION PARAMETERS 
35 
12.1 
Study variables 
35 


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12.1.1 
Primary variables 
35 
12.1.2 
Secondary variables 
35 
12.2 
Pharmacokinetic assessments 
35 
12.2.1 
Pharmacokinetic parameters 
35 
12.3 
Safety assessments 
36 
13 
STATISTICAL METHODS 
37 
13.1 
Analysis Sets 
37 
13.1.1 
Definitions 
37 
13.1.2 
Reasons for exclusion from the PK set 
38 
13.2 
Sample size and power considerations 
38 
13.3 
Demographic, baseline and background characteristics 
38 
13.4 
Analysis of pharmacokinetic parameters 
38 
13.5 
Safety and tolerability evaluation 
39 
13.5.1 
Adverse events 
39 
13.5.2 
Physical examination 
39 
13.5.3 
Laboratory data 
39 
13.5.4 
Vital signs 
39 
13.5.5 
Body weight 
39 
13.5.6 
ECG 
40 
14 
DEFINITION AND HANDLING OF AEs AND SAEs 
41 
14.1 
Applicable SOPs 
41 
14.2 
Definition of Adverse Event (AE) 
41 
14.3 
Definition of Adverse Drug Reaction (ADR) 
41 
14.4 
Definition of Serious Adverse Events or Serious Adverse Drug Reaction 
42 
14.5 
Definition of Severity of Adverse Events 
42 
14.6 
Definition of Adverse Event causality 
42 
14.7 
Adverse Events recording 
43 
14.8 
AEs monitoring window 
43 
14.9 
Adverse Events reporting 
43 
14.9.1 
SAEs reporting 
44 
14.10 
Follow-up for Adverse Events 
44 
14.11 
SUSARs management 
45 
14.12 
Other events qualified for expedited reporting 
45 
14.13 
SAEs: contacts 
46 
14.14 
Pregnancy 
46 
15 
DATA MANAGEMENT PROCEDURES 
46 
15.1 
Data collection – CRFs 
46 
15.2 
Database management 
47 
15.2.1 
Coding dictionaries 
47 
16 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
48 
16.1 
Monitoring 
48 
16.2 
Quality Control and Quality Assurance 
48 
16.3 
Applicable SOPs 
49 
16.4 
Data access 
49 
16.5 
Audits and inspections 
49 
17 
ETHICAL CONSIDERATIONS 
50 
17.1 
Ethics and Good Clinical Practice (GCP) 
50 
17.2 
Informed consent 
50 
17.3 
Insurance policy 
51 
17.4 
Withdrawal of subjects 
51 
17.4.1 
Primary reason for discontinuation 
51 
17.4.2 
Discontinuation procedures 
51 
17.5 
Study termination 
52 
18 
ADMINISTRATIVE PROCEDURES 
53 
18.1 
Material supplied to the clinical centre 
53 
18.2 
Protocol amendments 
53 
18.3 
Study documentation and record keeping 
53 
18.4 
Study subjects’ recruitment 
54 


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18.5 
Confidentiality and data protection 
54 
18.6 
Publication policy 
54 
19 
STUDY RESPONSIBLE PERSONS 
56 
19.1 
Sponsor 
56 
19.2 
Institutes performing the study 
56 
19.2.1 
Clinical centre 
56 
19.3 
Drug assay 
56 
19.4 
Co-ordination, data analysis & reporting 
56 
19.5 
Project Management and Monitoring 
56 
20 
REFERENCES 
58 
21 
APPENDIX 1 
59 
 
 
 
TABLES 
Page 
 
Table 6.1.2.1 
Study dose regimen 
20 
Table 10.3.1.1 
Tolerance ranges for the scheduled sampling times 
33 
 
 


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LIST OF ABBREVIATIONS 
 
-HCG
human chorionic gonadotropin 
-GT
-Glutamyl transpeptidase
ADR
Adverse Drug Reaction
AE
Adverse Event
ALCOAC
Attributable-Legible-Contemporaneous-Original-Accurate-Complete
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-t
Area under the concentration-time curve from time zero to time t
AUCss0-t or AUC0-t,ss
Area under the concentration-time curve at steady state
AUC0-
Area under the concentration vs. time curve up to infinity 
AUC0-24h
Area under the concentration-time curve in the tau interval 
AUCss0-24 or AUC0-24h,ss
Area under the concentration-time curve at steady state in the tau interval
BUN 
BCRP
Blood Urea Nitrogen 
Breast Cancer Resistance Protein
BLQL
Below Lower Quantification Limit
BMI
Body Mass Index
BP
Blood Pressure
CA
Competent Authority
CDISC
Clinical Data Interchange Standards Consortium
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence Interval
Cl/F
Apparent total body clearance
Cave_ss
Average drug concentration at steady state
Cmax
Maximum drug concentration
Cmax_ss
Maximum drug concentration at steady state
Cmix_ss
Trough drug concentration at steady state
CRF
Case Report Form
CRO
Contract Research Organisation
CS
Clinically Significant
CV
Coefficient of Variation
DF%
Peak-trough fluctuation over one dosing interval at steady-state
DBP
Diastolic Blood Pressure
EC
Ethics Committee
ECG
Electrocardiogram
EMA
European Medicines Agency
ETV
Early Termination Visit
FDA
Food and Drug Administration
FSFV
First Subject First Visit
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBs Ag
Hepatitis B virus surface antigen
HCV Ab
Hepatitis C virus antibodies
HIV
Human Immunodeficiency Virus
HR
Heart Rate
ICH
International Conference on Harmonisation
IRB/IEC
Institutional Review Board/Independent Ethics Committee
IMP
Investigational Medicinal Product
IUD
Intra-Uterine Device
Kel
Terminal elimination rate constant
LLOQ 
LQL
Lower Limit of Quantification 
Lower Quantification Limit
LSLV
Last Subject Last Visit
MAO
Monoamino oxidase
MCH
Mean Cell Haemoglobin
MCHC
Mean Cell Haemoglobin Concentration


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MCV
Mean Cell Volume
MedDRA
Medical Dictionary for Regulatory Activities
MRT
Mean residence time
MW
Molecular Weight
N
Normal
NA
Not Applicable
NC
Not calculated
NCS
Not clinically significant
OTC
Over The Counter
PD
Parkinson’s disease
PK
Pharmacokinetics
PT
Preferred Term
PTAE
Pre-Treatment Adverse Event
Racc
Accumulation ratio
RBC 
Red Blood Cells
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SmPC
Summary of Product Characteristics
SNRI
Serotonin–norepinephrine reuptake inhibitors
SOC
System Organ Class
SOP
Standard Operating Procedure
SSRI
Selective serotonin reuptake inhibitors
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
Test
T1
Xadago® 50 mg
T2
Xadago® 50 mg
TEAE
Treatment-Emergent Adverse Event
THC
Delta-9-tetrahydrocannabinol
t1/2
Apparent terminal elimination half-life
tmax
Time to achieve Cmax
Vd/F
Apparent volume of distribution associated with the terminal slope
WBC
White Blood Cells
WHODDE
World Health Organisation Drug Dictionary Enhanced
 
 
 


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4 
INTRODUCTION 
 
4.1 
Safinamide 
 
4.1.1 
Background 
 
The -aminoamide derivative safinamide [(S)-(+)-2-[4-(3-fluorobenzyloxy) benzylamino] 
propanamide], developed as methane sulfonate salt, is an original anticonvulsant and 
antiparkinson agent which has been granted marketing authorisation in 9 EU Member States 
(i.e. Germany, Italy, Spain, Portugal, United Kingdom, Belgium, The Netherlands, Sweden and 
Denmark), in Norway and in Switzerland under the brand name of Xadago®, 50 and 100 mg, 
film-coated tablets (2), for the treatment of adult patients with idiopathic Parkinson’s disease 
(PD) as add-on therapy to a stable dose of Levodopa (L-dopa) alone or in combination with 
other PD medicinal product in mid-to late-stage fluctuating patients (3).  
 
Safinamide uniquely combines potent, selective and reversible inhibition of monoamino 
oxidase B (MAO-B) with blockade of voltage-dependant Na+ and Ca2+ channels and inhibition 
of glutamate release (4,8), thus showing a novel mode of action, targeting both dopaminergic 
and glutaminergic systems (9,10).  
Data from Phase III clinical studies gave evidence that safinamide 50 or 100 mg/day improves 
the motor function in Parkinson’s disease when prescribed as add-on therapy to dopamine 
agonists or L-dopa (3).  
 
4.1.2 
Clinical pharmacology and pharmacokinetics 
 
Safinamide pharmacokinetics after single and multiple dose administrations have been 
described (11,12). At single ascending oral doses ranging from 2.5 to 10.0 mg/kg, safinamide 
was absorbed in a linear and dose-proportional fashion. Peak plasma levels were obtained on 
average at 1.8 to 2.8 h post-dose. Concentrations declined with a terminal half-life of 20 - 23h 
(11,12). Absolute bioavailability is high (95%), showing that safinamide is almost completely 
absorbed after oral administration and first pass metabolism is negligible (SmPC, 3). A 
complete long-lasting inhibition of platelet MAO-B activity was observed at all doses tested. 
Food intake prolonged the rate but did not affect the extent of safinamide absorption (11,12). 
Studies in healthy volunteers (13,15) demonstrated that safinamide does not affect oral tyramine 
metabolism mostly mediated by the intestinal MAO-A, and confirm that it can be administered 
without tyramine-related dietary restrictions. 
 
4.1.3 
Safety 
 
The overall safety profile of Xadago® is based on the clinical development program performed 
on over 3000 subjects, of which over 600 were treated for more than 2 years. 
 
The most common side effects related to safinamide are dyskinesia, somnolence, dizziness, 
headache, insomnia, nausea and orthostatic hypotension. Serious adverse reactions, such as 
hypertensive crisis (high blood pressure, collapse), neuroleptic malignant syndrome (confusion, 
sweating, muscle rigidity, hyperthermia, CPK increase), serotonin syndrome (confusion, 
hypertension, muscle stiffness, hallucinations), and hypotension, are known to occur with the 
concomitant use of SSRIs, SNRIs, tricyclic/tetracyclic antidepressants and MAO inhibitors. 


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With MAO-inhibitors there have been reports of drug interactions with concomitant use of 
sympathomimetic medicinal products. Impulse control disorders, pathological gambling, 
increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive 
eating can occur in patients treated with dopamine agonists and/or other dopaminergic 
treatments.  
 
A complete list of adverse reactions observed with safinamide is presented in the SmPC (3). 
 
4.2 
Study rationale 
 
The present study will be part of safinamide registration package in China and was designed 
according to CFDA guideline recommendations (1). 
Safinamide has been granted marketing authorization in EU (2015), US (2017) and Switzerland 
(2015).   
In the present study, safinamide pharmacokinetic profile, safety and tolerability after single 
dose and at steady state will be investigated for the first time in Chinese healthy male and female 
volunteers.  
 
4.3 
Risks and benefits 
 
For AEs occurred with safinamide in previous clinical studies, please refer to § 4.1.3 and the 
SmPC (3). The most common side effects are dyskinesia, somnolence, dizziness, headache, 
insomnia, nausea and orthostatic hypotension. 
 
Based on the clinical experience, no particular risks are expected for the study subjects 
considering safinamide 50 mg and 100 mg multiple dose administrations. 
 
 
 


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5 
STUDY OBJECTIVES 
 
The objective of the study is to evaluate safinamide pharmacokinetic profile, safety and 
tolerability after single and multiple dose administration to healthy adult Chinese volunteers 
 
5.1 
Primary end-point 
 
 To evaluate plasma safinamide pharmacokinetic parameters after single and multiple dose 
administration of the investigational products.  
 
5.2 
Secondary end-point 
 
 To collect safety and tolerability data after single and multiple dose administration of the 
investigational products. 
 


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6 
CLINICAL SUPPLIES 
 
6.1 
Treatment 
 
6.1.1 
Description of investigational products 
 
TEST PRODUCT 1 (T1)
Name
Xadago® 50 mg film-coated tablets
Active ingredient 
Safinamide methanesulphonate (corresponding to 50 mg 
safinamide)
Marketing Authorization 
Holder
Zambon S.p.A., Italy 
Pharmaceutical form
Film-coated tablets
Dose 
Single 50 mg dose on day 1 
Multiple 50 mg doses, once daily, for 7 days
Administration route
Oral
 
 
TEST PRODUCT 2 (T2)
Name
Xadago® 100 mg film-coated tablets
Active ingredient 
Safinamide methanesulphonate (corresponding to 100 mg 
safinamide)
Marketing Authorization 
Holder
Zambon S.p.A., Italy 
Pharmaceutical form
Film-coated tablets
Dose 
Single 100 mg dose on day 1 
Multiple 100 mg doses, once daily, for 7 days
Administration route
Oral
 
6.1.2 
Dose regimen 
 
Subjects will be randomised to 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), according 
to the study randomised, parallel-group design, as follows: 
 
 Cohort 1: One (1) safinamide 50 mg film-coated tablet will be administered on day 1 
followed by 7 safinamide 50 mg film-coated tablets administered o.d. from day 8 to day 
14. 
 
 Cohort 2: One (1) safinamide 100 mg film-coated tablet will be administered on day 1 
followed by 7 safinamide 100 mg film-coated tablets administered o.d. from day 8 to day 
14. 
 
 


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Dose regimens are also summarised in the scheme below: 
 
Table 6.1.2.1 Study dose regimen 
Cohort 
Period 1 - single dose 
Day 1 
Washout 
Period 2 - Multiple doses 
Days 8 - 14 
Cohort 1
50 mg po
7 days 
50 mg po o.d for 7 days
Cohort 2
100 mg po
100 mg po o.d. for 7 days
 
6.1.3 
Route and method of administration 
 
The investigational products will be orally administered in the morning, at 8:00±1h, 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. 
 
6.1.4 
Investigational product distribution 
 
All doses of the investigational products will be administered at the clinical centre by the 
investigator or by his/her deputy. The investigational products will be exclusively used for the 
present clinical study and will only be administered to the subjects enrolled in the study.  
 
6.2 
Packaging and labelling 
 
Packaging and labelling for the clinical study will be performed by a GMP compliant vendor, 
delegated by Zambon S.p.A., Italy. 
 
Subjects' kit labelling will report all the information according to the Annex 13 to the Good 
Manufacturing Practice (published by the Commission in The rules governing medicinal 
products in the European Community, Volume 4, 16), as follows: 
a. 
Name, address and telephone number of the sponsor, contract research organisation or 
investigator (the main contact for information on the product, clinical study) 
b. Pharmaceutical dosage form, route of administration, quantity of dosage units, and the 
name/identifier and strength/potency 
c. 
The batch and/or code number to identify the contents and packaging operation 
d. A study reference code allowing identification of the study, site, investigator and sponsor 
if not given elsewhere 
e. 
A blank space for subject enrolment Nr. (to be reported by hand by the Investigator) and 
where relevant, the visit number 
f. 
The name of the investigator (if not included in (a) or (d)) 
g. Directions for use (reference may be made to a leaflet or other explanatory document 
intended for the study subject or person administering the product) 
h. “For clinical study use only” or similar wording 


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i. 
The storage conditions 
j. 
Period of use (use-by date, expiry date or re-test date as applicable), in month/year format 
and in a manner that avoids any ambiguity 
k. “Keep out of reach of children” 
 
The label will be in Chinese language. 
 
6.3 
Storage conditions 
 
The investigational products will be stored at ≤ 25° C in a dry locked place, sheltered from light.  
 
6.4 
Drug accountability 
 
The vendor delegated by Zambon S.p.A., Italy, will provide the clinical centre with a sufficient 
number of individual subject kits to conduct the study, plus sufficient reserve kits.  
 
After receipt of the drug supply, the Pharmacist will confirm in writing by signing and dating 
standard drug accountability forms. At the end of the study, the drug product will be maintained 
in the original containers. 
 
At the end of the study, used, unused and partially used supplies of the investigational products, 
provided by the vendor delegated by Zambon S.p.A., Italy, will be stored as detailed in § 6.3 
above and then disposed of (upon sponsor written authorisation), after assessment of drug 
accountability. 
 
 
 


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7 
INVESTIGATIONAL PLAN 
 
7.1 
Overall study design 
 
Phase I, single centre, single and multiple-dose, open-label, randomised, parallel-group, 
pharmacokinetics, safety and tolerability clinical study. 
 
7.2 
Discussion of design 
 
Following a specific request of CFDA, the present study will be part of safinamide registration 
package in China and was designed according to CFDA guideline recommendations (1). 
 
Safinamide has recently been granted marketing authorization in EU, Norway and Switzerland 
on the basis of the results of clinical trials performed in European countries. In the present study, 
safinamide pharmacokinetic profile, safety and tolerability after single dose and at steady state 
will be investigated for the first time in Chinese healthy male and female volunteers.  
 
Two single doses (i.e. 50 and 100 mg) of safinamide will be administered to two subject' cohorts. 
The study will continue with multiple administrations of safinamide 50 and 100 mg, orally 
taken once a day for 7 days. 
 
The 50 and 100 mg oral doses have been selected according to the common clinical practice 
(see Xadago® SmPC). These doses were investigated in the previously performed Phase III 
clinical trials. The volunteers will be assigned to the two cohorts according to the study 
randomised, parallel-group design. 
 
Safinamide pharmacokinetic profile will be investigated after single dose, according to CFDA 
guidance requirements, and at steady state since multiple doses are administered in the clinical 
practice. Safinamide steady state should be reached after 5 or 6 days of treatment (day 13-14 in 
this study). Safinamide pre-dose concentrations will be assessed before the last 5 doses (days 
10-14).  
 
An open design was chosen. However, no bias on study outcome is expected considering that 
the study PK endpoints are based on the objective measurement of safinamide in plasma.  
Blood sampling time-points were selected on the basis of the known PK profile of safinamide. 
The sampling time lasts for about 4-7 elimination half-lives (mean PK half-life: 20-23 h) after 
both single dose and the last multiple dose administration. 
 
 


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8 
STUDY POPULATION 
 
8.1 
Target population 
 
Twenty-four (24) healthy male and female Chinese volunteers, aged 18-45 years inclusive, will 
be enrolled into the study. 
 
8.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfil all these 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: 
a. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 
2 months before the screening visit 
b. 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 
c. A male sexual partner who agrees to use a male condom with spermicide 
d. 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. 
 
8.3 
Exclusion criteria 
 
Subjects meeting any of these criteria will not be enrolled in the study: 
 
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 


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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 HMG-CoA reductase inhibitors in the 2 weeks before the screening visit; medicinal 
products that are BCRP substrates; treatment with morphine or other similar opioids, whose 
concomitant use with MAO-B inhibitors is contraindicated, SSRIs, SNRIs, tri- or tetracyclic 
antidepressant, tramadol, pethidine, dextromethorphan, 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 
 
8.3.1 
Not allowed treatments 
 
No medication, including OTC, herbal remedies and traditional Chinese remedies, will be 
allowed for 2 weeks before the start of the study and during the whole study duration. 
 
Statins and HMG-CoA reductase inhibitors use will not be allowed for 2 weeks before and 
during the study. Wash-out interval for the treatment with morphine or other similar opioids, 


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whose concomitant use with MAO-B inhibitors is contraindicated, SSRIs, SNRIs, tri- or 
tetracyclic antidepressant, tramadol, pethidine, dextromethorphan, MAO inhibitors (e.g. 
selegiline), meperidine derivatives, antiepileptic drugs and the treatment with any known 
enzyme inhibiting or inducing agent or any investigational drugs intake will be at least 4 weeks 
before the screening visit. Hormonal contraceptives are allowed. 
 
Paracetamol will be allowed as therapeutic counter-measure for adverse events (AEs) according 
to the investigator’s opinion. The intake of any other medication will be reported as a protocol 
deviation. However, it will lead to subject's discontinuation from the study only if the 
investigator, together with the sponsor, considers it could affect the study assessments or 
outcome. 
 
 
 


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9 
STUDY SCHEDULE 
 
The schedule of the study is summarised at page 10. 
 
9.1 
Study visits and procedures 
 
Each study subject completing the study will undergo 8 visits plus a final visit. 
 
The study protocol foresees 2 periods: in the first one the investigational products are 
administered in single dose, in the second one in multiple doses. The single dose in the first 
period and the first dose in the second period are separated by a wash-out interval of 7 days. 
Maximum and minimum study duration will be 32 and 20 days, respectively, screening visit 
included. 
 
The first subject first visit (FSFV) is defined as the 1st visit performed at the clinical centre by 
the 1st screened subject. The last subject last visit (LSLV) is defined as the last visit performed 
at the clinical centre (or a telephonic follow-up, if applicable) by the last subject, i.e. the last 
visit foreseen by the study protocol, independently of the fact that the subject is a completer or 
a withdrawn subject. 
 
The following phases, visits and procedures will be performed: 
 
 Screening phase 
 Screening – visit 1: between day -14 and day -2 
 Period 1 – visit 2: day -1 
 
 Interventional phase 
 Period 1 – visit 3: days 1-3: single dose and blood sampling for PK analysis 
 Period 1 – visit 4: days 4-5: ambulatory visits - blood sampling for PK analysis 
 Wash-out interval of 7 days 
 Period 2 – visit 5: days 8-9: first multiple dose and blood sampling for PK analysis 
 Period 2 – visit 6: days 10-13: ambulatory visits - multiple doses and blood sampling 
for PK analysis 
 Period 2 - visit 7: days 14-17: last multiple dose and blood sampling for PK analysis 
 Period 2 - visit 8: day 18: blood sampling for PK analysis 
 
 Final phase 
 Final visit/early termination visit (ETV). In case of early discontinuation, discontinued 
subjects will undergo an early termination visit (ETV) 
 
 
 


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Study schedule 
 
 
Day 
Procedures/Assessments 
Notes 
Screening – Visit 1 
From day -14 
to day -2 
 Explanation to the subject of study aims, procedures 
and possible risks 
 Informed consent signature 
 Subjects' screening number assignment 
 Demographic data and life style recording 
 Medical/surgical history 
 Previous/concomitant medications check 
 Full physical examination (body weight, height, vital 
signs, physical abnormalities) 
 ECG recording 
 Clinical laboratory analyses: haematology, blood 
chemistry, urinalysis, serum virology and serum 
pregnancy test (women) 
 Urine multi-drug kit test 
 Adverse events check 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 
Period 1 
Cohorts 1 and 2 - Visit 2 
Day -1 
 Alcohol breath test 
 Urine multi-drug kit test 
 Urine pregnancy test (women) 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment 
 Subjects' randomisation number assignment 
 Adverse events and concomitant medications check 
Day -1 
Arrival at the clinical 
centre in the evening  
Confinement until the 
morning 
of 
day 
3.  
Standardised dinner 
Fasting for at least 10 h 
(overnight) 
Period 1 
Cohorts 1 and 2 - Visit 3 
Days 1 - 3 
Day 1 
 Investigational product administration at 08:00 ± 1 h; 
 Vital signs measurement at pre-dose and 2 h post-dose 
 
Day 1 - Day 3 
 Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 
and 48 h post-dose 
 AEs and concomitant medications check 
Day 1 
Standardised lunch at 
approximately 5 h post-
dose.  
Standardised dinner at 
approximately 13 h post-
dose  
Day 2 
Standardised breakfast, 
lunch and dinner 
Day 3 
Discharge 
from 
the 
clinical centre in the 
morning after the 48-h 
blood sampling for PK 
analysis
 
 
 


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Study schedule, continued 
 
Period 1 
Cohorts 1 and 2 - Visit 4 
Days 4 - 5 
Ambulatory 
visits 
Days 4 - 5 
 Blood sample collection for pharmacokinetic analysis 
at 72 h (day 4) and 96 h (day 5) post-dose  
 Vital signs measurement at 96 h (day 5) post-dose 
 AEs and concomitant medications check 
Days 4 - 5 
The subjects will return 
to the clinical centre 
each day in the morning 
for ambulatory blood 
sampling 
and 
safety 
checks 
Day 5  
Subjects 
will 
be 
reminded to return to the 
clinical centre in the 
morning of day 8 for 
study Period 2. 
A wash-out of at least 7 days will elapse between the single dose administered on day 1 and the first multiple 
dose administered on day 8 
Period 2 
Cohorts 1 and 2 - Visit 5 
Days 8 -9 
Day 8 - Day 9 
 Investigational product administration at 08:00 ± 1 h; 
 Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 
h post-dose 
 AEs and concomitant medications check 
 
Day 8 only 
 Vital signs measurement at pre-dose and 2 h post-
dose  
 
Days 8-9 
Subjects 
will 
be 
confined 
from 
the 
morning of day 8 (before 
investigational product 
administration) up to the 
morning 
of 
day 
9. 
Subjects 
will 
be 
discharged after the 24-h 
blood sampling for PK 
analysis 
Day 8 
Standardised lunch at 
approximately 5 h post-
dose; 
Standardised 
dinner at approximately 
13 h post-dose 
Period 2 
Cohorts 1 and 2 - Visit 6 
Days 10 - 
13 
Ambulatory 
visits 
Days 10 - 13 
 Investigational product administration at 08:00 ± 1 h; 
 Blood sample collection for pharmacokinetic analysis 
at pre-dose on each day 
 Vital signs measurement before blood sampling and 
investigational product administration 
 AEs and concomitant medications check 
Days 10 - 13 
The subjects will return 
to the clinical centre 
each day in the morning 
for ambulatory pre-dose 
blood sampling for PK 
analysis, investigational 
product 
administration 
and safety checks 
 
 
 


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Study schedule, continued 
 
Period 2 
Cohorts 1 and 2 - Visit 7 
Days 14 - 17 
Day 14 
 Investigational product administration at 08:00 ± 1 h; 
 Vital signs measurement at pre-dose and 2 h post-dose 
 
Day 14 - Day 17 
 Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48 
and 72 h post-dose 
 AEs and concomitant medications check 
Day 14 
Standardised lunch at 
approximately 5 h post-
dose. 
Standardised 
dinner at approximately 
13 h post-dose  
Days 15-16 
Standardised breakfast, 
lunch and dinner. 
Day 17 
Discharge 
from 
the 
clinical centre in the 
morning after the 72-h 
blood sampling for PK 
analysis
Period 1 
Cohorts 1 and 2 - Visit 8 
Day 18 
Ambulatory 
visit 
Day 18 
 Blood sample collection for pharmacokinetic analysis 
at 96 h post-dose  
 Vital signs measurement at 96 h post-dose 
 AEs and concomitant medications check 
 
Final visit assessments (see below) and discharge 
Day 18 
The subjects will return 
to the clinical centre in 
the 
morning 
for 
ambulatory 
blood 
sampling 
and 
safety 
checks. 
 
Subjects 
will 
be 
discharged after final 
visit assessments (see 
Final visit/ETV below)
Final Visit/ETV 
Day 18. At 
ETV in case 
of early 
termination 
The following final assessments will be performed after 
the 96-h time-point assessments  (day 18) or at ETV in 
case of early discontinuation: 
 Physical examination (body weight, physical 
abnormalities)  
 ECG recording  
 Laboratory analyses: haematology, blood chemistry, 
urinalysis 
Vital signs assessments performed at 96 h post-dose on day 
18 will be considered as the final assessment. Vital signs 
will also be measured at ETV, in case of early 
discontinuation. 
AEs and concomitant medications will also be checked at 
final visit/ETV. AEs will be captured up to the end of study 
visit. 
 
In case of clinically significant results at the final visit, the 
subjects will be followed-up by the investigator until the 
normalisation of the concerned clinical parameter(s) 
Upon 
leaving, 
the 
subjects will be instructed 
to contact immediately 
the investigator in case of 
occurrence of any adverse 
reactions 
 
 
 


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9.2 
Diet, lifestyle and study restrictions 
 
During the study, the subjects will be confined at the clinical centre as follows: 
 
Period 1: 
 
from the evening preceding the first administration (study day -1) until the morning of day 
3.  
 
Period 2: 
 
from the morning of day 8 to the morning of day 9.  
 
from the morning of day 14 to the morning of day 17.  
 
Subjects will be discharged from the study after final assessments (Final visit or ETV). 
 
The subjects will not take any food or drinks (except water) for at least 10 h (i.e. overnight) 
before investigational product administration. On days 1, 8 and 14, subjects will remain under 
fasting conditions up to 5 h post-dose.  
Standardised meals will be served at the clinical centre according to the schedule below: 
 
 
Day -1: standardised dinner; 
 
Day 1, Day 8, Day 14: standardised lunch at approximately 5 h post-dose, standardised 
dinner at approximately 13 h post-dose;  
 
Day 2 and Days 15/16: standardised breakfast, lunch and dinner 
 
Water will be allowed as desired, except for 1 h before and 1 h after investigational product 
administration. Coffee, tea or food containing xanthines (i.e. coke, chocolate, etc.), alcohol and 
grapefruit will be forbidden during confinement starting 48 h before the first administration 
until the end of the study. Smoking is not allowed for the whole study duration. 
 
Routine ambulant daily activities will be strongly recommended. Hazardous, strenuous or 
athletic activities will not be permitted. 


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10 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
10.1 
Physical examination 
 
Full physical examinations will be performed at screening and final visit/ETV. Date of the 
physical examination, overall investigator’s interpretation (as normal or abnormal and, if 
abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be reported in the individual CRFs. 
All clinically significant abnormalities after the screening visit will be recorded as AEs. 
 
10.1.1 
Body weight 
 
Body weight will be recorded at screening and final visit/ETV. 
Subjects will be weighed (kg) lightly clothed without shoes. Height will be measured at 
screening only and Body Mass Index (BMI) will be recorded. BMI will be calculated as weight 
[kg]/(height [m] x height [m]). 
 
10.1.2 
Vital signs 
 
Subjects' blood pressure and heart rate will be measured by the investigator or his deputy after 
5 min at rest (sitting/supine position) at the following times:  
 at screening 
 on day 1, day 8 and day 14: at pre-dose and 2 h post-dose 
 on day 5 and day 18: at 96 h post-dose 
 on days 10-13: at pre-dose 
 at ETV (if applicable). 
 
10.1.3 
ECGs 
 
12-Leads ECGs will be performed (supine position) at screening and final visit/ETV. 
 
Date/time of the ECG recording, overall investigator's interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be reported in the individual CRFs. All clinically significant 
abnormalities after the screening visit will be recorded as AEs. Hard copies of the ECGs will 
be attached to the CRF. 
 
10.2 
Clinical laboratory assays 
 
Samples of blood and urine will be collected. The following laboratory analyses will be 
performed at the screening visit: 
 
HAEMATOLOGY 
Leukocytes and leukocyte differential count (percentage values and absolute values), 
erythrocytes, haemoglobin (conv. units), haemoglobin (IS units), haematocrit, MCV, MCH, 
MCHC, thrombocytes. 


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BLOOD CHEMISTRY 
Electrolytes: sodium, potassium, calcium, chloride, inorganic phosphorus 
Enzymes: alkaline phosphatase, γ-GT, AST, ALT 
Substrates/metabolites: total bilirubin, creatinine, glucose, urea or BUN, uric acid, total 
cholesterol, triglycerides 
Proteins: total proteins 
 
Serum pregnancy test (women). 
 
URINE ANALYSIS 
Urine chemical analysis (stick): pH, specific weight, appearance, colour, nitrites, proteins, 
glucose, urobilinogen, bilirubin, ketones, haematic pigments, leukocytes 
Urine sediment (analysis performed only if sediment is present): leukocytes, erythrocytes, flat 
cells, round cells, crystals, cylinders, mucus, bacteria 
 
SERUM VIROLOGY  
Hepatitis B (HBs antigen), Hepatitis C (HCV antibodies), HIV 1/2 (HIV Ag/Ab combo).  
 
A urine drug test will be performed at the clinical centre at screening, using a urine multi-drug 
kit. The following drugs will be assessed: cocaine, amphetamine, morphine, cannabis, 
benzodiazepines, barbital.  
 
A serum pregnancy test will be performed by the laboratory at screening, as listed above. Urine 
pregnancy test will be performed on day -1 of each study period at the clinical centre.  
 
The same analyses, with the exception of urine drug test, virology and pregnancy test, will be 
performed at the final visit/ETV. 
 
Date/time of samples collection, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
findings (if any) will be reported in the individual eCRFs. All clinically significant 
abnormalities after the screening visit will be recorded as AEs. 
 
10.3 
Sampling for pharmacokinetic analysis 
 
10.3.1 
Venous blood sampling 
 
Venous blood samples (up to 10 mL) will be collected from a forearm vein at the following 
times:  
 
 At pre-dose (0 h), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h post-dose after 
the first single dose (days 1-5) and the last multiple dose (days 14-18) 
 At pre-dose on days 10-13 
 At pre-dose (0 h) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose after the first 
multiple dose (days 8-9) 
 


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Actual sampling times for each subject will be recorded in the individual CRFs. The actual 
sampling times should not exceed the recommended tolerance ranges presented in the following 
table. Any deviation outside the recommended ranges will be verified through Data 
Clarification Forms and, if confirmed, will be reported as protocol deviation, although it will 
not automatically lead to the exclusion of the concerned subjects from the PK set. 
 
Table 10.3.1.1 
Tolerance ranges for the scheduled sampling times 
Sampling time 
Tolerance range 
Pre-dose (0) 
Within 30 minutes before  
investigational product administration
0.5 h (30 min)
± 1 min
1, 1.5 h
± 3 min
2, 3, 4 h
± 5 min
6, 8, 10, 12, 16, 24, 36, 48, 72, 96 h 
± 10 min
 
Blood samples for PK analysis will be collected using an indwelling catheter with switch valve. 
The cannula will be rinsed, after each sampling, with about 1 mL of sterile saline solution 
containing 20 I.U./mL Na-heparin. The first 2 mL of blood will be discarded at each collection 
time to avoid contamination of the sample with heparin. 
 
The remaining 8 mL will be collected from the catheter and transferred with a syringe into 
heparinised tubes (Li-heparin). 
Samples handling and processing is described in study specific lab manual.  
 
10.3.2 
Analytics  
 
The concentration of safinamide in plasma samples will be determined at a certified analytical 
laboratory (to be designated). Analyses will be performed according to the general Principles 
of “OECD Good Laboratory Practices for testing of chemicals" C(81) 30 (final) and GCP. 
 
The method validation report and the analytical report will be attached to the final report. 
 
10.3.3 
Labelling, storage and transport of samples 
 
10.3.3.1 
Samples labelling 
 
Labels and labelling process are described in the study specific lab manual.  
 
10.3.3.2 
Samples storage and transport 
 
During the study the samples will be stored at ≤- 70° C. At the end of each collection day, 
aliquots 1 and 2 will be stored in separate freezers. 
 
All aliquots 1, packed in sufficient dry ice, will be shipped by an authorised courier from the 
clinical centre (China) to the analytical laboratory.  
 
 


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11 
ASSIGNMENT OF STUDY TREATMENT 
 
11.1 
Randomisation 
 
Randomisation will be used to minimize bias in the assignment of subjects to treatment cohorts, 
to increase the likelihood that known and unknown subject attributes (e.g., demographic and 
baseline characteristics) will be evenly balanced across treatment cohorts. 
The randomisation schedulewill be computer-generated by the CRO biostatistician using SAS®. 
The randomisation schedulewill be attached to the final clinical study report. 
 
11.2 
Treatment allocation 
 
Subjects will be randomised to 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), according 
to the study randomised, parallel-group design. 
 
On day -1, Period 1, subjects will be assigned a randomisation number, which will be used to 
assign the study treatment according to the randomisation schedule, as detailed above. 
Subjects who prematurely discontinue participation after randomisation will not be replaced. 
 
11.3 
Blinding 
 
This is an open study. No masking procedure will be applied.  
The open label design is considered appropriate for the primary objective of pharmacokinetic 
characterization, because PK properties and assessments are not prone to bias of observation 
by the investigators or the subjects. 


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12 
EVALUATION PARAMETERS 
 
12.1 
Study variables 
 
12.1.1 
Primary variables 
 
The following safinamide PK parameters will be determined on day 1 (after the first dose), on 
day 8 (after the first multiple dose) and on day 14 (after the last dose): 
 
After single dose and first multiple dose (day 1 and day 8) 
 Cmax, tmax, AUC0-t, and AUC0-24h 
 
After single dose only (day 1): 
 Kel, t1/2, AUC0-, Vd/F, Cl/F and MRT 
 
After multiple dose (day 14): 
 Cmax_ss, tmax_ss, Cmin_ss, AUC0-t,ss, AUC0-24h,ss, Cave_ss, Racc, DF%, Vd,ss/F and Cl,ss/F 
 
12.1.2 
Secondary variables 
 
 Treatment emergent adverse events (TEAEs), vital signs (blood pressure, heart rate), 
body weight, physical examinations, clinical laboratory parameters, ECG. 
 
12.2 
Pharmacokinetic assessments 
 
12.2.1 
Pharmacokinetic parameters 
 
The following safinamide PK parameters will be measured and/or calculated with a Non-
Compartmental Analysis (NCA) using Phoenix WinNonlin v6.3 (or higher). 
 
After single dose and first multiple dose (day 1 and day 8): 
Cmax:
Maximum safinamide plasma concentration
tmax:
Time to achieve Cmax
AUC0-t: 
Area under the concentration-time curve from single dose administration to the 
last quantifiable concentration time t
AUC0-24h: 
Area under the concentration-time curve in the tau interval (from single dose 
administration to 24 h post dose)
 
After single dose (day 1): 
Kel: 
Apparent terminal elimination rate constant, calculated, if feasible, from the 
slope of a log-linear regression using at least 3 last concentration > LLOQ 
points
t1/2:
Apparent terminal elimination half-life, calculated, if feasible, as ln2/Kel
AUC0-: 
Area under the concentration-time curve extrapolated to infinity, calculated, if 
feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration
Vd/F: 
Apparent volume of distribution associated with the terminal slope, calculated, 
if feasible, as Dose/(AUC0-∞*Kel)


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Cl/F: 
Apparent total body clearance, calculated, if feasible, as Dose/AUC0-∞ 
MRT: 
Mean residence time, calculated, if feasible, as AUMC0-∞/AUC0-∞, were 
AUMC0-∞ is area under the moment concentration-time curve extrapolated to 
infinity
 
The sampling schedule is considered adequate if the ratio AUC0-t/AUC0- equals or exceeds a 
factor of 0.8 (i.e. if %AUCextra is <20%) for more than 80% of the individual PK profiles. This 
assures that AUC0-t covers a sufficient percentage of the theoretical total extent of exposure.  
 
The quality of log-linear regression (and, consequently, the reliability of the extrapolated PK 
parameters) should be demonstrated by a determination coefficient R2 ≥ 0.8. Individual 
extrapolated parameters, when considered unreliable, will be reported as NC (not calculated).  
 
After multiple dose (day 14): 
Cmax_ss:
Maximum safinamide plasma concentration at steady state
tmax_ss:
Time to achieve Cmax-ss
AUC0-t,ss: 
Area under the concentration-time curve at steady state from the last dose 
administration to the last quantifiable concentration time t
AUC0-24h,ss: Area under the concentration-time curve at steady state in the tau interval (from 
the last dose administration to 24 h post dose)
Cave_ss: 
Average safinamide plasma concentration at steady state, calculated as AUC0-
24h,ss /tau (24 h)
Racc:
Accumulation ratio, calculated as AUC0-24h,ss/ AUC0-24h
DF%: 
Peak-trough fluctuation over one dosing interval at steady-state, calculated as 
(Cmax,ss - Cmin,ss)/Cave,ss*100
Vd,/Fss 
apparent volume of distribution at steady-state associated with the terminal 
slope, calculated, if feasible, as Dose/( AUC0-24h,ss*Kel)
Cl,/Fss 
apparent total body clearance at steady-state, calculated, if feasible, as Dose/ 
AUC0-24h,ss
 
12.3 
Safety assessments 
 
Safety and general tolerability of the investigational products will be based on TEAEs, physical 
examinations, including body weight, vital signs, ECGs and routine haematology, blood 
chemistry and urinalysis laboratory tests. 
 


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13 
STATISTICAL METHODS 
 
The data documented in this study and the parameters measured will be evaluated using classic 
descriptive statistics, i.e. geometric mean, geometric CV (%) (PK data only), arithmetic mean, 
SD, CV (%), minimum, median and maximum values for quantitative variables, and 
frequencies for qualitative variables. 
 
Not available data will be evaluated as “missing values”. The statistical analysis of demographic 
and safety data will be performed using Statistical Analysis Software (SAS®) Version 9.3 or 
higher. 
The pharmacokinetic parameters will be calculated using the actual recoded sampling times and 
non-compartmental methods with Phoenix WinNonlin (Version 6.3 or higher). 
 
13.1 
Analysis Sets 
 
13.1.1 
Definitions 
 
A subject will be defined as screened after the signature of the informed consent, regardless of 
the completion of all the screening procedures. 
A subject will be defined as eligible if he/she meets all the inclusion criteria and not meet any 
exclusion criteria. Otherwise he/she will be defined as a screen failure.  
 
A subject will be defined as enrolled in the study if he/she is included into the interventional 
phase of the study. The enrolment will be performed through randomised allocation to a 
treatment cohort. An eligible but not enrolled subject will be defined as a reserve. 
A subject will be defined as randomised in the study when he/she is assigned to a randomised 
treatment cohort. 
 
The following analysis sets will be considered: 
 
 Randomised set: all randomised subjects. This analysis set will be used for demographic, 
baseline and background characteristics. 
 Safety set: 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.  
 PK set: all randomised subjects who fulfil the study protocol requirements in terms of 
investigational medicinal products intake and have evaluable PK data readouts, with no 
major deviations that may affect the PK results. This analysis set will be used for the PK 
analysis. 
 
Each subject will be coded as valid or not valid for the Randomised set, Safety set and PK set. 
Subjects will be evaluated according to the treatment they actually receive. 
 
 


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13.1.2 
Reasons for exclusion from the PK set 
 
Reasons for the exclusion of subjects from the PK set are the following: 
 
Before bioanalysis 
 vomiting and diarrhoea after drug intake which could render the plasma concentration-time 
profile unreliable 
 intake of concomitant medications which could render the plasma concentration-time 
profile unreliable 
 AEs which could render the plasma concentration-time profile unreliable 
 administration errors which could render the plasma concentration-time profile unreliable 
 other events which could render the plasma concentration-time profile unreliable 
If one of these events occurs, it will be noted in the CRF as the study is being conducted. 
 
After bioanalysis 
 
Exclusion of subjects on the basis of pharmacokinetic reasons is possible only for: 
 subjects with non-zero baseline concentrations > 5% of Cmax for single dose and first 
multiple dose (day 1 and day 8) 
The samples from the subjects excluded from the PK set should still be assayed and the results 
listed. Subjects should not be excluded from the PK set if the AUC0-t covers less than 80% of 
the AUC0-∞. 
Any data excluded will be discussed in the CSR. 
 
13.2 
Sample size and power considerations 
 
Twelve (12) healthy male and female Chinese volunteers / cohort (24 in total) will be included 
in the study in order to have at least 8 completers / cohort. Drop-out subjects will not be replaced. 
Since no hypothesis will be tested, no formal sample size calculation has been performed. The 
sample size of this study has been determined in agreement with the guidance issued by the 
Chinese Food and Drug Administration (CFDA) for clinical pharmacokinetic studies (1). 
 
13.3 
Demographic, baseline and background characteristics 
 
Demographic and background characteristics will be examined according to qualitative or 
quantitative data. Qualitative data will be summarised in contingency tables. Quantitative data 
will be summarised using classic descriptive statistics. The baseline will be the last pre-dose 
measurement. 
 
13.4 
Analysis of pharmacokinetic parameters 
 
A descriptive PK will be presented. The results will be displayed and summarised in tables and 
figures. Individual and mean curves (+SD at nominal times), indicating inter-subject variability, 
will be plotted. Data below the lower limit of quantification (BLQ) will be 


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considered as 0 in the calculations and presented as BLQ in listings and tables. As a 
consequence of BLQ(i.e. 0) values, calculated geometric means (if requested) could be null. 
For this reason, in the presence of any null value, the geometric mean will be reported as not 
calculated (NC). 
 
13.5 
Safety and tolerability evaluation 
 
13.5.1 
Adverse events 
 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT), 
using the Medical Dictionary for Regulatory Activities (MedDRA). 
AEs will be classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs), 
according to the period of occurrence, as follows:  
 PTAEs: all AEs occurring before the first dose of investigational product and not 
worsening after the first dose of investigational product.  
 TEAEs: all AEs occurring or worsening after the first dose of investigational product 
 
Individual PTAEs and TEAEs will be listed in subject data listings. No summary table will be 
provided for PTAEs. TEAEs will be summarised by treatment and overall. The number and 
percentage of subjects with any TEAE and the number of TEAEs will be tabulated by SOC and 
PT, seriousness, relationship with investigational product and severity.  
 
13.5.2 
Physical examination 
 
Date of the physical examination, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be listed. 
 
13.5.3 
Laboratory data  
 
Date/time of samples collection, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
findings (if any) will be listed. All laboratory results will be listed and a table of all the abnormal 
values will be presented. 
 
13.5.4 
Vital signs 
 
Vital signs values will be listed and summarised by descriptive statistics. 
 
13.5.5 
Body weight  
 
Body weight values will be listed and summarised by descriptive statistics. 
 
 


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13.5.6 
ECG 
 
Date/time of ECG recording, overall investigator’s interpretation (as normal or abnormal and, 
if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be listed. Hard copies of the ECGs will be attached to the CRF.  


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14 
DEFINITION AND HANDLING OF AEs AND SAEs 
 
14.1 
Applicable SOPs 
 
AEs definition, classification and management will follow the CRO’s SOPs, based upon 
applicable local and international regulations. The full SOPs or an operative summary will be 
made available in the CRO. 
 
A brief summary of AE definition, classification and management is reported below. 
 
14.2 
Definition of Adverse Event (AE) 
 
An Adverse Event is “any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment”. 
AEs include: 
 worsening (change in nature, severity or frequency) of conditions present at the onset 
of the trial 
 patient/subject deterioration due to the primary illness 
 intercurrent illnesses 
 drug interactions 
 events related or possibly related to concomitant medications 
 abnormal laboratory values, as well as significant shifts from baseline within the range 
of normal, which the investigator considers to be clinically significant. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not considered related to the investigational 
medicinal product. 
 
14.3 
Definition of Adverse Drug Reaction (ADR) 
 
An Adverse Reaction is “any untoward and unintended response to an investigational 
medicinal product related to any dose administered”. 
All AEs judged by either the reporting investigator or the sponsor as having a reasonable causal 
relationship to a medicinal product qualify as adverse reactions. The expression reasonable 
causal relationship means to convey in general that there is evidence or matter to suggest a 
causal relationship. 
 
 Unexpected Adverse Drug Reaction 
 
An unexpected ADR is: “An adverse reaction, the nature, or severity of which is not consistent 
with the applicable product information (Reference Safety Information [RSI]).  
 
 Reference Safety Information (RSI): in order to assess whether an adverse reaction is 
expected, the SmPC will be used. 


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14.4 
Definition of Serious Adverse Events or Serious Adverse Drug Reaction 
 
A Serious Adverse Event (SAE) is: “any untoward medical occurrence or effect that at any 
dose: 
 results in death 
 is life-threatening (i.e. the subject was at risk of death at the time of the event/reaction; it 
does not refer to an event/reaction which hypothetically might have caused death if it were 
more severe) 
 requires inpatient hospitalization or prolongation of existing hospitalization 
 results in persistent or significant disability/incapacity (where disability is defined as a 
permanent or substantial disruption of ability to carry out normal life functions, either 
reported or defined as per clinical judgement) 
 is a congenital anomaly/birth defect 
 is an important medical event that may not result in death, be life-threatening, or require 
hospitalization but, according to appropriate medical judgment, it may jeopardize the 
subject and may require medical or surgical intervention to prevent any of the outcomes 
listed in the definition above.  Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, and blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.  
 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse event. 
 
A Serious Adverse Drug Reaction (SADR) is an ADR that meets also the definition of SAE.  
 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is an ADR that is both 
unexpected (not consistent with the applicable product information, e.g. SmPC) and also meets 
the definition of a SAE. 
 
A non-serious adverse event is any adverse event that does not meet the criteria listed above for 
a serious adverse event. 
 
 
14.5 
Definition of Severity of Adverse Events 
 
The term “severe” is used to describe the intensity (severity) of a specific event: 
- 
Mild: causing no limitation of usual activities; the subject may experience slight 
discomfort. 
- 
Moderate: causing some limitation of usual activities; the subject may experience 
annoying discomfort. 
- 
Severe: causing inability to carry out usual activities; the subject may experience 
intolerable discomfort or pain. 
 
14.6 
Definition of Adverse Event causality 
 


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Causality shall be determined according to the definition of ADR given in 14.3. 
 
All AE judged by either the investigator or the sponsor as having a reasonable suspected causal 
relationship to an investigational medicinal product qualify as adverse reactions. The causality 
assessment given by the investigator should not be downgraded by the sponsor. 
 
The following binary decision for causality will be used: 
 Reasonable possibility that the IMP caused the event 
 No reasonable possibility that the IMP caused the event 
Features supportive of an association include: 
 temporal plausibility 
 pharmacological properties of the drug or of the substance class 
 course of the adverse event after dechallenge and, if applicable, after rechallenge 
 specific tests indicating involvement of the drug in the occurrence/worsening of the 
adverse event  
 alternative explanations 
 
14.7 
Adverse Events recording 
 
Each AE occurring to a subject, either spontaneously revealed by the subject or observed by 
the investigator, whether believed by the investigator to be related or unrelated to the IMP, must 
be recorded on the AE information page of the CRF (for SAEs information must be recorded 
also on the “Serious Adverse Event Form”).  
The Investigator will also perform an evaluation with respect to seriousness and causality 
(relationship of any AE to IMP) of the AEs. and record it on the appropriate section of the CRF 
and on the “Serious Adverse Event Form” (if appropriate).  
 
14.8 
AEs monitoring window 
 
 Start of monitoring: from immediately after the signature of the informed consent 
 End of monitoring: up to final study visit/ETV (observation window)  
An AE occurring after the final visit/ETV and coming to knowledge of the investigator (e.g. 
during a follow-up assessment or by spontaneous reporting by study subjects) must be recorded 
only if it is an ADR, according to the investigator’s judgment. 
 
14.9 
Adverse Events reporting 
 
The official language for reporting is English. The investigator and clinical staff of the present 
study are familiar with English language. 
 
The investigator must report to the CRO all AEs which occur during the study, regardless of 
their relationship to the IMP. Protocol specific AEs or laboratory abnormalities critical to safety 


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evaluations are to be identified in the protocol and reported to the sponsor according to reporting 
requirements and within the time periods specified. 
 
All AEs are recorded by the investigator on the AE information page of the CRF. 
 
In addition, SAE will have to be reported according to the following detailed procedure. 
 
14.9.1 
SAEs reporting 
 
The investigator must report the SAEs to the CRO no later than 24 hours from when he/she 
becomes aware of the SAE, by Electronic Data Capture (preferred method), or e-mailing as 
scanned attachment (back up plan) or by faxing the “Serious Adverse Event Form” (back up 
plan) to the CRO,  as stated in the "List of CRO/ personnel" in § 14.13 of this protocol. 
 
The standards of confidentiality must always be maintained and any relevant national 
legislation on data protection must be followed. 
 
Another copy of the “Serious Adverse Event Form ” will be sent to the Medical Affairs/Clinical 
Operations for the Sponsor’s file and another copy will be retained by the Investigator for the 
Investigator’s file. 
 
 
If the investigator becomes aware of any SAE occurred to a subject within the follow-up 
window established in the protocol, he/she will report the SAE as above. The SAE will be also 
reported in the CRF. 
 
If outside the follow-up window established in the protocol the investigator becomes aware of 
a SAE, if the investigator judges that the SAE is related to the study drug, it should be reported 
to the Sponsor. The Investigator might use the “Serious Adverse Event Form” via email or fax, 
but the SAE must not to be reported in the CRF, as it is not an event occurred within the study 
period. 
 
The investigator must report all SAEs that occur to the subjects to National Medical Products 
Administration/Local Ethics Committee/Provincial Food and Drug Administration/National 
Health and Family Planning Commission immediately no later than 24hours from when he/she 
becomes aware of SAE. Any SAEs that happen to the subjects outside the follow-up window 
should be reported by investigator to National Medical Products Administration/Local Ethics 
Committee/Provincial Food and Drug Administration/National Health and Family Planning 
Commission immediately. 
 
14.10 
Follow-up for Adverse Events 
 
A follow-up “Serious Adverse Event Form” will be filled in if important follow-up information 
(i.e. diagnosis, outcome, causality assessment, results of specific investigations) is made 
available after submission of the initial AE Form for immediate reporting. Follow-up “Serious 
Adverse Event Form” will be reported to the Sponsor as above-described, under Section 14.9.1. 
 


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In any case of an AE that, in the opinion of the investigator, requires the subject’s 
discontinuation, follow-up information relating to the subject’s subsequent course must be 
collected until the event has subsided or the condition stabilised or when the subject is lost to 
follow up or death. 
 
When follow-up data on non-serious AE are collected, information should be reported under 
“Comments” in the Final report of the CRF. 
 
14.11 
SUSARs management 
 
The clock for initial expedited reporting starts as soon as the information containing the 
minimum reporting criteria has been received by the CRO/sponsor (day 0).  
Fatal and life-threatening SUSARs, should be reported to Competent Authority as soon as 
possible and in any case within 7 days and to Ethics Committee per the requirement . 
If the initial report is incomplete, e.g. not all the information/assessments were available, a 
complete report should be sent within an additional 8 days. Complete follow-up report should 
be sent within 15 calendar days. 
SUSARs which are not fatal and not life-threatening are to be reported to Competent Authority 
within 15 days  and to Ethics Committee per the requirement. 
The minimum information to be reported includes: 
 Sponsor study number 
 One identifiable coded subject 
 One identifiable reporter 
 One SUSAR 
 One suspect IMP (including active substance name, code) 
 A causality assessment. 
 
14.12 
Other events qualified for expedited reporting 
 
Other safety issues also qualify for expedited reporting may be sent to Competent authority 
when they might materially alter the current benefit-risk assessment of a medicinal product or 
would be sufficient to consider changes in the medicinal product administration or in the overall 
conduct of the trial, for instance: 
 single case reports of an expected serious adverse reaction with an unexpected outcome 
(e.g. a fatal outcome) 
 an increase in the rate of occurrence of an expected serious adverse reaction, which is 
judged to be clinically important. 
 post-study SUSARs that occur after the subject has completed a clinical trial and are 
reported to the investigator by the subject. 
 new events relating to the conduct of the trial or the development of the medicinal 
product likely to affect the safety of the subjects, such as : 
 a SAE which could be associated with the trial procedures and which could modify 
the conduct of the trial 


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 a significant hazard to the subject population such as lack of efficacy of a medicinal 
product used for the treatment of a life-threatening disease 
 a major safety finding from a newly completed animal study (such as carcinogenicity) 
or from other clinical trials. 
 
14.13 
SAEs: contacts 
 
The investigator will report any SAE to the CRO. The CRO’s details for SAEs are the 
following: 
Email
 
 
The sponsor’s details for SAEs are the following: 
Phone: 
 
Fax: 
 
Email: 
 
 
14.14 
Pregnancy 
 
Subjects must be instructed that known or suspected pregnancy occurring during the study 
should be confirmed and reported to the Investigator, who must then withdraw the subject from 
the study without delay. The Investigator should also be notified of pregnancy occurring during 
the study but confirmed after its completion. In the event that a subject is subsequently found 
to be pregnant after inclusion in the study, then any pregnancy will be followed up to the end 
of pregnancy or pregnancy termination and the status of mother and child will be reported to 
the Sponsor after delivery through the Pregnancy Report Form provided by the Sponsor. The 
Investigator will send pregnancy reports to DSU within the timeframes of SAEs, with follow-
up information to be actively sought for the outcome of pregnancy.  
- 
Part I of the Form is completed at the time of awareness of foetal exposure during 
pregnancy.  
- 
Part II of the Form is filled in when information on pregnancy outcome becomes available. 
If pregnancy results in abnormal outcome (spontaneous miscarriage, stillbirth and congenital 
anomalies) will be considered as SAE. If the investigator considers this to be due to the IMP, 
this will be treated as an expedited ADR report. 
 
15 
DATA MANAGEMENT PROCEDURES 
 
15.1 
Data collection – CRFs 
 
The investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the eCRFs. He/she must also check that the data reported in the eCRFs correspond 
to those in the subject’s source documents.  
ECG and laboratory results must be printed and signed by the Investigator and kept as source 
data on site after entering outcome into the eCRF. 
All other data has to be documented in the subject file as source data first and then entered into 
the eCRF.  
Data must be entered into eCRFs in English by the designated site personnel as soon as possible 
after a subject visit, and monitors will have access to data recorded. These data will be reviewed 
PPD
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PPD
PPD


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versus source documents by trial monitors for completeness and acceptability during 
monitoring visits.  
If data correction is required for an eCRF after initial entry, the site personnel can make 
necessary corrections on their own or as a response to an automated query by the eCRF system. 
Monitor and Clinical Data Manager review the eCRF for accuracy and can also generate queries 
to the investigational staff for resolution.  
Any correction to the eCRFs' entries must be carried out by the Investigator or a designated 
member of staff. Corrections are recorded in an audit trail that records the old information, the 
new information, and identification of the person making the changes, date of correction made 
and reason for change. In the interests of completeness of data acquisition, the questions which 
are repeated in each section of the eCRFs should be answered in full, even if there are no 
changes from a previous examination. A reasonable explanation must be given by the 
Investigator for all missing data. The Investigator or his/her designees named in the clinical 
staff list will review the eCRF for accuracy and completeness. The Investigator must 
electronically sign and date the eCRF pages as indicated. 
 
15.2 
Database management 
 
The CRO will update and verify the database and create the final SAS data sets. The final data 
file will be transferred to the sponsor in the agreed format with all the other study documentation. 
 
15.2.1 
Coding dictionaries 
 
Medical/surgical history and underlying diseases, clinically significant physical examination 
abnormalities, AEs and previous and concomitant medications will be coded. 
Information on coding dictionaries will be provided in a Data Management Plan. 
 


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16 
STUDY MONITORING, QUALITY CONTROL AND 
QUALITY ASSURANCE 
 
16.1 
Monitoring 
 
The monitoring visits will be conducted by personnel of the CRO, PAREXEL.  
 
Monitoring activities, including monitoring purpose, selection and qualifications of monitors, 
extent and nature of monitoring, monitoring procedures, monitoring reports will comply with 
ICH-GCP chapter 5.18 requirements, CFDA-GCP and the monitoring plan. 
 
Adequate time and availability for monitoring activities should be ensured by the investigator 
and key study personnel. 
 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the investigator will assure support to the monitor at all times. 
 
The investigator agrees, by written consent to this protocol, to fully co-operate with compliance 
checks by allowing authorised individuals to have access to all the study documentation. In 
addition to the monitoring activities performed by the study monitor, the sponsor could perform 
some quality control activities to verify the compliance with the study procedures and the ICH-
GCP and CFDA-GCP guidelines 
 
16.2 
Quality Control and Quality Assurance  
 
The CRO has implemented and maintains a Quality System that includes quality controls and 
audits at different study steps with written SOPs to ensure that the study is conducted in 
compliance with the protocol and all effective amendments, ICH-GCP and CFDA-GCP, and 
the applicable regulatory requirement(s) and that data have been reliably and correctly 
generated, recorded, processed and reported, in agreement with the ALCOAC principles 
(Attributable-Legible-Contemporaneous-Original-Accurate-Complete). 
 
The clinical site(s) is responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, documented 
(recorded), and reported in compliance with the protocol, ICH-GCP, CFDA GCP and any 
applicable regulatory requirement(s). 
 
This protocol has been audited by the Sponsor QA.   
 
The CROs and the sponsor will be responsible for their respective activities. 
 
The sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a CRO, 
but the ultimate responsibility for the quality and integrity of the trial data always resides with 
the sponsor. 
 
 


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16.3 
Applicable SOPs 
 
The sponsor, the clinical centre and the CRO will follow their respective SOPs in the conduct 
of the respective activities, unless otherwise stated in written agreements. SOPs will be made 
available for Sponsor review, if required. 
 
16.4 
Data access 
 
The investigator and the CRO(s) will ensure that all source data, medical records, CRFs and all 
other documentation that is relevant to this study will be made accessible for monitoring 
activities, audits, IEC review, and regulatory inspections. 
 
16.5 
Audits and inspections 
 
The sponsors, independent bodies acting on behalf of the sponsor and the CRO have the right 
to perform audits according to ICH-GCP and CFDA responsibilities. 
 
The study may also be inspected by regulatory authorities.  
 
The investigator(s) and the CRO(s) agree, by written consent to this protocol, to fully co-operate 
and support audits and inspections compliance checks by allowing authorised individuals to 
have access to all the study documentation. 
 
 
 


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17 
ETHICAL CONSIDERATIONS 
 
17.1 
Ethics and Good Clinical Practice (GCP) 
 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
 
The approval of the study protocol by the relevant Ethics Committee will be obtained before 
the start of the study. 
Study notification to the Competent Authorities will be performed according to the current local 
regulations. 
 
The present clinical study will be carried out according to the current revision of Good Clinical 
Practice (GCP), ICH topic E6 (R2), CFDA Reg No. 25 “Good Clinical Practice (GCP) Mar 23, 
2016 and the applicable local law requirements. 
 
17.2 
Informed consent 
 
Before being enrolled into the clinical study, the subjects must have expressed their consent to 
participate, after the investigator has explained to them, clearly and in details, the scope, the 
procedures and the possible consequences of the clinical study. Information will be given in 
both oral and written form. The information sheet and informed consent form will be prepared 
in the local language by the CRO and must be approved by the EC and regulatory authorities. 
The document will include all the elements required by law according to the ICH-GCP 
recommendations.  
In addition to the standard requirements that physicians are currently obliged to observe when 
providing information, the following points must also be covered: 
 a description of the aims of the study and how it will be organised 
 the type of treatment (information on the IMP(s) and treatment procedures, as applicable) 
 any potential negative effects attributable to the study product or treatment 
 the freedom to ask for further information at any time 
 the subjects’ right to withdraw from the clinical study at any time without giving reasons 
and without jeopardising their further course of medical treatment  
 the existence of a subject insurance cover and obligations following from this cover 
 
Adequate time and opportunity to satisfy questions will be given to the subjects and the time 
will be recorded. 
 
The investigator will be supplied with an adequate number of blank informed consent forms to 
be used. The forms will be signed and dated by both the investigator and the subject.  
A copy of the signed form will be given to the subject. 
 
To ensure medical confidentiality and data protection, the signed informed consent forms will 
be stored in the investigator's study file according to the regulatory requirements. The 
investigator will allow inspection of the forms by authorised representatives of the sponsor, EC 


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members and regulatory authorities. He/she will confirm, by signing and dating the forms, that 
informed consent has been obtained. 
 
17.3 
Insurance policy 
 
An insurance cover has been issued in favour of the subjects participating in this clinical study. 
The insurance is in compliance with the local regulation and with the requirements of the Health 
Authorities. 
 
17.4 
Withdrawal of subjects 
 
It will be documented whether or not each subject completed the clinical study. If, for a subject, 
study treatment or observations are discontinued, the primary reason for discontinuation will 
be recorded. 
 
17.4.1 
Primary reason for discontinuation 
 
 Adverse event: Any (significant) adverse event that in the opinion of the investigator or 
concerned subject is not compatible with study continuation. For the definition of AE, 
please refer to § 14. 
 death: the absence of life or state of being dead 
 lost to follow-up: the loss or lack of continuation of a subject to follow-up 
 non-compliance with study drug: an indication that a subject has not agreed with or 
followed the instructions related to the study medication 
 physician decision: a position, opinion or judgment reached after consideration by a 
physician with reference to the subject 
 pregnancy: pregnancy is the state or condition of having a developing embryo or foetus in 
the body (uterus), after union of an ovum and spermatozoon, during the period from 
conception to birth 
 protocol deviation: an event or decision that stands in contrast to the guidelines set out by 
the protocol 
 study terminated by sponsor: an indication that a clinical study was stopped by its sponsor 
 technical problems: a problem with some technical aspect of a clinical study, usually 
related to an instrument 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 
 other: different than the ones previously specified 
 
17.4.2 
Discontinuation procedures 
 
For any subject discontinuing the study, the investigator will:  
 ask the subject to undergo, as far as possible, a final medical visit (ETV) to examine the 
subject's health conditions and perform the required blood sampling for the laboratory 


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assays. This examination will verify that all values tested at screening have remained within 
a clinically acceptable range (i.e. not clinically significant changes compared to screening) 
 arrange for alternative medical care of the withdrawn subject, if necessary 
 record the subject decision about the use of collected biological samples 
 report in the CRF date and time of the last dose administration, and date and primary reason 
of study discontinuation 
 record in the CRF any follow-up, if the subject is withdrawn for an AE 
 
Discontinued subjects will not be replaced.  
 
17.5 
Study termination 
 
The study will be considered terminated at the date of the last visit of the last subject or upon 
completion of any follow-up procedure described in the protocol. The investigator and the 
sponsor have the right to discontinue the study at any time for reasonable medical and/or 
administrative reasons. As far as possible, this should occur after mutual consultation. Reasons 
for discontinuation have to be documented appropriately. 


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18 
ADMINISTRATIVE PROCEDURES 
 
18.1 
Material supplied to the clinical centre 
 
Beside the investigational products, the following study material will be supplied to the clinical 
centre: 
 final version of the study protocol 
 access to the eCRF 
 copy of the SmPC relative to the investigational products 
 informed consent forms 
 investigator site file 
 laboratory supplies 
Moreover, before the start of the study, the investigator(s) will be provided with the following 
documents: ICH guidelines, confidentiality agreement (if applicable), protocol amendments (if 
any), declaration of Helsinki, insurance statement, SAE forms, financial agreement (if 
applicable), confidential subject identification code list form, drug accountability forms, 
investigator and study staff list form. 
 
18.2 
Protocol amendments 
 
In order to obtain interpretable results, neither the investigator nor the sponsor will alter the 
study conditions agreed upon and set out in this protocol. Amendments should be made by 
mutual agreement between the investigator and the sponsor. Any amendment must be set out 
in writing, giving the reasons, and being signed by all concerned parties. The amendment 
becomes then part of the protocol. 
 
All substantial amendments will be sent to the EC and concerned Competent Authorities, as 
appropriate. The amendment will be applicable only when it is approved, unless the changes 
consist of urgent safety measures to protect study subjects. 
 
Non-substantial amendments will be notified according to the current local regulations. 
 
18.3 
Study documentation and record keeping 
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the sponsor in the CRFs and in all required reports. 
 
The investigator must keep source documents for each subject in the study. Information present 
on the CRFs must be traceable to these source documents, which are generally stored in the 
subject's medical file. The source documents should contain all demographic and medical 
information, including laboratory data, ECGs, etc., and the original signed informed consent 
forms. 
 
Data reported on the CRF that are derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 


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The investigator and the sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirement(s).  
 
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are not 
limited to, study protocol, amendments, submission and approval of EC, raw data of subjects 
including lab tests and ECG tracing, insurance contracts, certificate of analysis of the IMP(s), 
drug accountability records, signed informed consent forms, confidential subjects identification 
code, CRFs, curricula vitae of the investigator and other participants in the study, study staff 
lists and responsibilities, monitoring reports and final study report. 
 
The investigator and the sponsor should take measures to prevent accidental or premature 
destruction of these documents. 
 
Study documents must be retained by the investigator and the sponsor as long as needed to 
comply with ICH-GCP, CFDA GCP national and international regulations. By signing the 
protocol, the investigator and the sponsor agree to adhere to these requirements. 
 
18.4 
Study subjects’ recruitment 
 
The CRO and its clinical site have detailed SOPs on the recruitment process. 
 
18.5 
Confidentiality and data protection 
 
By signing this protocol, the investigator agrees to keep all the information provided by the 
sponsor in strict confidentiality and to request the same confidentiality from his/her staff. Study 
documents provided by the sponsor (protocols, CRFs and other materials) will be stored 
appropriately to ensure confidentiality. The information provided by the sponsor to the 
investigator cannot be disclosed to others without direct written authorisation from the sponsor, 
except for the extent necessary to obtain the informed consent from the subjects wishing to 
participate in the study. 
 
Subjects data collected in the eCRFs during the study will be documented in an anonymous 
way. If, as an exception, for safety or regulatory reasons identification of a subject becomes 
necessary, the monitor, the sponsor and the investigator will be bound to keep this information 
confidential. 
 
18.6 
Publication policy 
 
The Investigator agrees to inform Zambon in advance about his/her intention to divulge any 
data, results concerning the Confidential Information and/or the study patient to this Agreement. 
As a consequence hereof, the Investigator hereby undertakes to submit to Zambon, at least with 
a sixty (60) days (30 in case of abstracts) prior written notice, the text and or the content of the 
concerned publication, divulgation as to allow Zambon to assess properly that such proposed 
publication respects and/or is not in conflict with Zambon’s rights to preserve and protect its 


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intellectual property rights and any confidentiality imposed to Zambon by the prevailing rules 
of the country where the study is conducted. 
Furthermore, without any prejudice to the Investigator’s right to divulge and save for what 
stated hereinabove, the Investigator intends to seek Zambon opinion and advice on and prior to 
the intended publication and/or disclosure, in consideration also of the contractual relationship 
in force between Zambon and Investigator and the nature of the study hereto. 
 
 


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19 
STUDY RESPONSIBLE PERSONS 
 
19.1 
Sponsor 
 
Zambon S.p.A., via Lillo del Duca 10, 20091 Bresso (Milan), Italy 
Phone: 
 
Fax: 
 
 
Protocol Review Committee Chairman  
 
 
 
Medical Expert 
 
 
 
19.2 
Institutes performing the study 
 
19.2.1 
Clinical centre 
 
"Denomination"  Address XXXXXXX, "Zip" "City", China 
Phone: 
+00.nnnnnnnnn 
Fax: 
+00.nnnnnnnnn 
Email: 
"Email"@"Specify".com 
 
Principal investigator 
"SpecifyName", MD 
 
19.3 
Drug assay 
 
Analytical Facility for PK/drug assay: 
 
United-Power Pharma Tech Co., Ltd. (UP-Pharma) 
2F, Tower B, No. 33 Science Park Road, 
Changping District, Beijing, P.R.China 
ZIP Code: 102206 
 
 
Analytical facilities and procedures are in compliance with the general principles of GLP 
regulations. 
 
19.4 
Co-ordination, data analysis & reporting 
 
PAREXEL International (IRL) Limited (“PAREXEL”), a corporation organized under the 
laws of Ireland with a registered address at 70 Sir John Rogerson’s Quay, Dublin 2, Ireland. 
 
19.5 
Project Management and Monitoring 
 
PPD
PPD
PPD
PPD
PPD
PPD


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PAREXEL International (IRL) Limited (“PAREXEL”), a corporation organized under the 
laws of Ireland with a registered address at 70 Sir John Rogerson’s Quay, Dublin 2, Ireland. 
 


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20 
REFERENCES 
 
1. CFDA Guidance 
2. EMA Commission Implementing Decision C (2015) 1390 (final)  – Xadago (safinamide). 24 February 2015 
3. Summary of Product Characteristics (SmPC) – Xadago 50 mg, 100 mg film-coated tablets 
4. Caccia C, Maj R, Calabresi M, Maestroni S, Faravelli L, Curatolo L, Salvati P, Fariello RG. Safinamide: from 
molecular targets to a new anti-Parkinson drug. Neurology. 2006 Oct 10;67(7 Suppl 2):S18-23. 
5. Schapira AH. Monoamine oxidase B inhibitors for the treatment of Parkinson's disease: a review of 
symptomatic and potential disease-modifying effects. CNS Drugs. 2011 Dec 1;25(12):1061-71 
6. Salvati P, Maj R, Caccia C, Cervini MA, Fornaretto MG, Lamberti E, Pevarello P, Skeen GA, White HS, 
Wolf HH, Faravelli L, Mazzanti M, Mancinelli E, Varasi M, Fariello RG. Biochemical and 
electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound. J 
Pharmacol Exp Ther. 1999 Mar;288(3):1151-1159. 
7. Pevarello P, Amici R, Bonsignori A, Caccia C, Amici R, McArthur RA, Fariello RG, Salvati P, Varasi M. 
Sodium channel activity and sigma binding of 2-aminopropanamide anticonvulsivants. Bioorg Med Chem 
Lett. 1999 Sep 6;9(17):2521-4. 
8. Binda C, Milczek EM, Bonivento D, Wang J, Mattevi A, Edmondson DE. Lights and shadows on monoamine 
oxidase inhibition in neuroprotective pharmacological therapies. Curr Top Med Chem. 2011 
Nov;11(22):2788-96. Review. 
9. Schapira AH. Safinamide in the treatment of Parkinson's disease. Expert Opin Pharmacother. 2010 
Sep;11(13):2261-8 
10. Onofrj M, Bonanni L, Thomas A. An expert opinion on safinamide in Parkinson's disease. Expert Opin 
Investig Drugs. 2008 Jul;17(7):1115-25 
11. Marzo A, Dal Bo L, Monti NC, Crivelli F, Ismaili S, Caccia C, Cattaneo C, Fariello RG. Pharmacokinetics 
and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity. 
Pharmacol Res 2004; 50(1):77-85 
12. Leuratti C, Sardina M, Ventura P, Assandri A, Müller M, Brunner M. Disposition and metabolism of 
safinamide, a novel drug for Parkinson's disease, in healthy male volunteers. Pharmacology. 2013;92(3-
4):207-16 
13. Marquet A, Kupas K, Johne A, Astruc B, Patat A, Krösser S, Kovar A. The effect of safinamide, a novel drug 
for Parkinson's disease, on pressor response to oral tyramine: a randomized, double-blind, clinical trial. Clin 
Pharmacol Ther. 2012 Oct;92(4):450-7  
14. Di Stefano AFD, Rusca A. Pressor response to oral tyramine during co-administration with safinamide in 
healthy volunteers. Naunyn-Schmiedeberg's Arch Pharmacol 2011; 384:505-515 
15. Cattaneo C, Caccia C, Marzo A, Maj R, Fariello RG. Pressor response to intravenous tyramine in healthy 
subjects after safinamide, a novel neuroprotectant with selective, reversible monoamine oxidase B inhibition. 
Clin Neuropharmacol. 2003 Jul-Aug;26(4):213-7. 
16. Guidelines on GMP, published by the Commission in The rules governing medicinal products in the European 
Community, Volume 4 
17. U.S. Department of Health and Human Services and U.S. Department of Agriculture, Nutrition and your 
health: 2015-2020 Dietary Guidelines, Appendix 9 
18. Safinamide Investigator’s Brochure, Edition Number 4, dated 13 February 2018.  
 
 
 
 
 


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21 
APPENDIX 1 
 
ACTIVITIES 
 
Period 1 
Screening
Single Dose  
Visit
V1
V2
V3
V4
Day 
Day -14/-2
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Informed consent 
x
Demography
x
Lifestyle 
x
Medical and surgical history  
x
Physical examination3
x
Prior and concomitant medications 
x
x
x
x
x
x
x
Height 
x
Body Weight3 
x
Laboratory analysis4 
x
Virology 
x
Serum pregnancy test (women) 
x
Urine multi-drug kit test 
x
x
Blood pressure and heart rate5 
x
x
x
x
Alcohol breath test 
x
Urine pregnancy test (women) 
x
ECG6 
x
Inclusion/exclusion criteria 
x
x
Subject eligibility
x
x
Enrolment and randomisation
x
Confinement 
x
x
x
Discharge 
x
Ambulatory visits 
x
Investigational product 
administration 
 
 
x7  
 
 
 
 
Blood sampling for PK analysis 
x8 
x8
x8
x8
x8
Standardised meals11  
x
x
x
x
Adverse event monitoring12 
x
x
x
x
x
x
x
 
 




Z7219J03 
 
 
Final v. 1.0; Date 10/December/2018                                                                                          Page 61 of 61 
1. 
Early termination visit (ETV) 
2. 
Final visit on day 18  
3. 
Physical examination, including body weight, at screening and final visit/ETV 
4. 
Laboratory analyses at screening and final visit/ETV  
5. 
At pre-dose, at 2 h and 96 h after day 1 single dose and day 14 last multiple dose. At pre-dose, 2 h and 24 h after the day 8 first multiple dose. Before blood sampling and 
investigational product administration during ambulatory visits 
6. 
At screening and final visit/ETV  
7. 
On day 1 (Period 1) and once daily from day 8 to day 14 (Period 2), at 8 00 ± 1 h 
8. 
At pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 36, 48, 72 and 96 h post-dose after the first single dose (day 1) and the last multiple dose (day 14);  
9. 
At pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose after the first multiple dose (day 8) 
10. At pre-dose (0) on each day (day 10-13) 
11. Day -1  standardised dinner; 
Day 1, Day 8, Day 14  standardised lunch at approximately 5 h post-dose,  standardised dinner at approximately 13 h post-dose;  
 
 
Day 2, Day 9 and Days 15/16  standardised breakfast, lunch and dinner 
12. Adverse events monitored starting at the screening visit, immediately after informed consent, up to the final visit/ETV 
 
 
 
 


Z7219J03 
 
 
Final v. 2.0; Date 18-APR-2019 
                                                                                          Page 1 of 60 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
 
A PHASE I, PHARMACOKINETICS, SAFETY AND TOLERABILITY 
STUDY OF SINGLE AND MULTIPLE ORAL DOSES OF SAFINAMIDE 
IN HEALTHY ADULT CHINESE VOLUNTEERS  
 
Phase I, single centre, single and multiple-dose, open-label, randomised, 
parallel-group, pharmacokinetics, safety and tolerability study 
 
 
 
Protocol Code: Z7219J03 
 
Date: 18 April 2019 
 
Version: Final 2.0 
 
 
 
 
Zambon SpA 
Via Lillo del Duca 10 
20091 Bresso - Milan - Italy 
 
 
 
 
 
 
THIS DOCUMENT IS ZAMBON'S SOLE PROPERTY AND OWNERSHIP. THIS DOCUMENT, AND ALL 
INFORMATION AND DATA CONTAINED HEREIN HAS TO BE CONSIDERED AND TREATED AS 
STRICTLY CONFIDENTIAL. THIS DOCUMENT SHALL BE USED ONLY FOR THE PURPOSE OF THE 
DISCLOSURE HEREIN PROVIDED. NO DISCLOSURE OR PUBLICATION SHALL BE MADE WITHOUT 
THE PRIOR WRITTEN CONSENT OF ZAMBON.  
 
 
 


Z7219J03 
 
 
Final v. 2.0; Date 18-APR-2019 
                                                                                          Page 2 of 60 
 
APPROVAL PAGE 
 
Clinical Trial Title: 
 
A phase I, pharmacokinetics, safety and 
tolerability study of single and multiple oral 
doses of safinamide in Chinese adult healthy 
volunteers.  
 
 
Protocol Code  
 
Date:  
 
Z7219J03 
 
18 April 2019 
 
Author: 
  
 
Sponsor Name and 
Address: 
Zambon SpA 
Via Lillo del Duca 10 
20091 Bresso, Milan, Italy 
 
 
 
As agreed and approved: 
 
 
 
______/______/_____      _____________________    ___________________ 
Date (dd/Mmm/yyyy) 
       Principal Investigator 
          SIGNATURE 
 
 
 
 
 
 
Accepted for the Sponsor 
 
 
 
______/______/_____      _______________________    ___________________ 
Date (dd/Mmm/yyyy) 
Global Chief Medical Officer 
and Patient’s Access Head 
         SIGNATURE 
 
 
 
 
PPD


Z7219J03 
 
 
Final v. 2.0; Date 18-APR-2019 
                                                                                          Page 3 of 60 
1 
STUDY SYNOPSIS 
 
Title: A phase I, pharmacokinetics, safety and tolerability study of single and multiple oral doses of safinamide in 
healthy adult Chinese volunteers 
 
Protocol number: Z7219J03 
 
Clinical phase: Phase I 
 
Study design: Phase I, single centre, single and multiple-dose, open-label, randomised, parallel-group, 
pharmacokinetics, safety and tolerability study 
 
Planned nr. of centres / countries: 1/China 
 
Investigator and centre: Principal investigator: TBD 
 
Investigational products:  
Test product 1: 
Xadago® 50 mg safinamide film-coated tablets, Zambon S.p.A., Italy 
Test product 2: 
Xadago® 100 mg safinamide film-coated tablets, Zambon S.p.A., Italy 
 
Dose regimen:  
Subjects will be randomised to 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 (1) safinamide 50 mg film-coated tablet will be administered on day 1 followed by 7 safinamide 
50 mg film-coated tablets administered o.d. from day 8 to day 14. 
Cohort 2: One (1) safinamide 100 mg film-coated tablet will be administered on day 1 followed by 7safinamide 
100 mg film-coated tablets administered o.d. from day 8 to day 14. 
Study treatment is also summarised in the scheme below: 
Cohort 
Period 1 - single dose 
Day 1 
Washout 
Period 2 - Multiple doses 
Days 8 - 14 
Cohort 1 
50 mg po 
7 days 
50 mg po o.d for 7 days 
Cohort 2 
100 mg po 
100 mg po o.d. for 7 days 
The investigational products will be orally administered in the morning, at 8:00±1h, 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. 
 
Objective: To evaluate safinamide pharmacokinetic profile, safety and tolerability after single and multiple dose 
administration to healthy adult Chinese volunteers. 
 
End-points:  
Primary end-point:  
➢ To evaluate plasma safinamide pharmacokinetic parameters after single and multiple dose administration of 
the Test investigational products.  
Secondary end-points:  
➢ To collect safety and tolerability data after single and multiple dose administration of the Test investigational 
products. 
 
Study variables: 
Primary variables - Pharmacokinetics: The following safinamide PK parameters will be determined on day 1 
(after the first dose), on day 8 (after the first multiple dose) and on day 14 (after the last dose): 
After single dose and first multiple dose (day 1 and day 8): 
➢ Cmax: maximum safinamide plasma concentration 
➢ tmax: time to achieve Cmax 
➢ AUC0-t: area under the concentration-time curve from single dose administration to the last observed 
concentration time t, calculated with the linear up/log down trapezoidal method 
➢ AUC0-24: area under the concentration-time curve in the tau interval (from single dose administration to 24 h 
post-dose), calculated with the linear up/log down trapezoidal method  


Z7219J03 
 
 
Final v. 2.0; Date 18-APR-2019 
                                                                                          Page 4 of 60 
STUDY SYNOPSIS (cont.) 
 
Study variables, continued: Primary variables - Pharmacokinetics, continued: 
After single dose only (day 1): 
➢ Kel: terminal elimination rate constant, calculated, if feasible, by log-linear regression using at least 3 points 
➢ t1/2: apparent terminal elimination half-life, calculated, if feasible, as ln2/Kel 
➢ AUC0-: 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 
➢ Vd/F: apparent volume of distribution associated with the terminal slope, calculated, if feasible, as 
Dose/(AUC0-∞*Kel) 
➢ Cl/F: apparent total body clearance, calculated, if feasible, as Dose/AUC0-∞ 
➢ MRT: Mean residence time calculated, if feasible, as AUMC0-∞/AUC0-∞, were AUMC0-∞ is area under the 
moment concentration-time curve extrapolated to infinity 
After multiple dose (day 14): 
➢ Cmax_ss: maximum safinamide plasma concentration at steady-state 
➢ tmax_ss: time to achieve Cmax,ss 
➢ Cmin_ss: trough safinamide plasma concentration at steady-state, measured as concentration at 24h 
➢ AUCss0-t: area under the concentration-time curve at steady-state from the last dose administration to the last 
observed concentration time t, calculated with the linear up/log down trapezoidal method 
➢ AUCss0-24: area under the concentration-time curve at steady-state in the tau interval (from the last dose 
administration to 24 h post dose), calculated with the linear up/log down trapezoidal method 
➢ Cave_ss: average safinamide plasma concentration at steady-state, calculated as AUCss0-24 /tau  
➢ R: accumulation ratio, calculated as AUCss0-24/ Day 8 AUC0-24 
➢ DF%: peak-trough fluctuation over one dosing interval at steady-state, calculated as (Cmax,ss - 
Cmin,ss)/Cave,ss*100 
➢ Vd,ss/F: apparent volume of distribution at steady-state associated with the terminal slope, calculated, if 
feasible, as Dose/( AUCss0-24*Kel) 
➢ Cl,ss/F: apparent total body clearance at steady-state, calculated, if feasible, as Dose/ AUCss0-24 
Secondary variables - Safety and tolerability:  
➢ Treatment emergent adverse events, vital signs (blood pressure, heart rate), body weight, physical 
examinations, clinical laboratory parameters, ECG. 
 
Analytics: Plasma samples for safinamide determination will be collected at: 
• pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 36, 48, 72 and 96 h post-dose after the first single dose (day 1) 
and the last multiple dose (day 14);  
• pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose after the first multiple dose (day 8) 
• pre-dose on days 10, 11, 12, 13. 
Analyses will be performed at a certified bioanalytical laboratory (to be designated). The analytical method will 
be detailed in the study analytical plan. Analytical facilities and procedures will be in compliance with the general 
principles of GLP regulations.  
 
Safety evaluation: Safety of the study treatments will be evaluated on the basis of treatment-emergent adverse 
events, clinical safety laboratory tests, vital signs, ECGs, and physical examinations.  
Adverse events will be collected throughout the study. Vital signs will be measured at screening, during the study 
and at final visit or early termination visit (ETV) in case of discontinuation. Physical examinations, ECGs and 
clinical laboratory tests will be performed at screening and final visit/ETV.  
 
Sample size: Twelve (12) healthy male and female Chinese volunteers per cohort (24 in total) will be included in 
the study in order to have at least 8 completers / cohort. Drop-out subjects will not be replaced. 
Since no hypothesis will be tested, no formal sample size calculation has been performed. The sample size of this 
study has been determined in agreement with the guidance issued by the Chinese Food and Drug Administration 
(CFDA) for clinical pharmacokinetic studies (1).  
 
Main selection 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 
 


Z7219J03 
 
 
Final v. 2.0; Date 18-APR-2019 
                                                                                          Page 5 of 60 
STUDY SYNOPSIS (cont.) 
 
Main selection criteria, continued: Inclusion criteria, continued: 
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: 
a. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the 
screening visit 
b. 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 
c. A male sexual partner who agrees to use a male condom with spermicide 
d. 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 HMG-CoA reductase inhibitors in 
the 2 weeks before the screening visit; medicinal products that are BCRP substrates; treatment with morphine 
or other similar opioids, whose concomitant use with MAO-B inhibitors is contraindicated, SSRIs, SNRIs, 
tri- or tetracyclic antidepressant, tramadol, pethidine, dextromethorphan, 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 


Z7219J03 
 
 
Final v. 2.0; Date 18-APR-2019 
                                                                                          Page 6 of 60 
STUDY SYNOPSIS (cont.) 
 
Schedule: 
Procedures and assessments during study visits are listed in the table below: 
 
 
Day 
Procedures/Assessments 
Notes 
Screening – Visit 1 
From  
day -14  
to day -2 
➢ Explanation to the subject of study aims, procedures 
and possible risks 
➢ Informed consent signature 
➢ Subjects' screening number assignment 
➢ Demographic data and life style recording 
➢ Medical/surgical history 
➢ Previous/concomitant medications check 
➢ Full physical examination (body weight, height, vital 
signs, physical abnormalities) 
➢ ECG recording 
➢ Clinical laboratory analyses: haematology, blood 
chemistry, urinalysis, serum virology and serum 
pregnancy test (women) 
➢ Urine multi-drug kit test 
➢ Adverse events check 
➢ Inclusion/exclusion criteria evaluation 
➢ Eligibility evaluation 
 
Period 1 
Cohorts 1 and 2 - Visit 2 
Day -1 
➢ Alcohol breath test 
➢ Urine multi-drug kit test 
➢ Urine pregnancy test (women) 
➢ Inclusion/exclusion criteria evaluation 
➢ Eligibility evaluation 
➢ Enrolment 
➢ Subjects' randomisation number assignment 
➢ Adverse events and concomitant medications check 
Day -1 
Arrival at the clinical 
centre in the evening.  
Confinement until the 
morning 
of 
day 
3. 
Standardized dinner 
Fasting for at least 10 h 
(overnight) 
Period 1 
Cohorts 1 and 2 - Visit 3 
Days 1 - 
3 
Day 1 
➢ Investigational product administration at 08:00 ± 1 h; 
➢ Vital signs measurement at pre-dose and 2 h post-dose 
 
Day 1 - Day 3 
➢ Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 
and 48 h post-dose 
➢ AEs and concomitant medications check 
Day 1 
Standardized lunch at 
approximately 5 h post-
dose.  
Standardized dinner at 
approximately 13 h post-
dose.  
Day 2 
Standardized breakfast, 
lunch and dinner 
Day 3 
Standardized breakfast. 
Discharge 
from 
the 
clinical centre in the 
morning after the 48-h 
blood sampling for PK 
analysis 
 
 


Z7219J03 
 
 
Final v. 2.0; Date 18-APR-2019 
                                                                                          Page 7 of 60 
STUDY SYNOPSIS (cont.) 
 
Study schedule, continued: 
Period 1 
Cohorts 1 and 2 - Visit 4 
Days 4 - 5 
Ambulator
y visits 
Days 4 - 5 
➢ Blood sample collection for pharmacokinetic analysis 
at 72 h (day 4) and 96 h (day 5) post-dose  
➢ AEs and concomitant medications check 
 
Days 5 
➢ Vital signs measurement at 96 h post-dose from Day 1  
 
Days 4 - 5 
The subjects will return 
to the clinical centre 
each day in the morning 
for ambulatory blood 
sampling 
and 
safety 
checks 
Day 5  
Subjects 
will 
be 
reminded to return to the 
clinical centre in the 
morning of day 8 for 
study Period 2. 
A wash-out of 7 days will elapse between the single dose administered on day 1 and the first multiple dose 
administered on day 8 
Period 2 
Cohorts 1 and 2 - Visit 5 
Days 8 -9 
Day 8 - Day 9 
➢ Investigational product administration at 08:00 ± 1 h; 
➢ Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 
h post-dose 
➢ AEs and concomitant medications check 
 
Day 8 only 
➢ Vital signs measurement at pre-dose and 2 h post-dose  
 
Days 8-9 
Subjects 
will 
be 
confined 
from 
the 
morning of day 8 (before 
investigational product 
administration) up to the 
morning of day 9.  
Day 8 
Standardized lunch at 
approximately 5 h post-
dose; 
Standardized 
dinner at approximately 
13 h post-dose  
Day 9 
Standardized breakfast. 
Subjects 
will 
be 
discharged 
in 
the 
morning, after the 24-h 
blood sampling for PK 
analysis standardized. 
Period 2 
Cohorts 1 and 2 - Visit 6 
Days 10 - 
13 
Ambulator
y visits 
Days 10 - 13 
➢ Investigational product administration at 08:00 ± 1 h; 
➢ Blood sample collection for pharmacokinetic analysis 
at pre-dose on each day 
➢ Vital signs measurement before blood sampling and 
investigational product administration 
➢ AEs and concomitant medications check 
Days 10 - 13 
The subjects will return 
to the clinical centre 
each day in the morning 
for ambulatory pre-dose 
blood sampling for PK 
analysis, investigational 
product 
administration 
and safety checks 
 
 
 


Z7219J03 
 
 
Final v. 2.0; Date 18-APR-2019 
                                                                                          Page 8 of 60 
STUDY SYNOPSIS (cont.) 
 
Period 2 
Cohorts 1 and 2 - Visit 7 
Days 14 - 
17 
Day 14 
➢ Investigational product administration at 08:00 ± 1 h; 
➢ Vital signs measurement at pre-dose and 2 h post-dose 
 
Day 14 - Day 17 
➢ Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 
48 and 72 h post-dose 
➢ AEs and concomitant medications check 
Day 14 
Standardized lunch at 
approximately 5 h post-
dose. 
Standardized 
dinner at approximately 
13 h post-dose  
Days 15-16 
Standardized breakfast, 
lunch and dinner. 
Day 17 
Standardized breakfast. 
Discharge 
from 
the 
clinical centre in the 
morning after the 72-h 
blood sampling for PK 
analysis 
Period 2 
Cohorts 1 and 2 - Visit 8 
Day 18 
Ambulator
y visit 
Day 18 
➢ Blood sample collection for pharmacokinetic analysis 
at 96 h post-dose  
➢ Vital signs measurement at 96 h post-dose from Day 
14 
➢ AEs and concomitant medications check 
 
Final visit assessments (see below) and discharge 
Day 18 
The subjects will return 
to the clinical centre in 
the 
morning 
for 
ambulatory 
blood 
sampling 
and 
safety 
checks 
 
Subjects 
will 
be 
discharged after final 
visit assessments (see 
Final visit/ETV below) 
Final Visit/ETV 
Day 18. At 
ETV in 
case of 
early 
terminatio
n 
The following final assessments will be performed after 
the 96-h time-point assessments (day 18) or at ETV in 
case of early discontinuation: 
➢ Physical examination (body weight, physical 
abnormalities)  
➢ ECG recording  
➢ Laboratory analyses: haematology, blood chemistry, 
urinalysis 
➢ Urine pregnancy test (women) 
Vital signs assessments performed at 96 h post-dose on day 
18 will be considered as the final assessment. Vital signs 
will also be measured at ETV, in case of early 
discontinuation. 
AEs and concomitant medications will also be checked at 
final visit/ETV. AEs will be captured up to the end of study 
visit. 
 
In case of clinically significant results at the final visit, the 
subjects will be followed-up by the investigator until the 
normalisation of the concerned clinical parameter(s) 
Upon 
leaving, 
the 
subjects will be instructed 
to contact immediately 
the investigator in case of 
occurrence of any adverse 
reactions 
 
 


Z7219J03 
 
 
Final v. 2.0; Date 18-APR-2019 
                                                                                          Page 9 of 60 
STUDY SYNOPSIS (cont.) 
 
Life style and constraints: 
During the study, the subjects will be confined as follows: 
➢ from the evening preceding the first administration (study day -1) until the morning of day 3.  
➢ from the morning of day 8 to the morning of day 9.  
➢ from the morning of day 14 to the morning of day 17.  
Subjects will be discharged from the study after final assessments, as specified above (Final visit/ETV). 
The subjects will not take any food or drinks (except water) for at least 10 h (i.e. overnight) before investigational 
product administration. On days 1, 8 and 14, subjects will remain fasted up to 5 h post-dose. Standardized meals 
will be served at the clinical centre according to the schedule above. Water will be allowed as desired, except for 
one hour before and one hour after investigational product administration. Coffee, tea or food containing 
xanthines (i.e. coke, chocolate, etc.), alcohol and grapefruit will be forbidden during confinement starting 48 h 
before the first administration until the end of the study. Smoking is not allowed for the whole study duration. 
Routine ambulant daily activities will be strongly recommended. Hazardous, strenuous or athletic activities will 
not be permitted. 
 
Data analysis:  
The data documented in this trial and the clinical parameters measured will be analysed using classic descriptive 
statistics for quantitative variables and frequencies for qualitative variables. 
Analysis set:  
Randomised set: all randomised subjects. This analysis set will be used for demographic, baseline and background 
characteristics 
Safety set: 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. 
PK set: all randomised subjects who fulfil the study protocol requirements in terms of investigational medicinal 
products intake and have evaluable PK data readouts, with no major deviations that may affect the PK results. This 
analysis set will be used for the PK analysis. 
 
Safety Assessments: 
The statistical analysis of demographic and safety data will be performed using SAS®. 
The safety and tolerability of the investigational products will be evaluated on the basis of treatment-emergent 
adverse events occurrence, laboratory tests and other safety assessments (see section above). 
All adverse events, adverse drug reactions (ADR) and serious adverse events (SAEs), if applicable, will be coded 
using the Medical Dictionary for regulatory Activities and summarized by system organ class and preferred term, 
incidence, severity and relationship to study drug. 
Pharmacokinetics: 
The pharmacokinetic parameters will be calculated with a Non-Compartmental Analysis (NCA) using Phoenix 
WinNonlin v6.3 (or higher). Pharmacokinetic data will be listed and summarised by descriptive statistics.  
 
Study duration: 
Maximum study duration for both cohort 1 and 2 will be 32 days including screening period, study Period 1, 
washout and study Period 2. 
 
 
 


Z7219J03 
 
 
Final v. 2.0; Date 18-APR-2019 
 
                                                                                           
 
 
          Page 10 of 60 
2 
STUDY SCHEDULE (A MORE DETAILED TABLE IS SHOWN IN APPENDIX 1) 
 
ACTIVITIES 
 
Period 1 
Period 2 
Final visit/ETV1 
Screening 
Single Dose  
Multiple Dose 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Day 
Day -14/-2 
Day -1 
Day 1/3 
Day 4/5 
Day 8/9 
Day 10/13 
Day 14/17 
Day 18 
Day 182 
Informed consent 
x 
 
 
 
 
 
 
 
 
Demography 
x 
 
 
 
 
 
 
 
 
Lifestyle 
x 
 
 
 
 
 
 
 
 
Medical and surgical history  
x 
 
 
 
 
 
 
 
 
Physical examination3 
x 
 
 
 
 
 
 
 
x 
Prior and concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
x 
 
 
 
 
 
 
 
 
Body Weight3 
x 
 
 
 
 
 
 
 
x 
Laboratory analysis4 
x 
 
 
 
 
 
 
 
x 
Virology 
x 
 
 
 
 
 
 
 
 
Serum pregnancy test (women) 
x 
 
 
 
 
 
 
 
 
Urine multi-drug kit test 
x 
x 
 
 
 
 
 
 
 
Blood pressure and heart rate5 
x 
 
x (Day 1: pre-dose, 
2 hours post-dose) 
x (Day 5: 96 hours 
after Day 1) 
x (Day 8: pre-dose, 2 
hours post-dose) 
x 
x (Day 14: pre-dose, 2 
hours post-dose) 
x (Day 18: 96 hours 
after Day 14) 
x 
Alcohol breath test 
 
x 
 
 
 
 
 
 
 
Urine pregnancy test (women) 
 
x 
 
 
 
 
 
 
x 
ECG6 
x 
 
 
 
 
 
 
 
x 
Inclusion/exclusion criteria  
x 
x 
 
 
 
 
 
 
 
Subject eligibility 
x 
x 
 
 
 
 
 
 
 
Enrolment and randomisation 
 
x 
 
 
 
 
 
 
 
Confinement 
 
x 
x 
 
x 
 
x 
 
 
Discharge 
 
 
x (Day 3) 
 
x (Day 9) 
 
x (Day 17) 
 
 
Ambulatory visits 
 
 
 
x 
 
x 
 
x 
 
Investigational product administration 
 
 
x7 (Day 1) 
 
x7 
x7 
x7 (Day 14) 
 
 
Blood sampling for PK analysis 
 
 
x8 
x8 
x9 
x10 
x8 
x8 
 
Standardized meals11  
 
x 
x 
 
x 
 
x 
 
 
Adverse event monitoring12 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
1. 
Early termination visit (ETV) 
2. 
Final visit on day 18  
3. 
Physical examination, including body weight, at screening and final visit/ETV 
4. 
Laboratory analyses at screening and final visit/ETV  
5. 
At pre-dose, at 2 h and 96 h after day 1 single dose and after day 14 last multiple dose. At pre-dose and 2 h after the day 8 first multiple dose. Before blood sampling and investigational product administration during ambulatory visits 
6. 
At screening and final visit/ETV  
7. 
On day 1 (Period 1) and once daily from day 8 to day 14 (Period 2), at 8:00 ± 1 h 
8. 
At pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 36, 48, 72 and 96 h post-dose after the first single dose (day 1) and the last multiple dose (day 14);  
9. 
At pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose after the first multiple dose (day 8) 
10. 
At pre-dose (0) on each day (day 10-13) 
11. 
Day -1: standardized dinner; 
Day 1, Day 8, Day 14: standardized lunch at approximately 5 h post-dose, standardized dinner at approximately 13 h post-dose;  
Day 2 and Days 15/16: standardized breakfast, lunch and dinner 
Day 3, Day 9, and Day 17: standardized breakfast 
12. 
Adverse events monitored starting at the screening visit, immediately after informed consent, up to the final visit/ETV 
 


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3 
TABLE OF CONTENTS 
 
Page 
CLINICAL TRIAL PROTOCOL 
1 
APPROVAL PAGE 
2 
1 
STUDY SYNOPSIS 
3 
2 
STUDY SCHEDULE (a more detailed table is shown in appendix 1) 
10 
3 
TABLE OF CONTENTS 
11 
4 
INTRODUCTION 
16 
4.1 
Safinamide 
16 
4.1.1 
Background 
16 
4.1.2 
Clinical pharmacology and pharmacokinetics 
16 
4.1.3 
Safety 
16 
4.2 
Study rationale 
17 
4.3 
Risks and benefits 
17 
5 
STUDY OBJECTIVES 
18 
5.1 
Primary end-point 
18 
5.2 
Secondary end-point 
18 
6 
CLINICAL SUPPLIES 
19 
6.1 
Treatment 
19 
6.1.1 
Description of investigational products 
19 
6.1.2 
Dose regimen 
19 
6.1.3 
Route and method of administration 
20 
6.1.4 
Investigational product distribution 
20 
6.2 
Packaging and labelling 
20 
6.3 
Storage conditions 
21 
6.4 
Drug accountability 
21 
7 
INVESTIGATIONAL PLAN 
22 
7.1 
Overall study design 
22 
7.2 
Discussion of design 
22 
8 
STUDY POPULATION 
23 
8.1 
Target population 
23 
8.2 
Inclusion criteria 
23 
8.3 
Exclusion criteria 
23 
8.3.1 
Not allowed treatments 
24 
9 
STUDY SCHEDULE 
26 
9.1 
Study visits and procedures 
26 
9.2 
Diet, lifestyle and study restrictions 
30 
10 
DESCRIPTION OF SPECIFIC PROCEDURES 
31 
10.1 
Physical examination 
31 
10.1.1 
Body weight 
31 
10.1.2 
Vital signs 
31 
10.1.3 
ECGs 
31 
10.2 
Clinical laboratory assays 
31 
10.3 
Sampling for pharmacokinetic analysis 
32 
10.3.1 
Venous blood sampling 
32 
10.3.2 
Analytics 
33 
10.3.3 
Labelling, storage and transport of samples 
33 
10.3.3.1 Samples labelling 
33 
10.3.3.2 Samples storage and transport 
33 
11 
ASSIGNMENT OF STUDY TREATMENT 
34 
11.1 
Randomisation 
34 
11.2 
Treatment allocation 
34 
11.3 
Blinding 
34 
12 
EVALUATION PARAMETERS 
35 
12.1 
Study variables 
35 


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12.1.1 
Primary variables 
35 
12.1.2 
Secondary variables 
35 
12.2 
Pharmacokinetic assessments 
35 
12.2.1 
Pharmacokinetic parameters 
35 
12.3 
Safety assessments 
36 
13 
STATISTICAL METHODS 
37 
13.1 
Analysis Sets 
37 
13.1.1 
Definitions 
37 
13.1.2 
Reasons for exclusion from the PK set 
38 
13.2 
Sample size and power considerations 
38 
13.3 
Demographic, baseline and background characteristics 
38 
13.4 
Analysis of pharmacokinetic parameters 
38 
13.5 
Safety and tolerability evaluation 
39 
13.5.1 
Adverse events 
39 
13.5.2 
Physical examination 
39 
13.5.3 
Laboratory data 
39 
13.5.4 
Vital signs 
39 
13.5.5 
Body weight 
39 
13.5.6 
ECG 
40 
14 
DEFINITION AND HANDLING OF AEs AND SAEs 
41 
14.1 
Applicable SOPs 
41 
14.2 
Definition of Adverse Event (AE) 
41 
14.3 
Definition of Adverse Drug Reaction (ADR) 
41 
14.4 
Definition of Serious Adverse Events or Serious Adverse Drug Reaction 
42 
14.5 
Definition of Severity of Adverse Events 
42 
14.6 
Definition of Adverse Event causality 
42 
14.7 
Adverse Events recording 
43 
14.8 
AEs monitoring window 
43 
14.9 
Adverse Events reporting 
43 
14.9.1 
SAEs reporting 
44 
14.10 
Follow-up for Adverse Events 
44 
14.11 
SUSARs management 
45 
14.12 
Other events qualified for expedited reporting 
45 
14.13 
SAEs: contacts 
46 
14.14 
Pregnancy 
46 
15 
DATA MANAGEMENT PROCEDURES 
46 
15.1 
Data collection – CRFs 
46 
15.2 
Database management 
47 
15.2.1 
Coding dictionaries 
47 
16 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
48 
16.1 
Monitoring 
48 
16.2 
Quality Control and Quality Assurance 
48 
16.3 
Applicable SOPs 
49 
16.4 
Data access 
49 
16.5 
Audits and inspections 
49 
17 
ETHICAL CONSIDERATIONS 
50 
17.1 
Ethics and Good Clinical Practice (GCP) 
50 
17.2 
Informed consent 
50 
17.3 
Insurance policy 
51 
17.4 
Withdrawal of subjects 
51 
17.4.1 
Primary reason for discontinuation 
51 
17.4.2 
Discontinuation procedures 
51 
17.5 
Study termination 
52 
18 
ADMINISTRATIVE PROCEDURES 
53 
18.1 
Material supplied to the clinical centre 
53 
18.2 
Protocol amendments 
53 
18.3 
Study documentation and record keeping 
53 
18.4 
Study subjects’ recruitment 
54 


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18.5 
Confidentiality and data protection 
54 
18.6 
Publication policy 
54 
19 
STUDY RESPONSIBLE PERSONS 
56 
19.1 
Sponsor 
56 
19.2 
Institutes performing the study 
56 
19.2.1 
Clinical centre 
56 
19.3 
Drug assay 
56 
19.4 
Co-ordination, data analysis & reporting 
56 
19.5 
Project Management and Monitoring 
56 
20 
REFERENCES 
57 
21 
APPENDIX 1 
58 
 
 
 
TABLES 
Page 
 
Table 6.1.2.1 
Study dose regimen 
20 
Table 10.3.1.1 
Tolerance ranges for the scheduled sampling times 
33 
 
 


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LIST OF ABBREVIATIONS 
 
-HCG 
human chorionic gonadotropin  
-GT 
-Glutamyl transpeptidase 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALCOAC 
Attributable-Legible-Contemporaneous-Original-Accurate-Complete 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC0-t 
Area under the concentration-time curve from time zero to time t 
AUCss0-t or AUC0-t,ss 
Area under the concentration-time curve at steady state 
AUC0- 
Area under the concentration vs. time curve up to infinity 
AUC0-24h 
Area under the concentration-time curve in the tau interval  
AUCss0-24 or AUC0-24h,ss 
Area under the concentration-time curve at steady state in the tau interval 
BUN 
BCRP 
Blood Urea Nitrogen 
Breast Cancer Resistance Protein 
BLQL 
Below Lower Quantification Limit 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CA 
Competent Authority 
CDISC 
Clinical Data Interchange Standards Consortium 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
Cl/F 
Apparent total body clearance 
Cave_ss 
Average drug concentration at steady state 
Cmax 
Maximum drug concentration 
Cmax_ss 
Maximum drug concentration at steady state 
Cmix_ss 
Trough drug concentration at steady state 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CS 
Clinically Significant 
CV 
Coefficient of Variation 
DF% 
Peak-trough fluctuation over one dosing interval at steady-state 
DBP 
Diastolic Blood Pressure 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
ETV 
Early Termination Visit 
FDA 
Food and Drug Administration 
FSFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBs Ag 
Hepatitis B virus surface antigen 
HCV Ab 
Hepatitis C virus antibodies 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IUD 
Intra-Uterine Device 
Kel 
Terminal elimination rate constant 
LLOQ 
LQL 
Lower Limit of Quantification 
Lower Quantification Limit 
LSLV 
Last Subject Last Visit 
MAO 
Monoamino oxidase 
MCH 
Mean Cell Haemoglobin 
MCHC 
Mean Cell Haemoglobin Concentration 


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MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
MW 
Molecular Weight 
N 
Normal 
NA 
Not Applicable 
NC 
Not calculated 
NCS 
Not clinically significant 
OTC 
Over The Counter 
PD 
Parkinson’s disease 
PK 
Pharmacokinetics 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
Racc 
Accumulation ratio 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SmPC 
Summary of Product Characteristics 
SNRI 
Serotonin–norepinephrine reuptake inhibitors 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SSRI 
Selective serotonin reuptake inhibitors 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T 
Test 
T1 
Xadago® 50 mg 
T2 
Xadago® 50 mg 
TEAE 
Treatment-Emergent Adverse Event 
THC 
Delta-9-tetrahydrocannabinol 
t1/2 
Apparent terminal elimination half-life 
tmax 
Time to achieve Cmax 
Vd/F 
Apparent volume of distribution associated with the terminal slope 
WBC 
White Blood Cells 
WHODDE 
World Health Organisation Drug Dictionary Enhanced 
 
 
 


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4 
INTRODUCTION 
 
4.1 
Safinamide 
 
4.1.1 
Background 
 
The -aminoamide derivative safinamide [(S)-(+)-2-[4-(3-fluorobenzyloxy) benzylamino] 
propanamide], developed as methane sulfonate salt, is an original anticonvulsant and 
antiparkinson agent which has been granted marketing authorisation in 9 EU Member States 
(i.e. Germany, Italy, Spain, Portugal, United Kingdom, Belgium, The Netherlands, Sweden and 
Denmark), in Norway and in Switzerland under the brand name of Xadago®, 50 and 100 mg, 
film-coated tablets (2), for the treatment of adult patients with idiopathic Parkinson’s disease 
(PD) as add-on therapy to a stable dose of Levodopa (L-dopa) alone or in combination with 
other PD medicinal product in mid-to late-stage fluctuating patients (3).  
 
Safinamide uniquely combines potent, selective and reversible inhibition of monoamino 
oxidase B (MAO-B) with blockade of voltage-dependant Na+ and Ca2+ channels and inhibition 
of glutamate release (4,8), thus showing a novel mode of action, targeting both dopaminergic 
and glutaminergic systems (9,10).  
Data from Phase III clinical studies gave evidence that safinamide 50 or 100 mg/day improves 
the motor function in Parkinson’s disease when prescribed as add-on therapy to dopamine 
agonists or L-dopa (3).  
 
4.1.2 
Clinical pharmacology and pharmacokinetics 
 
Safinamide pharmacokinetics after single and multiple dose administrations have been 
described (11,12). At single ascending oral doses ranging from 2.5 to 10.0 mg/kg, safinamide 
was absorbed in a linear and dose-proportional fashion. Peak plasma levels were obtained on 
average at 1.8 to 2.8 h post-dose. Concentrations declined with a terminal half-life of 20 - 23h 
(11,12). Absolute bioavailability is high (95%), showing that safinamide is almost completely 
absorbed after oral administration and first pass metabolism is negligible (SmPC, 3). A 
complete long-lasting inhibition of platelet MAO-B activity was observed at all doses tested. 
Food intake prolonged the rate but did not affect the extent of safinamide absorption (11,12). 
Studies in healthy volunteers (13,15) demonstrated that safinamide does not affect oral tyramine 
metabolism mostly mediated by the intestinal MAO-A, and confirm that it can be administered 
without tyramine-related dietary restrictions. 
 
4.1.3 
Safety 
 
The overall safety profile of Xadago® is based on the clinical development program performed 
on over 3000 subjects, of which over 600 were treated for more than 2 years. 
 
The most common side effects related to safinamide are dyskinesia, somnolence, dizziness, 
headache, insomnia, nausea and orthostatic hypotension. Serious adverse reactions, such as 
hypertensive crisis (high blood pressure, collapse), neuroleptic malignant syndrome (confusion, 
sweating, muscle rigidity, hyperthermia, CPK increase), serotonin syndrome (confusion, 
hypertension, muscle stiffness, hallucinations), and hypotension, are known to occur with the 
concomitant use of SSRIs, SNRIs, tricyclic/tetracyclic antidepressants and MAO inhibitors. 


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With MAO-inhibitors there have been reports of drug interactions with concomitant use of 
sympathomimetic medicinal products. Impulse control disorders, pathological gambling, 
increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive 
eating can occur in patients treated with dopamine agonists and/or other dopaminergic 
treatments.  
 
A complete list of adverse reactions observed with safinamide is presented in the SmPC (3). 
 
4.2 
Study rationale 
 
The present study will be part of safinamide registration package in China and was designed 
according to CFDA guideline recommendations (1). 
Safinamide has been granted marketing authorization in EU (2015), US (2017) and Switzerland 
(2015).   
In the present study, safinamide pharmacokinetic profile, safety and tolerability after single 
dose and at steady state will be investigated for the first time in Chinese healthy male and female 
volunteers.  
 
4.3 
Risks and benefits 
 
For AEs occurred with safinamide in previous clinical studies, please refer to § 4.1.3 and the 
SmPC (3). The most common side effects are dyskinesia, somnolence, dizziness, headache, 
insomnia, nausea and orthostatic hypotension. 
 
Based on the clinical experience, no particular risks are expected for the study subjects 
considering safinamide 50 mg and 100 mg multiple dose administrations. 
 
 
 


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5 
STUDY OBJECTIVES 
 
The objective of the study is to evaluate safinamide pharmacokinetic profile, safety and 
tolerability after single and multiple dose administration to healthy adult Chinese volunteers 
 
5.1 
Primary end-point 
 
➢ To evaluate plasma safinamide pharmacokinetic parameters after single and multiple dose 
administration of the investigational products.  
 
5.2 
Secondary end-point 
 
➢ To collect safety and tolerability data after single and multiple dose administration of the 
investigational products. 
 


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6 
CLINICAL SUPPLIES 
 
6.1 
Treatment 
 
6.1.1 
Description of investigational products 
 
TEST PRODUCT 1 (T1) 
 
Name 
Xadago® 50 mg film-coated tablets 
Active ingredient 
Safinamide methanesulphonate (corresponding to 50 mg 
safinamide) 
Marketing Authorization 
Holder 
Zambon S.p.A., Italy 
Pharmaceutical form 
Film-coated tablets 
Dose 
Single 50 mg dose on day 1 
Multiple 50 mg doses, once daily, for 7 days 
Administration route 
Oral 
 
 
TEST PRODUCT 2 (T2) 
 
Name 
Xadago® 100 mg film-coated tablets 
Active ingredient 
Safinamide methanesulphonate (corresponding to 100 mg 
safinamide) 
Marketing Authorization 
Holder 
Zambon S.p.A., Italy 
Pharmaceutical form 
Film-coated tablets 
Dose 
Single 100 mg dose on day 1 
Multiple 100 mg doses, once daily, for 7 days 
Administration route 
Oral 
 
6.1.2 
Dose regimen 
 
Subjects will be randomised to 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), according 
to the study randomised, parallel-group design, as follows: 
 
➢ Cohort 1: One (1) safinamide 50 mg film-coated tablet will be administered on day 1 
followed by 7 safinamide 50 mg film-coated tablets administered o.d. from day 8 to day 
14. 
 
➢ Cohort 2: One (1) safinamide 100 mg film-coated tablet will be administered on day 1 
followed by 7 safinamide 100 mg film-coated tablets administered o.d. from day 8 to day 
14. 
 
 


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Dose regimens are also summarised in the scheme below: 
 
Table 6.1.2.1 Study dose regimen 
Cohort 
Period 1 - single dose 
Day 1 
Washout 
Period 2 - Multiple doses 
Days 8 - 14 
Cohort 1 
50 mg po 
7 days 
50 mg po o.d for 7 days 
Cohort 2 
100 mg po 
100 mg po o.d. for 7 days 
 
6.1.3 
Route and method of administration 
 
The investigational products will be orally administered in the morning, at 8:00±1h, 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. 
 
6.1.4 
Investigational product distribution 
 
All doses of the investigational products will be administered at the clinical centre by the 
investigator or by his/her deputy. The investigational products will be exclusively used for the 
present clinical study and will only be administered to the subjects enrolled in the study.  
 
6.2 
Packaging and labelling 
 
Packaging and labelling for the clinical study will be performed by a GMP compliant vendor, 
delegated by Zambon S.p.A., Italy. 
 
Subjects' kit labelling will report all the information according to the Annex 13 to the Good 
Manufacturing Practice (published by the Commission in The rules governing medicinal 
products in the European Community, Volume 4, 16), as follows: 
a. 
Name, address and telephone number of the sponsor, contract research organisation or 
investigator (the main contact for information on the product, clinical study) 
b. Pharmaceutical dosage form, route of administration, quantity of dosage units, and the 
name/identifier and strength/potency 
c. 
The batch and/or code number to identify the contents and packaging operation 
d. A study reference code allowing identification of the study, site, investigator and sponsor 
if not given elsewhere 
e. 
A blank space for subject enrolment Nr. (to be reported by hand by the Investigator) and 
where relevant, the visit number 
f. 
The name of the investigator (if not included in (a) or (d)) 
g. Directions for use (reference may be made to a leaflet or other explanatory document 
intended for the study subject or person administering the product) 
h. “For clinical study use only” or similar wording 


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i. 
The storage conditions 
j. 
Period of use (use-by date, expiry date or re-test date as applicable), in month/year format 
and in a manner that avoids any ambiguity 
k. “Keep out of reach of children” 
 
The label will be in Chinese language. 
 
6.3 
Storage conditions 
 
The investigational products will be stored at ≤ 25° C in a dry locked place, sheltered from light.  
 
6.4 
Drug accountability 
 
The vendor delegated by Zambon S.p.A., Italy, will provide the clinical centre with a sufficient 
number of individual subject kits to conduct the study, plus sufficient reserve kits.  
 
After receipt of the drug supply, the Pharmacist will confirm in writing by signing and dating 
standard drug accountability forms. At the end of the study, the drug product will be maintained 
in the original containers. 
 
At the end of the study, used, unused and partially used supplies of the investigational products, 
provided by the vendor delegated by Zambon S.p.A., Italy, will be stored as detailed in § 6.3 
above and then disposed of (upon sponsor written authorisation), after assessment of drug 
accountability. 
 
 
 


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7 
INVESTIGATIONAL PLAN 
 
7.1 
Overall study design 
 
Phase I, single centre, single and multiple-dose, open-label, randomised, parallel-group, 
pharmacokinetics, safety and tolerability clinical study. 
 
7.2 
Discussion of design 
 
Following a specific request of CFDA, the present study will be part of safinamide registration 
package in China and was designed according to CFDA guideline recommendations (1). 
 
Safinamide has recently been granted marketing authorization in EU, Norway and Switzerland 
on the basis of the results of clinical trials performed in European countries. In the present study, 
safinamide pharmacokinetic profile, safety and tolerability after single dose and at steady state 
will be investigated for the first time in Chinese healthy male and female volunteers.  
 
Two single doses (i.e. 50 and 100 mg) of safinamide will be administered to two subject' cohorts. 
The study will continue with multiple administrations of safinamide 50 and 100 mg, orally 
taken once a day for 7 days. 
 
The 50 and 100 mg oral doses have been selected according to the common clinical practice 
(see Xadago® SmPC). These doses were investigated in the previously performed Phase III 
clinical trials. The volunteers will be assigned to the two cohorts according to the study 
randomised, parallel-group design. 
 
Safinamide pharmacokinetic profile will be investigated after single dose, according to CFDA 
guidance requirements, and at steady state since multiple doses are administered in the clinical 
practice. Safinamide steady state should be reached after 5 or 6 days of treatment (day 13-14 in 
this study). Safinamide pre-dose concentrations will be assessed before the last 5 doses (days 
10-14).  
 
An open design was chosen. However, no bias on study outcome is expected considering that 
the study PK endpoints are based on the objective measurement of safinamide in plasma.  
Blood sampling time-points were selected on the basis of the known PK profile of safinamide. 
The sampling time lasts for about 4-7 elimination half-lives (mean PK half-life: 20-23 h) after 
both single dose and the last multiple dose administration. 
 
 


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8 
STUDY POPULATION 
 
8.1 
Target population 
 
Twenty-four (24) healthy male and female Chinese volunteers, aged 18-45 years inclusive, will 
be enrolled into the study. 
 
8.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfil all these 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: 
a. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 
2 months before the screening visit 
b. 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 
c. A male sexual partner who agrees to use a male condom with spermicide 
d. 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. 
 
8.3 
Exclusion criteria 
 
Subjects meeting any of these criteria will not be enrolled in the study: 
 
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 


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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 HMG-CoA reductase inhibitors in the 2 weeks before the screening visit; medicinal 
products that are BCRP substrates; treatment with morphine or other similar opioids, whose 
concomitant use with MAO-B inhibitors is contraindicated, SSRIs, SNRIs, tri- or tetracyclic 
antidepressant, tramadol, pethidine, dextromethorphan, 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 
 
8.3.1 
Not allowed treatments 
 
No medication, including OTC, herbal remedies and traditional Chinese remedies, will be 
allowed for 2 weeks before the start of the study and during the whole study duration. 
 
Statins and HMG-CoA reductase inhibitors use will not be allowed for 2 weeks before and 
during the study. Wash-out interval for the treatment with morphine or other similar opioids, 


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whose concomitant use with MAO-B inhibitors is contraindicated, SSRIs, SNRIs, tri- or 
tetracyclic antidepressant, tramadol, pethidine, dextromethorphan, MAO inhibitors (e.g. 
selegiline), meperidine derivatives, antiepileptic drugs and the treatment with any known 
enzyme inhibiting or inducing agent or any investigational drugs intake will be at least 4 weeks 
before the screening visit. Hormonal contraceptives are allowed. 
 
Paracetamol will be allowed as therapeutic counter-measure for adverse events (AEs) according 
to the investigator’s opinion. The intake of any other medication will be reported as a protocol 
deviation. However, it will lead to subject's discontinuation from the study only if the 
investigator, together with the sponsor, considers it could affect the study assessments or 
outcome. 
 
 
 


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9 
STUDY SCHEDULE 
 
The schedule of the study is summarised at page 10. 
 
9.1 
Study visits and procedures 
 
Each study subject completing the study will undergo 8 visits plus a final visit. 
 
The study protocol foresees 2 periods: in the first one the investigational products are 
administered in single dose, in the second one in multiple doses. The single dose in the first 
period and the first dose in the second period are separated by a wash-out interval of 7 days. 
Maximum and minimum study duration will be 32 and 20 days, respectively, screening visit 
included. 
 
The first subject first visit (FSFV) is defined as the 1st visit performed at the clinical centre by 
the 1st screened subject. The last subject last visit (LSLV) is defined as the last visit performed 
at the clinical centre (or a telephonic follow-up, if applicable) by the last subject, i.e. the last 
visit foreseen by the study protocol, independently of the fact that the subject is a completer or 
a withdrawn subject. 
 
The following phases, visits and procedures will be performed: 
 
➢ Screening phase 
▪ Screening – visit 1: between day -14 and day -2 
▪ Period 1 – visit 2: day -1 
 
➢ Interventional phase 
▪ Period 1 – visit 3: days 1-3: single dose and blood sampling for PK analysis 
▪ Period 1 – visit 4: days 4-5: ambulatory visits - blood sampling for PK analysis 
▪ Wash-out interval of 7 days 
▪ Period 2 – visit 5: days 8-9: first multiple dose and blood sampling for PK analysis 
▪ Period 2 – visit 6: days 10-13: ambulatory visits - multiple doses and blood sampling 
for PK analysis 
▪ Period 2 - visit 7: days 14-17: last multiple dose and blood sampling for PK analysis 
▪ Period 2 - visit 8: day 18: blood sampling for PK analysis 
 
➢ Final phase 
▪ Final visit/early termination visit (ETV). In case of early discontinuation, discontinued 
subjects will undergo an early termination visit (ETV) 
 
 
 


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Study schedule 
 
 
Day 
Procedures/Assessments 
Notes 
Screening – Visit 1 
From day -14 
to day -2 
➢ Explanation to the subject of study aims, procedures 
and possible risks 
➢ Informed consent signature 
➢ Subjects' screening number assignment 
➢ Demographic data and life style recording 
➢ Medical/surgical history 
➢ Previous/concomitant medications check 
➢ Full physical examination (body weight, height, vital 
signs, physical abnormalities) 
➢ ECG recording 
➢ Clinical laboratory analyses: haematology, blood 
chemistry, urinalysis, serum virology and serum 
pregnancy test (women) 
➢ Urine multi-drug kit test 
➢ Adverse events check 
➢ Inclusion/exclusion criteria evaluation 
➢ Eligibility evaluation 
 
Period 1 
Cohorts 1 and 2 - Visit 2 
Day -1 
➢ Alcohol breath test 
➢ Urine multi-drug kit test 
➢ Urine pregnancy test (women) 
➢ Inclusion/exclusion criteria evaluation 
➢ Eligibility evaluation 
➢ Enrolment 
➢ Subjects' randomisation number assignment 
➢ Adverse events and concomitant medications check 
Day -1 
Arrival at the clinical 
centre in the evening  
Confinement until the 
morning 
of 
day 
3.  
Standardized dinner 
Fasting for at least 10 h 
(overnight) 
Period 1 
Cohorts 1 and 2 - Visit 3 
Days 1 - 3 
Day 1 
➢ Investigational product administration at 08:00 ± 1 h; 
➢ Vital signs measurement at pre-dose and 2 h post-dose 
 
Day 1 - Day 3 
➢ Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 
and 48 h post-dose 
➢ AEs and concomitant medications check 
Day 1 
Standardized lunch at 
approximately 5 h post-
dose.  
Standardized dinner at 
approximately 13 h post-
dose  
Day 2 
Standardized breakfast, 
lunch and dinner 
Day 3 
Standardized breakfast. 
Discharge 
from 
the 
clinical centre in the 
morning after the 48-h 
blood sampling for PK 
analysis 
 
 
 


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Study schedule, continued 
 
Period 1 
Cohorts 1 and 2 - Visit 4 
Days 4 - 5 
Ambulatory 
visits 
Days 4 - 5 
➢ Blood sample collection for pharmacokinetic analysis 
at 72 h (day 4) and 96 h (day 5) post-dose  
➢ AEs and concomitant medications check 
 
Days 5 
➢ Vital signs measurement at 96 h post-dose from Day 
1  
Days 4 - 5 
The subjects will return 
to the clinical centre 
each day in the morning 
for ambulatory blood 
sampling 
and 
safety 
checks 
Day 5  
Subjects 
will 
be 
reminded to return to the 
clinical centre in the 
morning of day 8 for 
study Period 2. 
A wash-out of at least 7 days will elapse between the single dose administered on day 1 and the first multiple 
dose administered on day 8 
Period 2 
Cohorts 1 and 2 - Visit 5 
Days 8 -9 
Day 8 - Day 9 
➢ Investigational product administration at 08:00 ± 1 h; 
➢ Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 
h post-dose 
➢ AEs and concomitant medications check 
 
Day 8 only 
➢ Vital signs measurement at pre-dose and 2 h post-
dose  
 
Days 8-9 
Subjects 
will 
be 
confined 
from 
the 
morning of day 8 (before 
investigational product 
administration) up to the 
morning of day 9.  
Day 8 
Standardized lunch at 
approximately 5 h post-
dose; 
Standardized 
dinner at approximately 
13 h post-dose  
Day 9 
Standardized breakfast. 
Subjects 
will 
be 
discharged 
in 
the 
morning, after the 24-h 
blood sampling for PK 
analysis 
Period 2 
Cohorts 1 and 2 - Visit 6 
Days 10 - 
13 
Ambulatory 
visits 
Days 10 - 13 
➢ Investigational product administration at 08:00 ± 1 h; 
➢ Blood sample collection for pharmacokinetic analysis 
at pre-dose on each day 
➢ Vital signs measurement before blood sampling and 
investigational product administration 
➢ AEs and concomitant medications check 
Days 10 - 13 
The subjects will return 
to the clinical centre 
each day in the morning 
for ambulatory pre-dose 
blood sampling for PK 
analysis, investigational 
product 
administration 
and safety checks 
 
 
 


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Study schedule, continued 
 
Period 2 
Cohorts 1 and 2 - Visit 7 
Days 14 - 17 
Day 14 
➢ Investigational product administration at 08:00 ± 1 h; 
➢ Vital signs measurement at pre-dose and 2 h post-dose 
 
Day 14 - Day 17 
➢ Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 
48 and 72 h post-dose 
➢ AEs and concomitant medications check 
Day 14 
Standardized lunch at 
approximately 5 h post-
dose. 
Standardized 
dinner at approximately 
13 h post-dose  
Days 15-16 
Standardized breakfast, 
lunch and dinner. 
Day 17 
Standardized breakfast. 
Discharge 
from 
the 
clinical centre in the 
morning after the 72-h 
blood sampling for PK 
analysis 
Period 2 
Cohorts 1 and 2 - Visit 8 
Day 18 
Ambulatory 
visit 
Day 18 
➢ Blood sample collection for pharmacokinetic analysis 
at 96 h post-dose  
➢ Vital signs measurement at 96 h post-dose from Day 
14 
➢ AEs and concomitant medications check 
 
Final visit assessments (see below) and discharge 
Day 18 
The subjects will return 
to the clinical centre in 
the 
morning 
for 
ambulatory 
blood 
sampling 
and 
safety 
checks. 
 
Subjects 
will 
be 
discharged after final 
visit assessments (see 
Final visit/ETV below) 
Final Visit/ETV 
Day 18. At 
ETV in case 
of early 
termination 
The following final assessments will be performed after 
the 96-h time-point assessments (day 18) or at ETV in 
case of early discontinuation: 
➢ Physical examination (body weight, physical 
abnormalities)  
➢ ECG recording  
➢ Laboratory analyses: haematology, blood chemistry, 
urinalysis 
➢ Urine pregnancy test (women) 
Vital signs assessments performed at 96 h post-dose on day 
18 will be considered as the final assessment. Vital signs 
will also be measured at ETV, in case of early 
discontinuation. 
AEs and concomitant medications will also be checked at 
final visit/ETV. AEs will be captured up to the end of study 
visit. 
 
In case of clinically significant results at the final visit, the 
subjects will be followed-up by the investigator until the 
normalisation of the concerned clinical parameter(s) 
Upon 
leaving, 
the 
subjects will be instructed 
to contact immediately 
the investigator in case of 
occurrence of any adverse 
reactions 
 
 
 


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9.2 
Diet, lifestyle and study restrictions 
 
During the study, the subjects will be confined at the clinical centre as follows: 
 
Period 1: 
• 
from the evening preceding the first administration (study day -1) until the morning of day 
3.  
 
Period 2: 
• 
from the morning of day 8 to the morning of day 9.  
• 
from the morning of day 14 to the morning of day 17.  
 
Subjects will be discharged from the study after final assessments (Final visit or ETV). 
 
The subjects will not take any food or drinks (except water) for at least 10 h (i.e. overnight) 
before investigational product administration. On days 1, 8 and 14, subjects will remain under 
fasting conditions up to 5 h post-dose.  
Standardized meals will be served at the clinical centre according to the schedule below: 
 
• 
Day -1: standardized dinner; 
• 
Day 1, Day 8, Day 14: standardized lunch at approximately 5 h post-dose, standardized 
dinner at approximately 13 h post-dose;  
• 
Day 2 and Days 15/16: standardized breakfast, lunch and dinner 
• 
Day 3, Day 9 and Days 17: standardized breakfast 
 
Water will be allowed as desired, except for 1 h before and 1 h after investigational product 
administration. Coffee, tea or food containing xanthines (i.e. coke, chocolate, etc.), alcohol and 
grapefruit will be forbidden during confinement starting 48 h before the first administration 
until the end of the study. Smoking is not allowed for the whole study duration. 
 
Routine ambulant daily activities will be strongly recommended. Hazardous, strenuous or 
athletic activities will not be permitted. 


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10 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
10.1 
Physical examination 
 
Full physical examinations will be performed at screening and final visit/ETV. Date of the 
physical examination, overall investigator’s interpretation (as normal or abnormal and, if 
abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be reported in the individual CRFs. 
All clinically significant abnormalities after the screening visit will be recorded as AEs. 
 
10.1.1 
Body weight 
 
Body weight will be recorded at screening and final visit/ETV. 
Subjects will be weighed (kg) lightly clothed without shoes. Height will be measured at 
screening only and Body Mass Index (BMI) will be recorded. BMI will be calculated as weight 
[kg]/(height [m] x height [m]). 
 
10.1.2 
Vital signs 
 
Subjects' blood pressure and heart rate will be measured by the investigator or his deputy after 
5 min at rest (sitting/supine position) at the following times:  
➢ at screening 
➢ on day 1, day 8 and day 14: at pre-dose and 2 h post-dose 
➢ on day 5 and day 18: at 96 h post-dose 
➢ on days 10-13: at pre-dose 
➢ at ETV (if applicable). 
 
10.1.3 
ECGs 
 
12-Leads ECGs will be performed (supine position) at screening and final visit/ETV. 
 
Date/time of the ECG recording, overall investigator's interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be reported in the individual CRFs. All clinically significant 
abnormalities after the screening visit will be recorded as AEs. Hard copies of the ECGs will 
be attached as source document at site. 
 
10.2 
Clinical laboratory assays 
 
Samples of blood and urine will be collected. The following laboratory analyses will be 
performed at the screening visit: 
 
HAEMATOLOGY 
Leukocytes and leukocyte differential count (percentage values and absolute values), 
erythrocytes, haemoglobin (conv. units), haematocrit, MCV, MCH, MCHC, thrombocytes. 
 


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BLOOD CHEMISTRY 
Electrolytes: sodium, potassium, calcium, chloride, inorganic phosphorus 
Enzymes: alkaline phosphatase, γ-GT, AST, ALT 
Substrates/metabolites: total bilirubin, creatinine, glucose, urea or BUN, uric acid, total 
cholesterol, triglycerides 
Proteins: total proteins 
 
Serum pregnancy test (women). 
 
URINE ANALYSIS 
Urinalysis: pH, specific gravity, appearance, colour, nitrites, proteins, glucose, urobilinogen, 
bilirubin, ketones, leukocytes, erythrocytes, flat cells, crystals, cylinders.  
 
SERUM VIROLOGY  
Hepatitis B (HBs antigen), Hepatitis C (HCV antibodies), HIV 1/2 (HIV Ag/Ab combo).  
 
A urine drug test will be performed at the clinical centre at screening, using a urine multi-drug 
kit. The following drugs will be assessed: cocaine, amphetamine, morphine, cannabis, 
benzodiazepines, barbital.  
 
A serum pregnancy test will be performed by the laboratory at screening, as listed above. Urine 
pregnancy test will be performed on day -1 of each study period at the clinical centre and at the 
final visit/ETV.  
 
The same analyses, with the exception of urine drug test and virology, will be performed at the 
final visit/ETV. 
 
Date/time of samples collection, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
findings (if any) will be reported in the individual eCRFs. All clinically significant 
abnormalities after the screening visit will be recorded as AEs. 
 
10.3 
Sampling for pharmacokinetic analysis 
 
10.3.1 
Venous blood sampling 
 
Venous blood samples (up to 10 mL) will be collected from a forearm vein at the following 
times:  
 
➢ At pre-dose (0 h), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h post-dose after 
the first single dose (days 1-5) and the last multiple dose (days 14-18) 
➢ At pre-dose on days 10-13 
➢ At pre-dose (0 h) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose after the first 
multiple dose (days 8-9) 
 
Actual sampling times for each subject will be recorded in the individual CRFs. The actual 
sampling times should not exceed the recommended tolerance ranges presented in the following 
table. Any deviation outside the recommended ranges will be verified through Data 


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Clarification Forms and, if confirmed, will be reported as protocol deviation, although it will 
not automatically lead to the exclusion of the concerned subjects from the PK set. 
 
Table 10.3.1.1 
Tolerance ranges for the scheduled sampling times 
Sampling time 
Tolerance range 
Pre-dose (0) 
Within 30 minutes before  
investigational product administration 
0.5 h (30 min) 
± 1 min 
1, 1.5 h 
± 3 min 
2, 3, 4 h 
± 5 min 
6, 8, 12, 16, 24, 36, 48, 72, 96 h   
± 10 min 
 
Blood samples for PK analysis will be collected using an indwelling catheter with switch valve. 
The cannula will be rinsed, after each sampling, with about 1 mL of sterile saline solution 
containing 20 I.U./mL Na-heparin. The first 2 mL of blood will be discarded at each collection 
time to avoid contamination of the sample with heparin. 
 
The remaining 8 mL will be collected from the catheter and transferred with a syringe into 
heparinised tubes (Li-heparin). 
Samples handling and processing is described in study specific lab manual.  
 
10.3.2 
Analytics  
 
The concentration of safinamide in plasma samples will be determined at a certified analytical 
laboratory (to be designated). Analyses will be performed according to the general Principles 
of “OECD Good Laboratory Practices for testing of chemicals" C(81) 30 (final) and GCP. 
 
The method validation report and the analytical report will be attached to the final report. 
 
10.3.3 
Labelling, storage and transport of samples 
 
10.3.3.1 
Samples labelling 
 
Labels and labelling process are described in the study specific lab manual.  
 
10.3.3.2 
Samples storage and transport 
 
During the study the samples will be stored at ≤- 70° C. At the end of each collection day, 
aliquots 1 and 2 will be stored in separate freezers. 
 
All aliquots 1, packed in sufficient dry ice, will be shipped by an authorised courier from the 
clinical centre (China) to the analytical laboratory.  
 
 


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11 
ASSIGNMENT OF STUDY TREATMENT 
 
11.1 
Randomisation 
 
Randomisation will be used to minimize bias in the assignment of subjects to treatment cohorts, 
to increase the likelihood that known and unknown subject attributes (e.g., demographic and 
baseline characteristics) will be evenly balanced across treatment cohorts. 
The randomisation schedule will be computer-generated by the CRO biostatistician using SAS®. 
The randomisation schedule will be attached to the final clinical study report. 
 
11.2 
Treatment allocation 
 
Subjects will be randomised to 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), according 
to the study randomised, parallel-group design. 
 
On day -1, Period 1, subjects will be assigned a randomisation number, which will be used to 
assign the study treatment according to the randomisation schedule, as detailed above. 
Subjects who prematurely discontinue participation after randomisation will not be replaced. 
 
11.3 
Blinding 
 
This is an open study. No masking procedure will be applied.  
The open label design is considered appropriate for the primary objective of pharmacokinetic 
characterization, because PK properties and assessments are not prone to bias of observation 
by the investigators or the subjects. 


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12 
EVALUATION PARAMETERS 
 
12.1 
Study variables 
 
12.1.1 
Primary variables 
 
The following safinamide PK parameters will be determined on day 1 (after the first dose), on 
day 8 (after the first multiple dose) and on day 14 (after the last dose): 
 
After single dose and first multiple dose (day 1 and day 8) 
➢ Cmax, tmax, AUC0-t, and AUC0-24h 
 
After single dose only (day 1): 
➢ Kel, t1/2, AUC0-, Vd/F, Cl/F and MRT 
 
After multiple dose (day 14): 
➢ Cmax_ss, tmax_ss, Cmin_ss, AUC0-t,ss, AUC0-24h,ss, Cave_ss, Racc, DF%, Vd,ss/F and Cl,ss/F 
 
12.1.2 
Secondary variables 
 
➢ Treatment emergent adverse events (TEAEs), vital signs (blood pressure, heart rate), 
body weight, physical examinations, clinical laboratory parameters, ECG. 
 
12.2 
Pharmacokinetic assessments 
 
12.2.1 
Pharmacokinetic parameters 
 
The following safinamide PK parameters will be measured and/or calculated with a Non-
Compartmental Analysis (NCA) using Phoenix WinNonlin v6.3 (or higher). 
 
After single dose and first multiple dose (day 1 and day 8): 
Cmax: 
Maximum safinamide plasma concentration 
tmax: 
Time to achieve Cmax 
AUC0-t: 
Area under the concentration-time curve from single dose administration to the 
last quantifiable concentration time t 
AUC0-24h: 
Area under the concentration-time curve in the tau interval (from single dose 
administration to 24 h post dose) 
 
After single dose (day 1): 
Kel: 
Apparent terminal elimination rate constant, calculated, if feasible, from the 
slope of a log-linear regression using at least 3 last concentration > LLOQ 
points 
t1/2: 
Apparent terminal elimination half-life, calculated, if feasible, as ln2/Kel 
AUC0-: 
Area under the concentration-time curve extrapolated to infinity, calculated, if 
feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration 
Vd/F: 
Apparent volume of distribution associated with the terminal slope, calculated, 
if feasible, as Dose/(AUC0-∞*Kel) 


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Cl/F: 
Apparent total body clearance, calculated, if feasible, as Dose/AUC0-∞ 
MRT: 
Mean residence time, calculated, if feasible, as AUMC0-∞/AUC0-∞, were 
AUMC0-∞ is area under the moment concentration-time curve extrapolated to 
infinity 
 
The sampling schedule is considered adequate if the ratio AUC0-t/AUC0- equals or exceeds a 
factor of 0.8 (i.e. if %AUCextra is <20%) for more than 80% of the individual PK profiles. This 
assures that AUC0-t covers a sufficient percentage of the theoretical total extent of exposure.  
 
The quality of log-linear regression (and, consequently, the reliability of the extrapolated PK 
parameters) should be demonstrated by a determination coefficient R2 ≥ 0.8. Individual 
extrapolated parameters, when considered unreliable, will be reported as NC (not calculated).  
 
After multiple dose (day 14): 
Cmax_ss: 
Maximum safinamide plasma concentration at steady state 
tmax_ss: 
Time to achieve Cmax-ss 
AUC0-t,ss: 
Area under the concentration-time curve at steady state from the last dose 
administration to the last quantifiable concentration time t 
AUC0-24h,ss: Area under the concentration-time curve at steady state in the tau interval (from 
the last dose administration to 24 h post dose) 
Cave_ss: 
Average safinamide plasma concentration at steady state, calculated as AUC0-
24h,ss  /tau (24 h) 
Racc: 
Accumulation ratio, calculated as AUC0-24h,ss/ AUC0-24h 
DF%: 
Peak-trough fluctuation over one dosing interval at steady-state, calculated as 
(Cmax,ss - Cmin,ss)/Cave,ss*100 
Vd,/Fss 
apparent volume of distribution at steady-state associated with the terminal 
slope, calculated, if feasible, as Dose/( AUC0-24h,ss*Kel) 
Cl,/Fss 
apparent total body clearance at steady-state, calculated, if feasible, as Dose/ 
AUC0-24h,ss 
 
12.3 
Safety assessments 
 
Safety and general tolerability of the investigational products will be based on TEAEs, physical 
examinations, including body weight, vital signs, ECGs and routine haematology, blood 
chemistry and urinalysis laboratory tests. 
 


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13 
STATISTICAL METHODS 
 
The data documented in this study and the parameters measured will be evaluated using classic 
descriptive statistics, i.e. geometric mean, geometric CV (%) (PK data only), arithmetic mean, 
SD, CV (%), minimum, median and maximum values for quantitative variables, and 
frequencies for qualitative variables. 
 
Not available data will be evaluated as “missing values”. The statistical analysis of demographic 
and safety data will be performed using Statistical Analysis Software (SAS®) Version 9.3 or 
higher. 
The pharmacokinetic parameters will be calculated using the actual recoded sampling times and 
non-compartmental methods with Phoenix WinNonlin (Version 6.3 or higher). 
 
13.1 
Analysis Sets 
 
13.1.1 
Definitions 
 
A subject will be defined as screened after the signature of the informed consent, regardless of 
the completion of all the screening procedures. 
A subject will be defined as eligible if he/she meets all the inclusion criteria and not meet any 
exclusion criteria. Otherwise he/she will be defined as a screen failure.  
 
A subject will be defined as enrolled in the study if he/she is included into the interventional 
phase of the study. The enrolment will be performed through randomised allocation to a 
treatment cohort. An eligible but not enrolled subject will be defined as a reserve. 
A subject will be defined as randomised in the study when he/she is assigned to a randomised 
treatment cohort. 
 
The following analysis sets will be considered: 
 
➢ Randomised set: all randomised subjects. This analysis set will be used for demographic, 
baseline and background characteristics. 
➢ Safety set: 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.  
➢ PK set: all randomised subjects who fulfil the study protocol requirements in terms of 
investigational medicinal products intake and have evaluable PK data readouts, with no 
major deviations that may affect the PK results. This analysis set will be used for the PK 
analysis. 
 
Each subject will be coded as valid or not valid for the Randomised set, Safety set and PK set. 
Subjects will be evaluated according to the treatment they actually receive. 
 
 


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13.1.2 
Reasons for exclusion from the PK set 
 
Reasons for the exclusion of subjects from the PK set are the following: 
 
Before bioanalysis 
➢ vomiting and diarrhoea after drug intake which could render the plasma concentration-time 
profile unreliable 
➢ intake of concomitant medications which could render the plasma concentration-time 
profile unreliable 
➢ AEs which could render the plasma concentration-time profile unreliable 
➢ administration errors which could render the plasma concentration-time profile unreliable 
➢ other events which could render the plasma concentration-time profile unreliable 
If one of these events occurs, it will be noted in the CRF as the study is being conducted. 
 
After bioanalysis 
 
Exclusion of subjects on the basis of pharmacokinetic reasons is possible only for: 
➢ subjects with non-zero baseline concentrations > 5% of Cmax for single dose and first 
multiple dose (day 1 and day 8) 
The samples from the subjects excluded from the PK set should still be assayed and the results 
listed. Subjects should not be excluded from the PK set if the AUC0-t covers less than 80% of 
the AUC0-∞. 
Any data excluded will be discussed in the CSR. 
 
13.2 
Sample size and power considerations 
 
Twelve (12) healthy male and female Chinese volunteers / cohort (24 in total) will be included 
in the study in order to have at least 8 completers / cohort. Drop-out subjects will not be replaced. 
Since no hypothesis will be tested, no formal sample size calculation has been performed. The 
sample size of this study has been determined in agreement with the guidance issued by the 
Chinese Food and Drug Administration (CFDA) for clinical pharmacokinetic studies (1). 
 
13.3 
Demographic, baseline and background characteristics 
 
Demographic and background characteristics will be examined according to qualitative or 
quantitative data. Qualitative data will be summarised in contingency tables. Quantitative data 
will be summarised using classic descriptive statistics. The baseline will be the last pre-dose 
measurement. 
 
13.4 
Analysis of pharmacokinetic parameters 
 
A descriptive PK will be presented. The results will be displayed and summarised in tables and 
figures. Individual and mean curves (+SD at nominal times), indicating inter-subject variability, 
will be plotted. Data below the lower limit of quantification (BLQ) will be 


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considered as 0 in the calculations and presented as BLQ in listings and tables. As a 
consequence of BLQ (i.e. 0) values, calculated geometric means (if requested) could be null. 
For this reason, in the presence of any null value, the geometric mean will be reported as not 
calculated (NC). 
 
13.5 
Safety and tolerability evaluation 
 
13.5.1 
Adverse events 
 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT), 
using the Medical Dictionary for Regulatory Activities (MedDRA). 
AEs will be classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs), 
according to the period of occurrence, as follows:  
➢ PTAEs: all AEs occurring before the first dose of investigational product and not 
worsening after the first dose of investigational product.  
➢ TEAEs: all AEs occurring or worsening after the first dose of investigational product 
 
Individual PTAEs and TEAEs will be listed in subject data listings. No summary table will be 
provided for PTAEs. TEAEs will be summarised by treatment and overall. The number and 
percentage of subjects with any TEAE and the number of TEAEs will be tabulated by SOC and 
PT, seriousness, relationship with investigational product and severity.  
 
13.5.2 
Physical examination 
 
Date of the physical examination, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be listed. 
 
13.5.3 
Laboratory data  
 
Date/time of samples collection, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
findings (if any) will be listed. All laboratory results will be listed and a table of all the abnormal 
values will be presented. 
 
13.5.4 
Vital signs 
 
Vital signs values will be listed and summarised by descriptive statistics. 
 
13.5.5 
Body weight  
 
Body weight values will be listed and summarised by descriptive statistics. 
 
 


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13.5.6 
ECG 
 
Date/time of ECG recording, overall investigator’s interpretation (as normal or abnormal and, 
if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be listed. Hard copies of the ECGs will be attached as source 
document at site.  


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14 
DEFINITION AND HANDLING OF AEs AND SAEs 
 
14.1 
Applicable SOPs 
 
AEs definition, classification and management will follow the CRO’s SOPs, based upon 
applicable local and international regulations. The full SOPs or an operative summary will be 
made available in the CRO. 
 
A brief summary of AE definition, classification and management is reported below. 
 
14.2 
Definition of Adverse Event (AE) 
 
An Adverse Event is “any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment”. 
AEs include: 
➢ worsening (change in nature, severity or frequency) of conditions present at the onset 
of the trial 
➢ patient/subject deterioration due to the primary illness 
➢ intercurrent illnesses 
➢ drug interactions 
➢ events related or possibly related to concomitant medications 
➢ abnormal laboratory values, as well as significant shifts from baseline within the range 
of normal, which the investigator considers to be clinically significant. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not considered related to the investigational 
medicinal product. 
 
14.3 
Definition of Adverse Drug Reaction (ADR) 
 
An Adverse Reaction is “any untoward and unintended response to an investigational 
medicinal product related to any dose administered”. 
All AEs judged by either the reporting investigator or the sponsor as having a reasonable causal 
relationship to a medicinal product qualify as adverse reactions. The expression reasonable 
causal relationship means to convey in general that there is evidence or matter to suggest a 
causal relationship. 
 
➢ Unexpected Adverse Drug Reaction 
 
An unexpected ADR is: “An adverse reaction, the nature, or severity of which is not consistent 
with the applicable product information (Reference Safety Information [RSI]).  
 
➢ Reference Safety Information (RSI): in order to assess whether an adverse reaction is 
expected, the SmPC will be used. 


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14.4 
Definition of Serious Adverse Events or Serious Adverse Drug Reaction 
 
A Serious Adverse Event (SAE) is: “any untoward medical occurrence or effect that at any 
dose: 
➢ results in death 
➢ is life-threatening (i.e. the subject was at risk of death at the time of the event/reaction; it 
does not refer to an event/reaction which hypothetically might have caused death if it were 
more severe) 
➢ requires inpatient hospitalization or prolongation of existing hospitalization 
➢ results in persistent or significant disability/incapacity (where disability is defined as a 
permanent or substantial disruption of ability to carry out normal life functions, either 
reported or defined as per clinical judgement) 
➢ is a congenital anomaly/birth defect 
➢ is an important medical event that may not result in death, be life-threatening, or require 
hospitalization but, according to appropriate medical judgment, it may jeopardize the 
subject and may require medical or surgical intervention to prevent any of the outcomes 
listed in the definition above.  Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, and blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.  
 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse event. 
 
A Serious Adverse Drug Reaction (SADR) is an ADR that meets also the definition of SAE.  
 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is an ADR that is both 
unexpected (not consistent with the applicable product information, e.g. SmPC) and also meets 
the definition of a SAE. 
 
A non-serious adverse event is any adverse event that does not meet the criteria listed above for 
a serious adverse event. 
 
 
14.5 
Definition of Severity of Adverse Events 
 
The term “severe” is used to describe the intensity (severity) of a specific event: 
- 
Mild: causing no limitation of usual activities; the subject may experience slight 
discomfort. 
- 
Moderate: causing some limitation of usual activities; the subject may experience 
annoying discomfort. 
- 
Severe: causing inability to carry out usual activities; the subject may experience 
intolerable discomfort or pain. 
 
14.6 
Definition of Adverse Event causality 
 


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Causality shall be determined according to the definition of ADR given in 14.3. 
 
All AE judged by either the investigator or the sponsor as having a reasonable suspected causal 
relationship to an investigational medicinal product qualify as adverse reactions. The causality 
assessment given by the investigator should not be downgraded by the sponsor. 
 
The following binary decision for causality will be used: 
▪ Reasonable possibility that the IMP caused the event 
▪ No reasonable possibility that the IMP caused the event 
Features supportive of an association include: 
• temporal plausibility 
• pharmacological properties of the drug or of the substance class 
• course of the adverse event after dechallenge and, if applicable, after rechallenge 
• specific tests indicating involvement of the drug in the occurrence/worsening of the 
adverse event  
• alternative explanations 
 
14.7 
Adverse Events recording 
 
Each AE occurring to a subject, either spontaneously revealed by the subject or observed by 
the investigator, whether believed by the investigator to be related or unrelated to the IMP, must 
be recorded on the AE information page of the CRF (for SAEs information must be recorded 
also on the “Serious Adverse Event Form”).  
The Investigator will also perform an evaluation with respect to seriousness and causality 
(relationship of any AE to IMP) of the AEs. and record it on the appropriate section of the CRF 
and on the “Serious Adverse Event Form” (if appropriate).  
 
14.8 
AEs monitoring window 
 
➢ Start of monitoring: from immediately after the signature of the informed consent 
➢ End of monitoring: up to final study visit/ETV (observation window)  
An AE occurring after the final visit/ETV and coming to knowledge of the investigator (e.g. 
during a follow-up assessment or by spontaneous reporting by study subjects) must be recorded 
only if it is an ADR, according to the investigator’s judgment. 
 
14.9 
Adverse Events reporting 
 
The official language for reporting is English. The investigator and clinical staff of the present 
study are familiar with English language. 
 
The investigator must report to the CRO all AEs which occur during the study, regardless of 
their relationship to the IMP. Protocol specific AEs or laboratory abnormalities critical to safety 


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evaluations are to be identified in the protocol and reported to the sponsor according to reporting 
requirements and within the time periods specified. 
 
All AEs are recorded by the investigator on the AE information page of the CRF. 
 
In addition, SAE will have to be reported according to the following detailed procedure. 
 
14.9.1 
SAEs reporting 
 
The investigator must report the SAEs to the CRO no later than 24 hours from when he/she 
becomes aware of the SAE, by Electronic Data Capture (preferred method), or e-mailing as 
scanned attachment (back up plan) or by faxing the “Serious Adverse Event Form” (back up 
plan) to the CRO,  as stated in the "List of CRO/ personnel" in § 14.13 of this protocol. 
 
The standards of confidentiality must always be maintained and any relevant national 
legislation on data protection must be followed. 
 
Another copy of the “Serious Adverse Event Form” will be sent to the Medical Affairs/Clinical 
Operations for the Sponsor’s file and another copy will be retained by the Investigator for the 
Investigator’s file. 
 
 
If the investigator becomes aware of any SAE occurred to a subject within the follow-up 
window established in the protocol, he/she will report the SAE as above. The SAE will be also 
reported in the CRF. 
 
If outside the follow-up window established in the protocol the investigator becomes aware of 
a SAE, if the investigator judges that the SAE is related to the study drug, it should be reported 
to the Sponsor. The Investigator might use the “Serious Adverse Event Form” via email or fax, 
but the SAE must not to be reported in the CRF, as it is not an event occurred within the study 
period. 
 
The investigator must report all SAEs that occur to the subjects to National Medical Products 
Administration/Local Ethics Committee/Provincial Food and Drug Administration/National 
Health and Family Planning Commission immediately no later than 24hours from when he/she 
becomes aware of SAE. Any SAEs that happen to the subjects outside the follow-up window 
should be reported by investigator to National Medical Products Administration/Local Ethics 
Committee/Provincial Food and Drug Administration/National Health and Family Planning 
Commission immediately. 
 
14.10 
Follow-up for Adverse Events 
 
A follow-up “Serious Adverse Event Form” will be filled in if important follow-up information 
(i.e. diagnosis, outcome, causality assessment, results of specific investigations) is made 
available after submission of the initial AE Form for immediate reporting. Follow-up “Serious 
Adverse Event Form” will be reported to the Sponsor as above-described, under Section 14.9.1. 
 


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In any case of an AE that, in the opinion of the investigator, requires the subject’s 
discontinuation, follow-up information relating to the subject’s subsequent course must be 
collected until the event has subsided or the condition stabilised or when the subject is lost to 
follow up or death. 
 
When follow-up data on non-serious AE are collected, information should be reported under 
“Comments” in the Final report of the CRF. 
 
14.11 
SUSARs management 
 
The clock for initial expedited reporting starts as soon as the information containing the 
minimum reporting criteria has been received by the CRO/sponsor (day 0).  
Fatal and life-threatening SUSARs, should be reported to Competent Authority as soon as 
possible and in any case within 7 days and to Ethics Committee per the requirement. 
If the initial report is incomplete, e.g. not all the information/assessments were available, a 
complete report should be sent within an additional 8 days. Complete follow-up report should 
be sent within 15 calendar days. 
SUSARs which are not fatal and not life-threatening are to be reported to Competent Authority 
within 15 days and to Ethics Committee per the requirement. 
The minimum information to be reported includes: 
➢ Sponsor study number 
➢ One identifiable coded subject 
➢ One identifiable reporter 
➢ One SUSAR 
➢ One suspect IMP (including active substance name, code) 
➢ A causality assessment. 
 
14.12 
Other events qualified for expedited reporting 
 
Other safety issues also qualify for expedited reporting may be sent to Competent authority 
when they might materially alter the current benefit-risk assessment of a medicinal product or 
would be sufficient to consider changes in the medicinal product administration or in the overall 
conduct of the trial, for instance: 
➢ single case reports of an expected serious adverse reaction with an unexpected outcome 
(e.g. a fatal outcome) 
➢ an increase in the rate of occurrence of an expected serious adverse reaction, which is 
judged to be clinically important. 
➢ post-study SUSARs that occur after the subject has completed a clinical trial and are 
reported to the investigator by the subject. 
➢ new events relating to the conduct of the trial or the development of the medicinal 
product likely to affect the safety of the subjects, such as : 
− a SAE which could be associated with the trial procedures and which could modify 
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 a significant hazard to the subject population such as lack of efficacy of a medicinal 
product used for the treatment of a life-threatening disease 
 a major safety finding from a newly completed animal study (such as carcinogenicity) 
or from other clinical trials. 
 
14.13 
SAEs: contacts 
 
The investigator will report any SAE to the CRO. The CRO’s details for SAEs are the 
following: 
Email:
 
 
The sponsor’s details for SAEs are the following: 
Phone: 
 
Fax: 
 
Email: 
 
 
14.14 
Pregnancy 
 
Subjects must be instructed that known or suspected pregnancy occurring during the study 
should be confirmed and reported to the Investigator, who must then withdraw the subject from 
the study without delay. The Investigator should also be notified of pregnancy occurring during 
the study but confirmed after its completion. In the event that a subject is subsequently found 
to be pregnant after inclusion in the study, then any pregnancy will be followed up to the end 
of pregnancy or pregnancy termination and the status of mother and child will be reported to 
the Sponsor after delivery through the Pregnancy Report Form provided by the Sponsor. The 
Investigator will send pregnancy reports to DSU within the timeframes of SAEs, with follow-
up information to be actively sought for the outcome of pregnancy.  
- 
Part I of the Form is completed at the time of awareness of foetal exposure during 
pregnancy.  
- 
Part II of the Form is filled in when information on pregnancy outcome becomes available. 
If pregnancy results in abnormal outcome (spontaneous miscarriage, stillbirth and congenital 
anomalies) will be considered as SAE. If the investigator considers this to be due to the IMP, 
this will be treated as an expedited ADR report. 
 
15 
DATA MANAGEMENT PROCEDURES 
 
15.1 
Data collection – CRFs 
 
The investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the eCRFs. He/she must also check that the data reported in the eCRFs correspond 
to those in the subject’s source documents.  
ECG and laboratory results must be printed and signed by the Investigator and kept as source 
data on site after entering outcome into the eCRF. 
All other data has to be documented in the subject file as source data first and then entered into 
the eCRF.  
Data must be entered into eCRFs in English by the designated site personnel as soon as possible 
after a subject visit, and monitors will have access to data recorded. These data will be reviewed 
PPD
PPD
PPD
PPD


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versus source documents by trial monitors for completeness and acceptability during 
monitoring visits.  
If data correction is required for an eCRF after initial entry, the site personnel can make 
necessary corrections on their own or as a response to an automated query by the eCRF system. 
Monitor and Clinical Data Manager review the eCRF for accuracy and can also generate queries 
to the investigational staff for resolution.  
Any correction to the eCRFs' entries must be carried out by the Investigator or a designated 
member of staff. Corrections are recorded in an audit trail that records the old information, the 
new information, and identification of the person making the changes, date of correction made 
and reason for change. In the interests of completeness of data acquisition, the questions which 
are repeated in each section of the eCRFs should be answered in full, even if there are no 
changes from a previous examination. A reasonable explanation must be given by the 
Investigator for all missing data. The Investigator or his/her designees named in the clinical 
staff list will review the eCRF for accuracy and completeness. The Investigator must 
electronically sign and date the eCRF pages as indicated. 
 
15.2 
Database management 
 
The CRO will update and verify the database and create the final SAS data sets. The final data 
file will be transferred to the sponsor in the agreed format with all the other study documentation. 
 
15.2.1 
Coding dictionaries 
 
Medical/surgical history and underlying diseases, clinically significant physical examination 
abnormalities, AEs and previous and concomitant medications will be coded. 
Information on coding dictionaries will be provided in a Data Management Plan. 
 


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16 
STUDY MONITORING, QUALITY CONTROL AND 
QUALITY ASSURANCE 
 
16.1 
Monitoring 
 
The monitoring visits will be conducted by personnel of the CRO, PAREXEL.  
 
Monitoring activities, including monitoring purpose, selection and qualifications of monitors, 
extent and nature of monitoring, monitoring procedures, monitoring reports will comply with 
ICH-GCP chapter 5.18 requirements, CFDA-GCP and the monitoring plan. 
 
Adequate time and availability for monitoring activities should be ensured by the investigator 
and key study personnel. 
 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the investigator will assure support to the monitor at all times. 
 
The investigator agrees, by written consent to this protocol, to fully co-operate with compliance 
checks by allowing authorised individuals to have access to all the study documentation. In 
addition to the monitoring activities performed by the study monitor, the sponsor could perform 
some quality control activities to verify the compliance with the study procedures and the ICH-
GCP and CFDA-GCP guidelines 
 
16.2 
Quality Control and Quality Assurance  
 
The CRO has implemented and maintains a Quality System that includes quality controls and 
audits at different study steps with written SOPs to ensure that the study is conducted in 
compliance with the protocol and all effective amendments, ICH-GCP and CFDA-GCP, and 
the applicable regulatory requirement(s) and that data have been reliably and correctly 
generated, recorded, processed and reported, in agreement with the ALCOAC principles 
(Attributable-Legible-Contemporaneous-Original-Accurate-Complete). 
 
The clinical site(s) is responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, documented 
(recorded), and reported in compliance with the protocol, ICH-GCP, CFDA GCP and any 
applicable regulatory requirement(s). 
 
This protocol has been audited by the Sponsor QA.   
 
The CROs and the sponsor will be responsible for their respective activities. 
 
The sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a CRO, 
but the ultimate responsibility for the quality and integrity of the trial data always resides with 
the sponsor. 
 
 


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16.3 
Applicable SOPs 
 
The sponsor, the clinical centre and the CRO will follow their respective SOPs in the conduct 
of the respective activities, unless otherwise stated in written agreements. SOPs will be made 
available for Sponsor review, if required. 
 
16.4 
Data access 
 
The investigator and the CRO(s) will ensure that all source data, medical records, CRFs and all 
other documentation that is relevant to this study will be made accessible for monitoring 
activities, audits, IEC review, and regulatory inspections. 
 
16.5 
Audits and inspections 
 
The sponsors, independent bodies acting on behalf of the sponsor and the CRO have the right 
to perform audits according to ICH-GCP and CFDA responsibilities. 
 
The study may also be inspected by regulatory authorities.  
 
The investigator(s) and the CRO(s) agree, by written consent to this protocol, to fully co-operate 
and support audits and inspections compliance checks by allowing authorised individuals to 
have access to all the study documentation. 
 
 
 


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17 
ETHICAL CONSIDERATIONS 
 
17.1 
Ethics and Good Clinical Practice (GCP) 
 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
 
The approval of the study protocol by the relevant Ethics Committee will be obtained before 
the start of the study. 
Study notification to the Competent Authorities will be performed according to the current local 
regulations. 
 
The present clinical study will be carried out according to the current revision of Good Clinical 
Practice (GCP), ICH topic E6 (R2), CFDA Reg No. 25 “Good Clinical Practice (GCP) Mar 23, 
2016 and the applicable local law requirements. 
 
17.2 
Informed consent 
 
Before being enrolled into the clinical study, the subjects must have expressed their consent to 
participate, after the investigator has explained to them, clearly and in details, the scope, the 
procedures and the possible consequences of the clinical study. Information will be given in 
both oral and written form. The information sheet and informed consent form will be prepared 
in the local language by the CRO and must be approved by the EC and regulatory authorities. 
The document will include all the elements required by law according to the ICH-GCP 
recommendations.  
In addition to the standard requirements that physicians are currently obliged to observe when 
providing information, the following points must also be covered: 
➢ a description of the aims of the study and how it will be organised 
➢ the type of treatment (information on the IMP(s) and treatment procedures, as applicable) 
➢ any potential negative effects attributable to the study product or treatment 
➢ the freedom to ask for further information at any time 
➢ the subjects’ right to withdraw from the clinical study at any time without giving reasons 
and without jeopardising their further course of medical treatment  
➢ the existence of a subject insurance cover and obligations following from this cover 
 
Adequate time and opportunity to satisfy questions will be given to the subjects and the time 
will be recorded. 
 
The investigator will be supplied with an adequate number of blank informed consent forms to 
be used. The forms will be signed and dated by both the investigator and the subject.  
A copy of the signed form will be given to the subject. 
 
To ensure medical confidentiality and data protection, the signed informed consent forms will 
be stored in the investigator's study file according to the regulatory requirements. The 
investigator will allow inspection of the forms by authorised representatives of the sponsor, EC 


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members and regulatory authorities. He/she will confirm, by signing and dating the forms, that 
informed consent has been obtained. 
 
17.3 
Insurance policy 
 
An insurance cover has been issued in favour of the subjects participating in this clinical study. 
The insurance is in compliance with the local regulation and with the requirements of the Health 
Authorities. 
 
17.4 
Withdrawal of subjects 
 
It will be documented whether or not each subject completed the clinical study. If, for a subject, 
study treatment or observations are discontinued, the primary reason for discontinuation will 
be recorded. 
 
17.4.1 
Primary reason for discontinuation 
 
➢ Adverse event: Any (significant) adverse event that in the opinion of the investigator or 
concerned subject is not compatible with study continuation. For the definition of AE, 
please refer to § 14. 
➢ death: the absence of life or state of being dead 
➢ lost to follow-up: the loss or lack of continuation of a subject to follow-up 
➢ non-compliance with study drug: an indication that a subject has not agreed with or 
followed the instructions related to the study medication 
➢ physician decision: a position, opinion or judgment reached after consideration by a 
physician with reference to the subject 
➢ pregnancy: pregnancy is the state or condition of having a developing embryo or foetus in 
the body (uterus), after union of an ovum and spermatozoon, during the period from 
conception to birth 
➢ protocol deviation: an event or decision that stands in contrast to the guidelines set out by 
the protocol 
➢ study terminated by sponsor: an indication that a clinical study was stopped by its sponsor 
➢ technical problems: a problem with some technical aspect of a clinical study, usually 
related to an instrument 
➢ withdrawal by subject: study discontinuation requested by a subject for whatever reason 
➢ other: different than the ones previously specified 
 
17.4.2 
Discontinuation procedures 
 
For any subject discontinuing the study, the investigator will:  
➢ ask the subject to undergo, as far as possible, a final medical visit (ETV) to examine the 
subject's health conditions and perform the required blood sampling for the laboratory 


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assays. This examination will verify that all values tested at screening have remained within 
a clinically acceptable range (i.e. not clinically significant changes compared to screening) 
➢ arrange for alternative medical care of the withdrawn subject, if necessary 
➢ record the subject decision about the use of collected biological samples 
➢ report in the CRF date and time of the last dose administration, and date and primary reason 
of study discontinuation 
➢ record in the CRF any follow-up, if the subject is withdrawn for an AE 
 
Discontinued subjects will not be replaced.  
 
17.5 
Study termination 
 
The study will be considered terminated at the date of the last visit of the last subject or upon 
completion of any follow-up procedure described in the protocol. The investigator and the 
sponsor have the right to discontinue the study at any time for reasonable medical and/or 
administrative reasons. As far as possible, this should occur after mutual consultation. Reasons 
for discontinuation have to be documented appropriately. 


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18 
ADMINISTRATIVE PROCEDURES 
 
18.1 
Material supplied to the clinical centre 
 
Beside the investigational products, the following study material will be supplied to the clinical 
centre: 
➢ final version of the study protocol 
➢ access to the eCRF 
➢ copy of the SmPC relative to the investigational products 
➢ informed consent forms 
➢ investigator site file 
➢ laboratory supplies 
Moreover, before the start of the study, the investigator(s) will be provided with the following 
documents: ICH guidelines, confidentiality agreement (if applicable), protocol amendments (if 
any), declaration of Helsinki, insurance statement, SAE forms, financial agreement (if 
applicable), confidential subject identification code list form, drug accountability forms, 
investigator and study staff list form. 
 
18.2 
Protocol amendments 
 
In order to obtain interpretable results, neither the investigator nor the sponsor will alter the 
study conditions agreed upon and set out in this protocol. Amendments should be made by 
mutual agreement between the investigator and the sponsor. Any amendment must be set out 
in writing, giving the reasons, and being signed by all concerned parties. The amendment 
becomes then part of the protocol. 
 
All substantial amendments will be sent to the EC and concerned Competent Authorities, as 
appropriate. The amendment will be applicable only when it is approved, unless the changes 
consist of urgent safety measures to protect study subjects. 
 
Non-substantial amendments will be notified according to the current local regulations. 
 
18.3 
Study documentation and record keeping 
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the sponsor in the CRFs and in all required reports. 
 
The investigator must keep source documents for each subject in the study. Information present 
on the CRFs must be traceable to these source documents, which are generally stored in the 
subject's medical file. The source documents should contain all demographic and medical 
information, including laboratory data, ECGs, etc., and the original signed informed consent 
forms. 
 
Data reported on the CRF that are derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 


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The investigator and the sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirement(s).  
 
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are not 
limited to, study protocol, amendments, submission and approval of EC, raw data of subjects 
including lab tests and ECG tracing, insurance contracts, certificate of analysis of the IMP(s), 
drug accountability records, signed informed consent forms, confidential subjects identification 
code, CRFs, curricula vitae of the investigator and other participants in the study, study staff 
lists and responsibilities, monitoring reports and final study report. 
 
The investigator and the sponsor should take measures to prevent accidental or premature 
destruction of these documents. 
 
Study documents must be retained by the investigator and the sponsor as long as needed to 
comply with ICH-GCP, CFDA GCP national and international regulations. By signing the 
protocol, the investigator and the sponsor agree to adhere to these requirements. 
 
18.4 
Study subjects’ recruitment 
 
The CRO and its clinical site have detailed SOPs on the recruitment process. 
 
18.5 
Confidentiality and data protection 
 
By signing this protocol, the investigator agrees to keep all the information provided by the 
sponsor in strict confidentiality and to request the same confidentiality from his/her staff. Study 
documents provided by the sponsor (protocols, CRFs and other materials) will be stored 
appropriately to ensure confidentiality. The information provided by the sponsor to the 
investigator cannot be disclosed to others without direct written authorisation from the sponsor, 
except for the extent necessary to obtain the informed consent from the subjects wishing to 
participate in the study. 
 
Subjects data collected in the eCRFs during the study will be documented in an anonymous 
way. If, as an exception, for safety or regulatory reasons identification of a subject becomes 
necessary, the monitor, the sponsor and the investigator will be bound to keep this information 
confidential. 
 
18.6 
Publication policy 
 
The Investigator agrees to inform Zambon in advance about his/her intention to divulge any 
data, results concerning the Confidential Information and/or the study patient to this Agreement. 
As a consequence hereof, the Investigator hereby undertakes to submit to Zambon, at least with 
a sixty (60) days (30 in case of abstracts) prior written notice, the text and or the content of the 
concerned publication, divulgation as to allow Zambon to assess properly that such proposed 
publication respects and/or is not in conflict with Zambon’s rights to preserve and protect its 


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intellectual property rights and any confidentiality imposed to Zambon by the prevailing rules 
of the country where the study is conducted. 
Furthermore, without any prejudice to the Investigator’s right to divulge and save for what 
stated hereinabove, the Investigator intends to seek Zambon opinion and advice on and prior to 
the intended publication and/or disclosure, in consideration also of the contractual relationship 
in force between Zambon and Investigator and the nature of the study hereto. 
 
 


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19 
STUDY RESPONSIBLE PERSONS 
 
19.1 
Sponsor 
 
Zambon S.p.A., via Lillo del Duca 10, 20091 Bresso (Milan), Italy 
Phone: 
 
Fax: 
 
 
Protocol Review Committee Chairman  
, 
 
 
Medical Expert 
, 
 
 
19.2 
Institutes performing the study 
 
19.2.1 
Clinical centre 
 
"Denomination"  Address XXXXXXX, "Zip" "City", China 
Phone: 
+00.nnnnnnnnn 
Fax: 
+00.nnnnnnnnn 
Email: 
"Email"@"Specify".com 
 
Principal investigator 
"SpecifyName", MD 
 
19.3 
Drug assay 
 
Analytical Facility for PK/drug assay: 
 
United-Power Pharma Tech Co., Ltd. (UP-Pharma) 
Building 30, Lane 908, Ziping Road, Pudong New Area, Shanghai, P.R.China 
ZIP Code: 201318 
 
Analytical facilities and procedures are in compliance with the general principles of GLP 
regulations. 
 
19.4 
Co-ordination, data analysis & reporting 
 
PAREXEL International (IRL) Limited (“PAREXEL”), a corporation organized under the 
laws of Ireland with a registered address at 70 Sir John Rogerson’s Quay, Dublin 2, Ireland. 
 
19.5 
Project Management and Monitoring 
 
PAREXEL International (IRL) Limited (“PAREXEL”), a corporation organized under the 
laws of Ireland with a registered address at 70 Sir John Rogerson’s Quay, Dublin 2, Ireland. 
 
PPD
PPD
PPD
PPD
PPD
PPD


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Final v. 2.0; Date 18-Apr-2019                                                                                           Page 57 of 60 
20 
REFERENCES 
 
1. CFDA Guidance 
2. EMA Commission Implementing Decision C (2015) 1390 (final)  – Xadago (safinamide). 24 February 2015 
3. Summary of Product Characteristics (SmPC) – Xadago 50 mg, 100 mg film-coated tablets 
4. Caccia C, Maj R, Calabresi M, Maestroni S, Faravelli L, Curatolo L, Salvati P, Fariello RG. Safinamide: from 
molecular targets to a new anti-Parkinson drug. Neurology. 2006 Oct 10;67(7 Suppl 2):S18-23. 
5. Schapira AH. Monoamine oxidase B inhibitors for the treatment of Parkinson's disease: a review of 
symptomatic and potential disease-modifying effects. CNS Drugs. 2011 Dec 1;25(12):1061-71 
6. Salvati P, Maj R, Caccia C, Cervini MA, Fornaretto MG, Lamberti E, Pevarello P, Skeen GA, White HS, 
Wolf HH, Faravelli L, Mazzanti M, Mancinelli E, Varasi M, Fariello RG. Biochemical and 
electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound. J 
Pharmacol Exp Ther. 1999 Mar;288(3):1151-1159. 
7. Pevarello P, Amici R, Bonsignori A, Caccia C, Amici R, McArthur RA, Fariello RG, Salvati P, Varasi M. 
Sodium channel activity and sigma binding of 2-aminopropanamide anticonvulsivants. Bioorg Med Chem 
Lett. 1999 Sep 6;9(17):2521-4. 
8. Binda C, Milczek EM, Bonivento D, Wang J, Mattevi A, Edmondson DE. Lights and shadows on monoamine 
oxidase inhibition in neuroprotective pharmacological therapies. Curr Top Med Chem. 2011 
Nov;11(22):2788-96. Review. 
9. Schapira AH. Safinamide in the treatment of Parkinson's disease. Expert Opin Pharmacother. 2010 
Sep;11(13):2261-8 
10. Onofrj M, Bonanni L, Thomas A. An expert opinion on safinamide in Parkinson's disease. Expert Opin 
Investig Drugs. 2008 Jul;17(7):1115-25 
11. Marzo A, Dal Bo L, Monti NC, Crivelli F, Ismaili S, Caccia C, Cattaneo C, Fariello RG. Pharmacokinetics 
and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity. 
Pharmacol Res 2004; 50(1):77-85 
12. Leuratti C, Sardina M, Ventura P, Assandri A, Müller M, Brunner M. Disposition and metabolism of 
safinamide, a novel drug for Parkinson's disease, in healthy male volunteers. Pharmacology. 2013;92(3-
4):207-16 
13. Marquet A, Kupas K, Johne A, Astruc B, Patat A, Krösser S, Kovar A. The effect of safinamide, a novel drug 
for Parkinson's disease, on pressor response to oral tyramine: a randomized, double-blind, clinical trial. Clin 
Pharmacol Ther. 2012 Oct;92(4):450-7  
14. Di Stefano AFD, Rusca A. Pressor response to oral tyramine during co-administration with safinamide in 
healthy volunteers. Naunyn-Schmiedeberg's Arch Pharmacol 2011; 384:505-515 
15. Cattaneo C, Caccia C, Marzo A, Maj R, Fariello RG. Pressor response to intravenous tyramine in healthy 
subjects after safinamide, a novel neuroprotectant with selective, reversible monoamine oxidase B inhibition. 
Clin Neuropharmacol. 2003 Jul-Aug;26(4):213-7. 
16. Guidelines on GMP, published by the Commission in The rules governing medicinal products in the European 
Community, Volume 4 
17. U.S. Department of Health and Human Services and U.S. Department of Agriculture, Nutrition and your 
health: 2015-2020 Dietary Guidelines, Appendix 9 
18. Safinamide Investigator’s Brochure, Edition Number 4, dated 13 February 2018.  
 
 
 
 
 


Z7219J03 
 
 
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21 
APPENDIX 1 
 
ACTIVITIES 
 
Period 1 
Screening 
Single Dose  
Visit 
V1 
V2 
V3 
V4 
Day 
Day -14/-2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Informed consent 
x 
 
 
 
 
 
 
Demography 
x 
 
 
 
 
 
 
Lifestyle 
x 
 
 
 
 
 
 
Medical and surgical history  
x 
 
 
 
 
 
 
Physical examination3 
x 
 
 
 
 
 
 
Prior and concomitant medications 
x 
x 
x 
x 
x 
x 
x 
Height 
x 
 
 
 
 
 
 
Body Weight3 
x 
 
 
 
 
 
 
Laboratory analysis4 
x 
 
 
 
 
 
 
Virology 
x 
 
 
 
 
 
 
Serum pregnancy test (women) 
x 
 
 
 
 
 
 
Urine multi-drug kit test 
x 
x 
 
 
 
 
 
Blood pressure and heart rate5 
x 
 
x 
 
 
 
x 
Alcohol breath test 
 
x 
 
 
 
 
 
Urine pregnancy test (women) 
 
x 
 
 
 
 
 
ECG6 
x 
 
 
 
 
 
 
Inclusion/exclusion criteria  
x 
x 
 
 
 
 
 
Subject eligibility 
x 
x 
 
 
 
 
 
Enrolment and randomisation 
 
x 
 
 
 
 
 
Confinement 
 
x 
x 
x 
 
 
 
Discharge 
 
 
 
 
x 
 
 
Ambulatory visits 
 
 
 
 
 
x 
 
Investigational product 
administration 
 
 
x7  
 
 
 
 
Blood sampling for PK analysis 
 
 
x8 
x8 
x8 
x8 
x8 
Standardized meals11  
 
x 
x 
x 
x 
 
 
Adverse event monitoring12 
x 
x 
x 
x 
x 
x 
x 
 
 


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Final v. 2.0; Date 18-Apr-2019                                                                                           Page 59 of 60 
ACTIVITIES 
Period 2 
 
Final visit /ETV1 
 
Multiple Dose 
Visit 
V5 
V6 
V7 
V8 
Day 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 Day 13 
Day 14 
Day 15 Day 16 
Day 17 
Day 18 
Day 182 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
 
 
 
 
 
 
 
 
 
 
 
 
Lifestyle 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history  
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination3 
 
 
 
 
 
 
 
 
 
 
 
x 
Prior and concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight3 
 
 
 
 
 
 
 
 
 
 
 
x 
Laboratory analysis4 
 
 
 
 
 
 
 
 
 
 
 
x 
Virology 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (women) 
 
 
 
 
 
 
 
 
 
 
 
 
Urine multi-drug kit test 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure and heart rate5 
x 
 
x 
x 
x 
x 
x 
 
 
 
x 
x 
Alcohol breath test 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (women) 
 
 
 
 
 
 
 
 
 
 
 
x 
ECG6 
 
 
 
 
 
 
 
 
 
 
 
x 
Inclusion/exclusion criteria  
 
 
 
 
 
 
 
 
 
 
 
 
Subject eligibility 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment and randomisation 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement 
x 
 
 
 
 
 
x 
x 
x 
 
 
 
Discharge 
 
x 
 
 
 
 
 
 
 
x 
 
 
Ambulatory visits 
 
 
x 
x 
x 
x 
 
 
 
 
x 
 
Investigational product 
administration 
x7 
x7 
x7 
x7 
x7 
x7 
x7  
 
 
 
 
 
Blood sampling for PK analysis 
x9 
x9 
x10 
x10 
x10 
x10 
x8 
x8 
x8 
x8 
x8 
 
Standardized meals11  
x 
x 
 
 
 
 
x 
x 
x 
x 
 
 
Adverse event monitoring12 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 


Z7219J03 
 
 
Final v. 2.0; Date 18-Apr-2019                                                                                           Page 60 of 60 
1. 
Early termination visit (ETV) 
2. 
Final visit on day 18  
3. 
Physical examination, including body weight, at screening and final visit/ETV 
4. 
Laboratory analyses at screening and final visit/ETV  
5. 
At pre-dose, at 2 h and 96 h after day 1 single dose and after day 14 last multiple dose. At pre-dose and 2 h  after the day 8 first multiple dose. Before blood sampling and 
investigational product administration during ambulatory visits 
6. 
At screening and final visit/ETV  
7. 
On day 1 (Period 1) and once daily from day 8 to day 14 (Period 2), at 8:00 ± 1 h 
8. 
At pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 36, 48, 72 and 96 h post-dose after the first single dose (day 1) and the last multiple dose (day 14);  
9. 
At pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose after the first multiple dose (day 8) 
10. At pre-dose (0) on each day (day 10-13) 
11. Day -1: standardized dinner; 
Day 1, Day 8, Day 14: standardized lunch at approximately 5 h post-dose, standardized dinner at approximately 13 h post-dose;  
 
 
Day 2, and Days 15/16: standardized breakfast, lunch and dinner 
Day 3, Day 9 and Days 17: standardized breakfast 
12. Adverse events monitored starting at the screening visit, immediately after informed consent, up to the final visit/ETV 
 
 
 
 


Z7219J03 
 
 
Final v. 3.0; Date 07-JUL-2020 
                                                                                          Page 1 of 64 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
 
A PHASE I, PHARMACOKINETICS, SAFETY AND TOLERABILITY 
STUDY OF SINGLE AND MULTIPLE ORAL DOSES OF SAFINAMIDE 
IN HEALTHY ADULT CHINESE VOLUNTEERS  
 
Phase I, single centre, single and multiple-dose, open-label, randomised, 
parallel-group, pharmacokinetics, safety and tolerability study 
 
 
 
Protocol Code: Z7219J03 
 
Date: 07 July 2020 
 
Version: Final 3.0 
 
 
 
 
Zambon SpA 
Via Lillo del Duca 10 
20091 Bresso - Milan - Italy 
 
 
 
 
 
 
THIS DOCUMENT IS ZAMBON'S SOLE PROPERTY AND OWNERSHIP. THIS DOCUMENT, AND ALL 
INFORMATION AND DATA CONTAINED HEREIN HAS TO BE CONSIDERED AND TREATED AS 
STRICTLY CONFIDENTIAL. THIS DOCUMENT SHALL BE USED ONLY FOR THE PURPOSE OF THE 
DISCLOSURE HEREIN PROVIDED. NO DISCLOSURE OR PUBLICATION SHALL BE MADE WITHOUT 
THE PRIOR WRITTEN CONSENT OF ZAMBON.  
 
 
 


Z7219J03 
 
 
Final v. 3.0; Date 07-JUL-2020 
                                                                                          Page 2 of 64 
PROTOCOL AMENDMENT SUMMARY of CHANGES TABLE 
 
DOCUMENT HISTORY
Document
Version
Date
Amendment 2 
Version 3.0 
07 July 2020 
Amendment 1 
Version 2.0 
18 April 2019 
Original Protocol 
Version 1.0 
10 December 2018 
 
 
PROTOCOL AMENDMENT n.2 
The overall rationale for the changes implemented in the protocol amendment is to 
address study site considerations and local laboratory limitation, including drug dosage 
clarity, routine practice and windows for venous blood sampling, period for subject 
confinement in the clinical centre, and parameters for urinalysis. Part of these changes 
were earlier captured in clinical study protocol memorandums (dated 05 July 2019, 
07 October 2019, and 15 January 2020). In addition, protocol amendment summary of 
changes table and protocol amendment history are added. Minor editorial changes 
were made throughout the text for abbreviations, punctuation, spacing, formatting, 
consistency, improvement of clarity, etc. 
 
Substantial changes are detailed as follows: 
Protocol 
section
Description of Change 
Rational for the 
change
Section 1 
STUDY 
SYNOPSIS 
Section 2 
STUDY 
SCHEDULE 
Section 9.1 
Study visits 
and 
procedures 
Section 9.2 
Diet, lifestyle 
and study 
restrictions 
Section 21-
Appendix 1 
The descriptions for study procedures, study 
schedule, and diet, lifestyle, and study 
restrictions are revised as follows: 
(1) Wordings are added or revised to specify 
that subjects will be confined at the study 
centre throughout the study (Day 1 to 
Day 18). 
(2) The wordings indicating discharge on 
Day 3, Day 9, and Day 17 are removed.  
(3) The wording “returning of subjects” is 
removed for Visit 4 (Days 4 and 5), Visit 6 
(Days 10 to 13), and Visit 8 (Day 18). 
(4) The wording “ambulatory visits” is 
removed for Visit 4 (Days 4 and 5). Visit 6 
(Days 10 to 13), and Visit 8 (Day 18). 
(5) Standardized meal supplement is updated 
to cover the whole confinement period 
from Day -1 to Day 18 as follows: 
- 
Day -1: standardized dinner will be 
provided; 
- 
Days 1, 8, and 14: standardized lunch 
and dinner will be provided 5 h and 
13 h after study drug administration; 
To change the 
three subject 
confinement 
periods (Day -1 
to Day 3, Day 8 
to Day 9, and 
Day 14 to 
Day 17) to a total 
confinement 
(Day -1 to 
Day 18). This 
change is 
accompanied 
with standardized 
meal supplement 
throughout the 
confinement 
period. 


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Final v. 3.0; Date 07-JUL-2020 
                                                                                          Page 3 of 64 
- 
Day 2 to Day 5: standardized breakfast 
(after PK sampling), lunch, and dinner 
will be provided; 
- 
Days 6 and 7: standardized breakfast, 
lunch, and dinner will be provided; 
- 
Day 9 to Day 13 and Day 15 to Day 17: 
standardized breakfast (after PK 
sampling), lunch, and dinner will be 
provided; 
- 
Day 18: standardized breakfast (after 
PK sampling) will be provided. 
(6) The tables for study schedule and the 
corresponding footnotes are updated to 
address points (1) to (5) listed above.
Section 1 
STUDY 
SYNOPSIS 
Section 2 
STUDY 
SCHEDULE 
Section 9.1 
Study visits 
and 
procedures 
Section 10.1.2 
Vital signs 
Section 21-
Appendix 1 
Pre-dose and post-dose vital sign 
measurements are performed as follows: 
- 
Days 1, 8, and 14: pre-dose (before 
blood sampling and within 30 min of 
investigational product administration) 
and 2 h post-dose (± 15 min); 
- 
Days 5 and 18: at 96 h post-dose 
(± 15 min); 
- 
Day 10 to Day 13: pre-dose (before 
blood sampling and within 30 min of 
investigational product administration). 
To specify the 
timing for 
pre-dose and 
post-dose vital 
sign 
measurements 
Table 10.3.1.1, 
Section 10.3.1 
Venous blood 
sampling 
(1) The windows for venous blood sampling at 
36- and 48-hours post-dose are changed 
from ± 10 min to ± 30 min. 
(2) The windows for venous blood sampling at 
72- and 96-hours post-dose are changed 
from ± 10 min to ± 60 min. 
To allow a wider 
tolerance range 
for venous blood 
sampling at 36-, 
48-, 72-, and 
96-hours 
post-dose. 
 
Administrative changes are detailed as follows: 
Protocol 
section 
Text of the protocol 
version 2.0 
Amended text of the 
protocol version 3.0 
Rational for the 
change 
Section 1 
STUDY 
SYNOPSIS 
Section 6.1.2 
Dosage 
regimen 
Cohort 1: One (1) 
safinamide 50 mg 
film-coated tablet will 
be administered on 
day 1 followed by 
7 safinamide 50 mg 
film-coated tablets 
Cohort 1: One (1) 
safinamide 50 mg 
film-coated tablet will 
be administered on 
day 1 followed by 
7 safinamide 50 mg 
film-coated tablets in 
The descriptions 
for the study 
cohort 1 and 
cohort 2 are 
rephrased to 
avoid 
misunderstanding 


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Final v. 3.0; Date 07-JUL-2020 
                                                                                          Page 4 of 64 
administered o.d. 
from day 8 to day 14. 
Cohort 2: One (1) 
safinamide 100 mg 
film-coated tablet will 
be administered on 
day 1 followed by 
7 safinamide 100 mg 
film-coated tablets 
administered o.d. 
from day 8 to day 14. 
total from day 8 to 
day 14 and hence 
administered 1 tablet 
o.d. from day 8 to 
day 14. 
Cohort 2: One (1) 
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 
o.d. from day 8 to 
day 14. 
for the study drug 
dosage. 
Section 10.2 
Clinical 
laboratory 
assays 
Urinalysis: pH, 
specific gravity, 
appearance, colour, 
nitrites, proteins, 
glucose, urobilinogen, 
bilirubin, ketones, 
leukocytes, 
erythrocytes, flat 
cells, crystals, 
cylinders. 
Urinalysis: pH, 
specific gravity, 
appearance, colour, 
nitrites, proteins, 
glucose, 
urobilinogen, 
bilirubin, ketones, 
leukocytes, 
erythrocytes, 
epithelial cells, 
crystals, cylinders.  
To adjust the 
parameters for 
urinalysis by 
taking equipment 
limitation of the 
local laboratory 
into 
consideration. 
Section 10.3.1 
Venous blood 
sampling 
Blood samples for PK 
analysis will be 
collected using an 
indwelling catheter 
with switch valve. The 
cannula will be rinsed, 
after each sampling, 
with about 1 mL of 
sterile saline solution 
containing 20 I.U./mL 
Na-heparin. The first 
2 mL of blood will be 
discarded at each 
collection time to 
avoid contamination 
of the sample with 
heparin. 
 
The remaining 8 mL 
will be collected from 
Blood samples for PK 
analysis will be 
collected using an 
indwelling catheter 
with switch valve. 
The cannula will be 
rinsed, after each 
sampling, with about 
1 mL of sterile saline 
solution. The first 
2 mL of blood will be 
discarded at each 
collection time. 
 
The remaining 6 mL 
will be collected from 
the catheter into 
blood collection tube 
(Li-heparin). 
To revise the 
procedures for 
venous blood 
sampling to 
address that (1) 
sterile saline 
solution without 
Na-heparin is 
used as site 
routine practice 
to rinse cannula 
after each 
sampling and (2) 
blood will be 
directly collected 
into the 
evacuated blood 
collection tube 
containing 
anticoagulant 


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Final v. 3.0; Date 07-JUL-2020 
                                                                                          Page 5 of 64 
the catheter and 
transferred with a 
syringe into 
heparinised tubes 
(Li-heparin). 
(Li-heparin), as 
recommended by 
the World Health 
Organization 
(WHO) and used 
as site routine 
practice. 
 
 
 
 






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                                                                                          Page 8 of 64 
STUDY SYNOPSIS (cont.) 
 
Study variables, continued: Primary variables - Pharmacokinetics, continued: 
After single dose only (day 1): 
 Kel: terminal elimination rate constant, calculated, if feasible, by log-linear regression using at least 3 points 
 t1/2: apparent terminal elimination half-life, calculated, if feasible, as ln2/Kel 
 AUC0-: 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 
 Vd/F: apparent volume of distribution associated with the terminal slope, calculated, if feasible, as 
Dose/(AUC0-∞*Kel) 
 Cl/F: apparent total body clearance, calculated, if feasible, as Dose/AUC0-∞ 
 MRT: Mean residence time calculated, if feasible, as AUMC0-∞/AUC0-∞, were AUMC0-∞ is area under the 
moment concentration-time curve extrapolated to infinity 
After multiple dose (day 14): 
 Cmax_ss: maximum safinamide plasma concentration at steady-state 
 tmax_ss: time to achieve Cmax,ss 
 Cmin_ss: trough safinamide plasma concentration at steady-state, measured as concentration at 24h 
 AUCss0-t: area under the concentration-time curve at steady-state from the last dose administration to the last 
observed concentration time t, calculated with the linear up/log down trapezoidal method 
 AUCss0-24: area under the concentration-time curve at steady-state in the tau interval (from the last dose 
administration to 24 h post dose), calculated with the linear up/log down trapezoidal method 
 Cave_ss: average safinamide plasma concentration at steady-state, calculated as AUCss0-24 /tau  
 R: accumulation ratio, calculated as AUCss0-24/ Day 8 AUC0-24 
 DF%: peak-trough fluctuation over one dosing interval at steady-state, calculated as (Cmax,ss - 
Cmin,ss)/Cave,ss*100 
 Vd,ss/F: apparent volume of distribution at steady-state associated with the terminal slope, calculated, if 
feasible, as Dose/( AUCss0-24*Kel) 
 Cl,ss/F: apparent total body clearance at steady-state, calculated, if feasible, as Dose/ AUCss0-24 
Secondary variables - Safety and tolerability:  
 Treatment emergent adverse events, vital signs (blood pressure, heart rate), body weight, physical 
examinations, clinical laboratory parameters, ECG. 
 
Analytics: Plasma samples for safinamide determination will be collected at: 
 pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 36, 48, 72 and 96 h post-dose after the first single dose (day 1) 
and the last multiple dose (day 14);  
 pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose after the first multiple dose (day 8) 
 pre-dose on days 10, 11, 12, 13. 
Analyses will be performed at a certified bioanalytical laboratory (to be designated). The analytical method will 
be detailed in the study analytical plan. Analytical facilities and procedures will be in compliance with the general 
principles of GLP regulations.  
Safety evaluation: Safety of the study treatments will be evaluated on the basis of treatment-emergent adverse 
events, clinical safety laboratory tests, vital signs, ECGs, and physical examinations.  
Adverse events will be collected throughout the study. Vital signs will be measured at screening, during the study 
and at final visit or early termination visit (ETV) in case of discontinuation. Physical examinations, ECGs and 
clinical laboratory tests will be performed at screening and final visit/ETV.  
 
Sample size: Twelve (12) healthy male and female Chinese volunteers per cohort (24 in total) will be included in 
the study in order to have at least 8 completers / cohort. Drop-out subjects will not be replaced. 
Since no hypothesis will be tested, no formal sample size calculation has been performed. The sample size of this 
study has been determined in agreement with the guidance issued by the Chinese Food and Drug Administration 
(CFDA) for clinical pharmacokinetic studies (1). 
 
Main selection 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
 


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Final v. 3.0; Date 07-JUL-2020 
                                                                                          Page 9 of 64 
STUDY SYNOPSIS (cont.) 
 
Main selection criteria, continued: Inclusion criteria, continued: 
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: 
a. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the 
screening visit 
b. 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 
c. A male sexual partner who agrees to use a male condom with spermicide 
d. 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 HMG-CoA reductase inhibitors in 
the 2 weeks before the screening visit; medicinal products that are BCRP substrates; treatment with morphine 
or other similar opioids, whose concomitant use with MAO-B inhibitors is contraindicated, SSRIs, SNRIs, 
tri- or tetracyclic antidepressant, tramadol, pethidine, dextromethorphan, 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


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Final v. 3.0; Date 07-JUL-2020 
                                                                                          Page 10 of 64 
STUDY SYNOPSIS (cont.) 
 
Schedule: 
Procedures and assessments during study visits are listed in the table below: 
 
 
Day 
Procedures/Assessments 
Notes 
Screening – Visit 1 
From  
day -14 
to day -2 
 Explanation to the subject of study aims, procedures 
and possible risks 
 Informed consent signature 
 Subjects' screening number assignment 
 Demographic data and lifestyle recording 
 Medical/surgical history 
 Previous/concomitant medications check 
 Full physical examination (body weight, height, vital 
signs, physical abnormalities) 
 ECG recording 
 Clinical laboratory analyses: haematology, blood 
chemistry, urinalysis, serum virology and serum 
pregnancy test (women) 
 Urine multi-drug kit test 
 Adverse events check 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 
Period 1 
Cohorts 1 and 2 - Visit 
2 
Day -1 
 Alcohol breath test 
 Urine multi-drug kit test 
 Urine pregnancy test (women) 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment 
 Subjects' randomisation number assignment 
 Adverse events and concomitant medications check 
Day -1 
Arrival at the clinical 
centre in the evening.  
Standardized dinner. 
Fasting for at least 10 h 
(overnight) 
Period 1 
Cohorts 1 and 2 - Visit 3 
Days 1 - 
3 
Day 1 
 Investigational product administration at 08:00 ± 1 h; 
 Vital signs measurement at pre-dose (before blood 
sampling and within 30 min of investigational product 
administration) and 2 h post-dose (± 15 min) 
 
Day 1 - Day 3 
 Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 
and 48 h post-dose 
 AEs and concomitant medications check 
Day 1 
Standardized lunch at 
approximately 5 h post-
dose.  
Standardized dinner at 
approximately 13 h post-
dose.  
Day 2 
Standardized breakfast 
(after 
PK 
sampling), 
lunch and dinner 
Day 3 
Standardized breakfast 
(after 
PK 
sampling), 
lunch, and dinner.
 
 


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STUDY SYNOPSIS (cont.) 
 
Study schedule, continued: 
Period 1 
Cohorts 1 and 2 - Visit 4 
Days 4 - 5 
Days 4 - 5 
 Blood sample collection for pharmacokinetic analysis 
at 72 h (day 4) and 96 h (day 5) post-dose  
 AEs and concomitant medications check 
 
Day 5 
 Vital signs measurement at 96 h post-dose (± 15 min) 
from Day 1  
 
Days 4 - 5 
Subjects are to remain at 
the 
clinical 
centre 
throughout, 
with 
standardized 
breakfast 
(after 
PK 
sampling), 
lunch, and dinner. 
A wash-out of 7 days will elapse between the single dose administered on Day 1 and the first multiple dose 
administered on day 8. All subjects will be confined in the clinical centre from Day -1 to the last visit on Day 18.
Period 2 
Cohorts 1 and 2 - Visit 5 
Days 8 -9 
Day 8 - Day 9 
 Investigational product administration at 08:00 ± 1 h; 
 Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 
h post-dose 
 AEs and concomitant medications check 
 
Day 8 only 
 Vital signs measurement at pre-dose (before blood 
sampling and within 30 min of investigational product 
administration) and 2 h post-dose (± 15 min) 
 
Day 8 
Standardized lunch at 
approximately 5 h post-
dose. 
Standardized 
dinner at approximately 
13 h post-dose.  
Day 9 
Standardized breakfast 
(after 
PK 
sampling), 
lunch, and dinner. 
 
Period 2 
Cohorts 1 and 2 - Visit 6 
Days 10 - 
13 
Days 10 - 13 
 Investigational product administration at 08:00 ± 1 h; 
 Blood sample collection for pharmacokinetic analysis 
at pre-dose on each day 
 Vital signs measurement pre-dose (before blood 
sampling and within 30 min of investigational product 
administration) 
 AEs and concomitant medications check 
Days 10 - 13 
Standardized breakfast 
(after 
PK 
sampling), 
lunch, and dinner. 
 
 
 


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STUDY SYNOPSIS (cont.) 
 
Period 2 
Cohorts 1 and 2 - Visit 7 
Days 14 - 
17 
Day 14 
 Investigational product administration at 08:00 ± 1 h; 
 Vital signs measurement at pre-dose (before blood 
sampling and within 30 min of investigational product 
administration) and 2 h post-dose (± 15 min) 
 
Day 14 - Day 17 
 Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 
48 and 72 h post-dose 
 AEs and concomitant medications check 
Day 14 
Standardized lunch at 
approximately 5 h post-
dose. 
Standardized 
dinner at approximately 
13 h post-dose.  
Days 15-16 
Standardized breakfast 
(after 
PK 
sampling), 
lunch, and dinner. 
Day 17 
Standardized breakfast 
(after 
PK 
sampling), 
lunch, and dinner.
Period 2 
Cohorts 1 and 2 - Visit 8 
Day 18 
Day 18 
 Blood sample collection for pharmacokinetic analysis 
at 96 h post-dose  
 Vital signs measurement at 96 h post-dose from Day 
14 (± 15 min) 
 AEs and concomitant medications check 
 Final visit assessments (see below) and discharge 
Day 18 
Standardized breakfast 
(after PK sampling). 
 
Subjects 
will 
be 
discharged after final 
visit assessments (see 
Final visit/ETV below) 
Final Visit/ETV 
Day 18. At 
ETV in 
case of 
early 
terminatio
n 
The following final assessments will be performed after 
the 96-h time-point assessments (day 18) or at ETV in 
case of early discontinuation: 
 Physical examination (body weight, physical 
abnormalities)  
 ECG recording  
 Laboratory analyses: haematology, blood chemistry, 
urinalysis 
 Urine pregnancy test (women) 
Vital signs assessments performed at 96 h post-dose 
(± 15 min) on day 18 will be considered as the final 
assessment. Vital signs will also be measured at ETV, in 
case of early discontinuation. 
AEs and concomitant medications will also be checked at 
final visit/ETV. AEs will be captured up to the end of study 
visit. 
 
In case of clinically significant results at the final visit, the 
subjects will be followed-up by the investigator until the 
normalisation of the concerned clinical parameter(s) 
Upon 
leaving, 
the 
subjects will be instructed 
to contact immediately 
the investigator in case of 
occurrence of any adverse 
reactions 
 
 


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STUDY SYNOPSIS (cont.) 
 
Lifestyle and constraints: 
During the study, the subjects will be confined from the evening preceding the first administration (study day -1) 
until the morning of day 18. 
Subjects will be discharged from the study after final assessments, as specified above (Final visit/ETV). 
The subjects will not take any food or drinks (except water) for at least 10 h (i.e. overnight) before investigational 
product administration. On days 1, 8 and 14, subjects will remain fasted up to 5 h post-dose. Standardized meals 
will be served at the clinical centre throughout the confinement period. Water will be allowed as desired, except 
for one hour before and one hour after investigational product administration. Coffee, tea or food containing 
xanthines (i.e. coke, chocolate, etc.), alcohol and grapefruit will be forbidden during confinement starting 48 h 
before the first administration until the end of the study. Smoking is not allowed for the whole study duration. 
Routine ambulant daily activities will be strongly recommended. Hazardous, strenuous or athletic activities will 
not be permitted. 
Data analysis:  
The data documented in this trial and the clinical parameters measured will be analysed using classic descriptive 
statistics for quantitative variables and frequencies for qualitative variables. 
Analysis set:  
Randomised set: all randomised subjects. This analysis set will be used for demographic, baseline and background 
characteristics 
Safety set: 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. 
PK set: all randomised subjects who fulfil the study protocol requirements in terms of investigational medicinal 
products intake and have evaluable PK data readouts, with no major deviations that may affect the PK results. This 
analysis set will be used for the PK analysis. 
 
Safety Assessments: 
The statistical analysis of demographic and safety data will be performed using SAS®. 
The safety and tolerability of the investigational products will be evaluated on the basis of treatment-emergent 
adverse events occurrence, laboratory tests and other safety assessments (see section above). 
All adverse events, adverse drug reactions (ADR) and serious adverse events (SAEs), if applicable, will be coded 
using the Medical Dictionary for regulatory Activities and summarized by system organ class and preferred term, 
incidence, severity and relationship to study drug. 
Pharmacokinetics: 
The pharmacokinetic parameters will be calculated with a Non-Compartmental Analysis (NCA) using Phoenix 
WinNonlin v6.3 (or higher). Pharmacokinetic data will be listed and summarised by descriptive statistics. 
 
Study duration: 
Maximum study duration for both cohort 1 and 2 will be 32 days including screening period, study Period 1, 
washout and study Period 2.
 
 
 




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3 
TABLE OF CONTENTS 
 
Page 
CLINICAL TRIAL PROTOCOL 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
 
APPROVAL PAGE 
 
1 
STUDY SYNOPSIS 
7 
2 
STUDY SCHEDULE (a more detailed table is shown in appendix 1) 
14 
3 
TABLE OF CONTENTS 
15 
4 
INTRODUCTION 
20 
4.1 
Safinamide 
20 
4.1.1 
Background 
20 
4.1.2 
Clinical pharmacology and pharmacokinetics 
20 
4.1.3 
Safety 
20 
4.2 
Study rationale 
21 
4.3 
Risks and benefits 
21 
5 
STUDY OBJECTIVES 
22 
5.1 
Primary end-point 
22 
5.2 
Secondary end-point 
22 
6 
CLINICAL SUPPLIES 
23 
6.1 
Treatment 
23 
6.1.1 
Description of investigational products 
23 
6.1.2 
Dose regimen 
23 
6.1.3 
Route and method of administration 
24 
6.1.4 
Investigational product distribution 
24 
6.2 
Packaging and labelling 
24 
6.3 
Storage conditions 
25 
6.4 
Drug accountability 
25 
7 
INVESTIGATIONAL PLAN 
26 
7.1 
Overall study design 
26 
7.2 
Discussion of design 
26 
8 
STUDY POPULATION 
27 
8.1 
Target population 
27 
8.2 
Inclusion criteria 
27 
8.3 
Exclusion criteria 
27 
8.3.1 
Not allowed treatments 
28 
9 
STUDY SCHEDULE 
30 
9.1 
Study visits and procedures 
30 
9.2 
Diet, lifestyle and study restrictions 
34 
10 
DESCRIPTION OF SPECIFIC PROCEDURES 
35 
10.1 
Physical examination 
35 
10.1.1 
Body weight 
35 
10.1.2 
Vital signs 
35 
10.1.3 
ECGs 
35 
10.2 
Clinical laboratory assays 
35 
10.3 
Sampling for pharmacokinetic analysis 
36 
10.3.1 
Venous blood sampling 
36 
10.3.2 
Analytics 
37 
10.3.3 
Labelling, storage and transport of samples 
37 
10.3.3.1 Samples labelling 
37 
10.3.3.2 Samples storage and transport 
37 
11 
ASSIGNMENT OF STUDY TREATMENT 
38 
11.1 
Randomisation 
38 
11.2 
Treatment allocation 
38 
11.3 
Blinding 
38 
12 
EVALUATION PARAMETERS 
39 


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12.1 
Study variables 
39 
12.1.1 
Primary variables 
39 
12.1.2 
Secondary variables 
39 
12.2 
Pharmacokinetic assessments 
39 
12.2.1 
Pharmacokinetic parameters 
39 
12.3 
Safety assessments 
40 
13 
STATISTICAL METHODS 
41 
13.1 
Analysis Sets 
41 
13.1.1 
Definitions 
41 
13.1.2 
Reasons for exclusion from the PK set 
42 
13.2 
Sample size and power considerations 
42 
13.3 
Demographic, baseline and background characteristics 
42 
13.4 
Analysis of pharmacokinetic parameters 
42 
13.5 
Safety and tolerability evaluation 
43 
13.5.1 
Adverse events 
43 
13.5.2 
Physical examination 
43 
13.5.3 
Laboratory data 
43 
13.5.4 
Vital signs 
43 
13.5.5 
Body weight 
43 
13.5.6 
ECG 
44 
14 
DEFINITION AND HANDLING OF AEs AND SAEs 
45 
14.1 
Applicable SOPs 
45 
14.2 
Definition of Adverse Event (AE) 
45 
14.3 
Definition of Adverse Drug Reaction (ADR) 
45 
14.4 
Definition of Serious Adverse Events or Serious Adverse Drug Reaction 
46 
14.5 
Definition of Severity of Adverse Events 
46 
14.6 
Definition of Adverse Event causality 
46 
14.7 
Adverse Events recording 
47 
14.8 
AEs monitoring window 
47 
14.9 
Adverse Events reporting 
47 
14.9.1 
SAEs reporting 
48 
14.10 
Follow-up for Adverse Events 
48 
14.11 
SUSARs management 
49 
14.12 
Other events qualified for expedited reporting 
49 
14.13 
SAEs: contacts 
50 
14.14 
Pregnancy 
50 
15 
DATA MANAGEMENT PROCEDURES 
51 
15.1 
Data collection – CRFs 
51 
15.2 
Database management 
51 
15.2.1 
Coding dictionaries 
51 
16 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
52 
16.1 
Monitoring 
52 
16.2 
Quality Control and Quality Assurance 
52 
16.3 
Applicable SOPs 
53 
16.4 
Data access 
53 
16.5 
Audits and inspections 
53 
17 
ETHICAL CONSIDERATIONS 
54 
17.1 
Ethics and Good Clinical Practice (GCP) 
54 
17.2 
Informed consent 
54 
17.3 
Insurance policy 
55 
17.4 
Withdrawal of subjects 
55 
17.4.1 
Primary reason for discontinuation 
55 
17.4.2 
Discontinuation procedures 
55 
17.5 
Study termination 
56 
18 
ADMINISTRATIVE PROCEDURES 
57 
18.1 
Material supplied to the clinical centre 
57 
18.2 
Protocol amendments 
57 
18.3 
Study documentation and record keeping 
57 


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18.4 
Study subjects’ recruitment 
58 
18.5 
Confidentiality and data protection 
58 
18.6 
Publication policy 
58 
19 
STUDY RESPONSIBLE PERSONS 
60 
19.1 
Sponsor 
60 
19.2 
Institutes performing the study 
60 
19.2.1 
Clinical centre 
60 
19.3 
Drug assay 
60 
19.4 
Co-ordination, data analysis & reporting 
60 
19.5 
Project Management and Monitoring 
60 
20 
REFERENCES 
61 
21 
APPENDIX 1 
62 
 
 
 
 
TABLES 
Page 
 
Table 6.1.2.1 
Study dose regimen 
24 
Table 10.3.1.1 
Tolerance ranges for the scheduled sampling times 
37 
 
 


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LIST OF ABBREVIATIONS 
 
-HCG
human chorionic gonadotropin 
-GT
-Glutamyl transpeptidase
ADR
Adverse Drug Reaction
AE
Adverse Event
ALCOAC
Attributable-Legible-Contemporaneous-Original-Accurate-Complete
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-t
Area under the concentration-time curve from time zero to time t
AUCss0-t or AUC0-t,ss
Area under the concentration-time curve at steady state
AUC0-
Area under the concentration vs. time curve up to infinity 
AUC0-24h
Area under the concentration-time curve in the tau interval 
AUCss0-24 or AUC0-24h,ss
Area under the concentration-time curve at steady state in the tau interval
BUN 
BCRP
Blood Urea Nitrogen 
Breast Cancer Resistance Protein
BLQL
Below Lower Quantification Limit
BMI
Body Mass Index
BP
Blood Pressure
CA
Competent Authority
CDISC
Clinical Data Interchange Standards Consortium
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence Interval
Cl/F
Apparent total body clearance
Cave_ss
Average drug concentration at steady state
Cmax
Maximum drug concentration
Cmax_ss
Maximum drug concentration at steady state
Cmix_ss
Trough drug concentration at steady state
CRF
Case Report Form
CRO
Contract Research Organisation
CS
Clinically Significant
CV
Coefficient of Variation
DF%
Peak-trough fluctuation over one dosing interval at steady-state
DBP
Diastolic Blood Pressure
EC
Ethics Committee
ECG
Electrocardiogram
EMA
European Medicines Agency
ETV
Early Termination Visit
FDA
Food and Drug Administration
FSFV
First Subject First Visit
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBs Ag
Hepatitis B virus surface antigen
HCV Ab
Hepatitis C virus antibodies
HIV
Human Immunodeficiency Virus
HR
Heart Rate
ICH
International Conference on Harmonisation
IRB/IEC
Institutional Review Board/Independent Ethics Committee
IMP
Investigational Medicinal Product
IUD
Intra-Uterine Device
Kel
Terminal elimination rate constant
LLOQ 
LQL
Lower Limit of Quantification 
Lower Quantification Limit
LSLV
Last Subject Last Visit
MAO
Monoamino oxidase
MCH
Mean Cell Haemoglobin
MCHC
Mean Cell Haemoglobin Concentration


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MCV
Mean Cell Volume
MedDRA
Medical Dictionary for Regulatory Activities
MRT
Mean residence time
MW
Molecular Weight
N
Normal
NA
Not Applicable
NC
Not calculated
NCS
Not clinically significant
OTC
Over The Counter
PD
Parkinson’s disease
PK
Pharmacokinetics
PT
Preferred Term
PTAE
Pre-Treatment Adverse Event
Racc
Accumulation ratio
RBC 
Red Blood Cells
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SmPC
Summary of Product Characteristics
SNRI
Serotonin–norepinephrine reuptake inhibitors
SOC
System Organ Class
SOP
Standard Operating Procedure
SSRI
Selective serotonin reuptake inhibitors
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
Test
T1
Xadago® 50 mg
T2
Xadago® 50 mg
TEAE
Treatment-Emergent Adverse Event
THC
Delta-9-tetrahydrocannabinol
t1/2
Apparent terminal elimination half-life
tmax
Time to achieve Cmax
Vd/F
Apparent volume of distribution associated with the terminal slope
WBC
White Blood Cells
WHO
World Health Organisation
WHODDE
World Health Organisation Drug Dictionary Enhanced
 
 
 


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4 
INTRODUCTION 
 
4.1 
Safinamide 
 
4.1.1 
Background 
 
The -aminoamide derivative safinamide [(S)-(+)-2-[4-(3-fluorobenzyloxy) benzylamino] 
propanamide], developed as methane sulfonate salt, is an original anticonvulsant and 
antiparkinson agent which has been granted marketing authorisation in 9 EU Member States 
(i.e. Germany, Italy, Spain, Portugal, United Kingdom, Belgium, The Netherlands, Sweden and 
Denmark), in Norway and in Switzerland under the brand name of Xadago®, 50 and 100 mg, 
film-coated tablets (2), for the treatment of adult patients with idiopathic Parkinson’s disease 
(PD) as add-on therapy to a stable dose of Levodopa (L-dopa) alone or in combination with 
other PD medicinal product in mid-to late-stage fluctuating patients (3).  
 
Safinamide uniquely combines potent, selective and reversible inhibition of monoamino 
oxidase B (MAO-B) with blockade of voltage-dependant Na+ and Ca2+ channels and inhibition 
of glutamate release (4,8), thus showing a novel mode of action, targeting both dopaminergic 
and glutaminergic systems (9,10).  
Data from Phase III clinical studies gave evidence that safinamide 50 or 100 mg/day improves 
the motor function in Parkinson’s disease when prescribed as add-on therapy to dopamine 
agonists or L-dopa (3).  
 
4.1.2 
Clinical pharmacology and pharmacokinetics 
 
Safinamide pharmacokinetics after single and multiple dose administrations have been 
described (11,12). At single ascending oral doses ranging from 2.5 to 10.0 mg/kg, safinamide 
was absorbed in a linear and dose-proportional fashion. Peak plasma levels were obtained on 
average at 1.8 to 2.8 h post-dose. Concentrations declined with a terminal half-life of 20 - 23h 
(11,12). Absolute bioavailability is high (95%), showing that safinamide is almost completely 
absorbed after oral administration and first pass metabolism is negligible (SmPC, 3). A 
complete long-lasting inhibition of platelet MAO-B activity was observed at all doses tested. 
Food intake prolonged the rate but did not affect the extent of safinamide absorption (11,12). 
Studies in healthy volunteers (13,15) demonstrated that safinamide does not affect oral tyramine 
metabolism mostly mediated by the intestinal MAO-A, and confirm that it can be administered 
without tyramine-related dietary restrictions. 
 
4.1.3 
Safety 
 
The overall safety profile of Xadago® is based on the clinical development program performed 
on over 3000 subjects, of which over 600 were treated for more than 2 years. 
 
The most common side effects related to safinamide are dyskinesia, somnolence, dizziness, 
headache, insomnia, nausea and orthostatic hypotension. Serious adverse reactions, such as 
hypertensive crisis (high blood pressure, collapse), neuroleptic malignant syndrome (confusion, 
sweating, muscle rigidity, hyperthermia, CPK increase), serotonin syndrome (confusion, 
hypertension, muscle stiffness, hallucinations), and hypotension, are known to occur with the 
concomitant use of SSRIs, SNRIs, tricyclic/tetracyclic antidepressants and MAO inhibitors. 


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With MAO-inhibitors there have been reports of drug interactions with concomitant use of 
sympathomimetic medicinal products. Impulse control disorders, pathological gambling, 
increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive 
eating can occur in patients treated with dopamine agonists and/or other dopaminergic 
treatments.  
 
A complete list of adverse reactions observed with safinamide is presented in the SmPC (3). 
 
4.2 
Study rationale 
 
The present study will be part of safinamide registration package in China and was designed 
according to CFDA guideline recommendations (1). 
Safinamide has been granted marketing authorization in EU (2015), US (2017) and Switzerland 
(2015).   
In the present study, safinamide pharmacokinetic profile, safety and tolerability after single 
dose and at steady state will be investigated for the first time in Chinese healthy male and female 
volunteers.  
 
4.3 
Risks and benefits 
 
For AEs occurred with safinamide in previous clinical studies, please refer to § 4.1.3 and the 
SmPC (3). The most common side effects are dyskinesia, somnolence, dizziness, headache, 
insomnia, nausea and orthostatic hypotension. 
 
Based on the clinical experience, no particular risks are expected for the study subjects 
considering safinamide 50 mg and 100 mg multiple dose administrations. 
 
 
 


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5 
STUDY OBJECTIVES 
 
The objective of the study is to evaluate safinamide pharmacokinetic profile, safety and 
tolerability after single and multiple dose administration to healthy adult Chinese volunteers 
 
5.1 
Primary end-point 
 
 To evaluate plasma safinamide pharmacokinetic parameters after single and multiple dose 
administration of the investigational products.  
 
5.2 
Secondary end-point 
 
 To collect safety and tolerability data after single and multiple dose administration of the 
investigational products. 
 


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6 
CLINICAL SUPPLIES 
 
6.1 
Treatment 
 
6.1.1 
Description of investigational products 
 
TEST PRODUCT 1 (T1)
Name
Xadago® 50 mg film-coated tablets
Active ingredient 
Safinamide methanesulphonate (corresponding to 50 mg 
safinamide)
Marketing Authorization 
Holder
Zambon S.p.A., Italy 
Pharmaceutical form
Film-coated tablets
Dose 
Single 50 mg dose on day 1 
Multiple 50 mg doses, once daily, for 7 days
Administration route
Oral
 
 
TEST PRODUCT 2 (T2)
Name
Xadago® 100 mg film-coated tablets
Active ingredient 
Safinamide methanesulphonate (corresponding to 100 mg 
safinamide)
Marketing Authorization 
Holder
Zambon S.p.A., Italy 
Pharmaceutical form
Film-coated tablets
Dose 
Single 100 mg dose on day 1 
Multiple 100 mg doses, once daily, for 7 days
Administration route
Oral
 
6.1.2 
Dose regimen 
 
Subjects will be randomised to 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), according 
to the study randomised, parallel-group design, as follows: 
 
 Cohort 1: One (1) 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 o.d. from day 8 to day 14. 
 
 Cohort 2: One (1) 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 o.d. from day 8 to day 14. 
 
 


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Dose regimens are also summarised in the scheme below: 
 
Table 6.1.2.1 Study dose regimen 
Cohort 
Period 1 - single dose 
Day 1 
Washout 
Period 2 - Multiple doses 
Days 8 - 14 
Cohort 1
50 mg po
7 days 
50 mg po o.d for 7 days
Cohort 2
100 mg po
100 mg po o.d. for 7 days
 
6.1.3 
Route and method of administration 
 
The investigational products will be orally administered in the morning, at 8:00±1h, 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. 
 
6.1.4 
Investigational product distribution 
 
All doses of the investigational products will be administered at the clinical centre by the 
investigator or by his/her deputy. The investigational products will be exclusively used for the 
present clinical study and will only be administered to the subjects enrolled in the study.  
 
6.2 
Packaging and labelling 
 
Packaging and labelling for the clinical study will be performed by a GMP compliant vendor, 
delegated by Zambon S.p.A., Italy. 
 
Subjects' kit labelling will report all the information according to the Annex 13 to the Good 
Manufacturing Practice (published by the Commission in The rules governing medicinal 
products in the European Community, Volume 4, 16), as follows: 
a. 
Name, address and telephone number of the sponsor, contract research organisation or 
investigator (the main contact for information on the product, clinical study) 
b. Pharmaceutical dosage form, route of administration, quantity of dosage units, and the 
name/identifier and strength/potency 
c. 
The batch and/or code number to identify the contents and packaging operation 
d. A study reference code allowing identification of the study, site, investigator and sponsor 
if not given elsewhere 
e. 
A blank space for subject enrolment Nr. (to be reported by hand by the Investigator) and 
where relevant, the visit number 
f. 
The name of the investigator (if not included in (a) or (d)) 
g. Directions for use (reference may be made to a leaflet or other explanatory document 
intended for the study subject or person administering the product) 
h. “For clinical study use only” or similar wording 


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i. 
The storage conditions 
j. 
Period of use (use-by date, expiry date or re-test date as applicable), in month/year format 
and in a manner that avoids any ambiguity 
k. “Keep out of reach of children” 
 
The label will be in Chinese language. 
 
6.3 
Storage conditions 
 
The investigational products will be stored at ≤ 25° C in a dry locked place, sheltered from light.  
 
6.4 
Drug accountability 
 
The vendor delegated by Zambon S.p.A., Italy, will provide the clinical centre with a sufficient 
number of individual subject kits to conduct the study, plus sufficient reserve kits.  
 
After receipt of the drug supply, the Pharmacist will confirm in writing by signing and dating 
standard drug accountability forms. At the end of the study, the drug product will be maintained 
in the original containers. 
 
At the end of the study, used, unused and partially used supplies of the investigational products, 
provided by the vendor delegated by Zambon S.p.A., Italy, will be stored as detailed in § 6.3 
above and then disposed of (upon sponsor written authorisation), after assessment of drug 
accountability. 
 
 
 


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7 
INVESTIGATIONAL PLAN 
 
7.1 
Overall study design 
 
Phase I, single centre, single and multiple-dose, open-label, randomised, parallel-group, 
pharmacokinetics, safety and tolerability clinical study. 
 
7.2 
Discussion of design 
 
Following a specific request of CFDA, the present study will be part of safinamide registration 
package in China and was designed according to CFDA guideline recommendations (1). 
 
Safinamide has recently been granted marketing authorization in EU, Norway and Switzerland 
on the basis of the results of clinical trials performed in European countries. In the present study, 
safinamide pharmacokinetic profile, safety and tolerability after single dose and at steady state 
will be investigated for the first time in Chinese healthy male and female volunteers.  
 
Two single doses (i.e. 50 and 100 mg) of safinamide will be administered to two subject' cohorts. 
The study will continue with multiple administrations of safinamide 50 and 100 mg, orally 
taken once a day for 7 days. 
 
The 50 and 100 mg oral doses have been selected according to the common clinical practice 
(see Xadago® SmPC). These doses were investigated in the previously performed Phase III 
clinical trials. The volunteers will be assigned to the two cohorts according to the study 
randomised, parallel-group design. 
 
Safinamide pharmacokinetic profile will be investigated after single dose, according to CFDA 
guidance requirements, and at steady state since multiple doses are administered in the clinical 
practice. Safinamide steady state should be reached after 5 or 6 days of treatment (day 13-14 in 
this study). Safinamide pre-dose concentrations will be assessed before the last 5 doses (days 
10-14).  
 
An open design was chosen. However, no bias on study outcome is expected considering that 
the study PK endpoints are based on the objective measurement of safinamide in plasma.  
Blood sampling time-points were selected on the basis of the known PK profile of safinamide. 
The sampling time lasts for about 4-7 elimination half-lives (mean PK half-life: 20-23 h) after 
both single dose and the last multiple dose administration. 
 
 


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8 
STUDY POPULATION 
 
8.1 
Target population 
 
Twenty-four (24) healthy male and female Chinese volunteers, aged 18-45 years inclusive, will 
be enrolled into the study. 
 
8.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfil all these 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: 
a. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 
2 months before the screening visit 
b. 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 
c. A male sexual partner who agrees to use a male condom with spermicide 
d. 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. 
 
8.3 
Exclusion criteria 
 
Subjects meeting any of these criteria will not be enrolled in the study: 
 
1. Electrocardiogram (12-lead ECG in supine position): clinically significant abnormalities 
2. Physical findings: clinically significant abnormal physical findings which could interfere 
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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 HMG-CoA reductase inhibitors in the 2 weeks before the screening visit; medicinal 
products that are BCRP substrates; treatment with morphine or other similar opioids, whose 
concomitant use with MAO-B inhibitors is contraindicated, SSRIs, SNRIs, tri- or tetracyclic 
antidepressant, tramadol, pethidine, dextromethorphan, 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 
 
8.3.1 
Not allowed treatments 
 
No medication, including OTC, herbal remedies and traditional Chinese remedies, will be 
allowed for 2 weeks before the start of the study and during the whole study duration. 
 
Statins and HMG-CoA reductase inhibitors use will not be allowed for 2 weeks before and 
during the study. Wash-out interval for the treatment with morphine or other similar opioids, 


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whose concomitant use with MAO-B inhibitors is contraindicated, SSRIs, SNRIs, tri- or 
tetracyclic antidepressant, tramadol, pethidine, dextromethorphan, MAO inhibitors (e.g. 
selegiline), meperidine derivatives, antiepileptic drugs and the treatment with any known 
enzyme inhibiting or inducing agent or any investigational drugs intake will be at least 4 weeks 
before the screening visit. Hormonal contraceptives are allowed. 
 
Paracetamol will be allowed as therapeutic counter-measure for adverse events (AEs) according 
to the investigator’s opinion. The intake of any other medication will be reported as a protocol 
deviation. However, it will lead to subject's discontinuation from the study only if the 
investigator, together with the sponsor, considers it could affect the study assessments or 
outcome. 
 
 
 


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9 
STUDY SCHEDULE 
 
The schedule of the study is summarised in Section 2. 
 
9.1 
Study visits and procedures 
 
Each study subject completing the study will undergo 8 visits plus a final visit. 
 
The study protocol foresees 2 periods: in the first one the investigational products are 
administered in single dose, in the second one in multiple doses. The single dose in the first 
period and the first dose in the second period are separated by a wash-out interval of 7 days. 
Maximum and minimum study duration will be 32 and 20 days, respectively, screening visit 
included. 
 
The first subject first visit (FSFV) is defined as the 1st visit performed at the clinical centre by 
the 1st screened subject. The last subject last visit (LSLV) is defined as the last visit performed 
at the clinical centre (or a telephonic follow-up, if applicable) by the last subject, i.e. the last 
visit foreseen by the study protocol, independently of the fact that the subject is a completer or 
a withdrawn subject. 
 
The following phases, visits and procedures will be performed: 
 
 Screening phase 
 Screening – visit 1: between day -14 and day -2 
 Period 1 – visit 2: day -1 
 
 Interventional phase 
 Period 1 – visit 3: days 1-3: single dose and blood sampling for PK analysis 
 Period 1 – visit 4: days 4-5: blood sampling for PK analysis 
 Wash-out interval of 7 days 
 Period 2 – visit 5: days 8-9: first multiple dose and blood sampling for PK analysis 
 Period 2 – visit 6: days 10-13: multiple doses and blood sampling for PK analysis 
 Period 2 - visit 7: days 14-17: last multiple dose and blood sampling for PK analysis 
 Period 2 - visit 8: day 18: blood sampling for PK analysis 
 
 Final phase 
 Final visit/early termination visit (ETV). In case of early discontinuation, discontinued 
subjects will undergo an early termination visit (ETV) 
 
 
 


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Study schedule 
 
 
Day 
Procedures/Assessments 
Notes 
Screening – Visit 1 
From day -14 
to day -2 
 Explanation to the subject of study aims, procedures 
and possible risks 
 Informed consent signature 
 Subjects' screening number assignment 
 Demographic data and lifestyle recording 
 Medical/surgical history 
 Previous/concomitant medications check 
 Full physical examination (body weight, height, vital 
signs, physical abnormalities) 
 ECG recording 
 Clinical laboratory analyses: haematology, blood 
chemistry, urinalysis, serum virology and serum 
pregnancy test (women) 
 Urine multi-drug kit test 
 Adverse events check 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 
Period 1 
Cohorts 1 and 2 - Visit 
Day -1 
 Alcohol breath test 
 Urine multi-drug kit test 
 Urine pregnancy test (women) 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment 
 Subjects' randomisation number assignment 
 Adverse events and concomitant medications check 
Day -1 
Arrival at the clinical 
centre in the evening  
Standardized dinner. 
Fasting for at least 10 h 
(overnight) 
Period 1 
Cohorts 1 and 2 - Visit 3 
Days 1 - 3 
Day 1 
 Investigational product administration at 08:00 ± 1 h; 
 Vital signs measurement at pre-dose (before blood 
sampling and within 30 min of investigational product 
administration) and 2 h post-dose (± 15 min) 
 
Day 1 - Day 3 
 Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 
and 48 h post-dose 
 AEs and concomitant medications check 
Day 1 
Standardized lunch at 
approximately 5 h post-
dose.  
Standardized dinner at 
approximately 13 h post-
dose.  
Day 2 
Standardized breakfast 
(after 
PK 
sampling), 
lunch and dinner. 
Day 3 
Standardized breakfast 
(after 
PK 
sampling), 
lunch, and dinner.
 
 
 


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Study schedule, continued 
 
Period 1 
Cohorts 1 and 2 - Visit 4 
Days 4 - 5 
Days 4 - 5 
 Blood sample collection for pharmacokinetic analysis 
at 72 h (day 4) and 96 h (day 5) post-dose  
 AEs and concomitant medications check 
 
Day 5 
 Vital signs measurement at 96 h post-dose (± 15 min) 
from Day 1  
Days 4 - 5 
Subjects are to remain at 
the 
clinical 
centre 
throughout, 
with 
standardized 
breakfast 
(after 
PK 
sampling), 
lunch, and dinner. 
A wash-out of at least 7 days will elapse between the single dose administered on Day 1 and the first multiple 
dose administered on day 8. All subjects will be confined in the clinical centre from Day -1 to the last visit on 
Day 18. 
Period 2 
Cohorts 1 and 2 - Visit 5 
Days 8 -9 
Day 8 - Day 9 
 Investigational product administration at 08:00 ± 1 h; 
 Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 
h post-dose 
 AEs and concomitant medications check 
 
Day 8 only 
 Vital signs measurement at pre-dose (before blood 
sampling and within 30 min of investigational 
product administration) and 2 h post-dose (± 15 min) 
 
Day 8 
Standardized lunch at 
approximately 5 h post-
dose. 
Standardized 
dinner at approximately 
13 h post-dose.  
Day 9 
Standardized breakfast 
(after 
PK 
sampling), 
lunch, and dinner. 
Period 2 
Cohorts 1 and 2 - Visit 
6 
Days 10 - 
13 
Days 10 - 13 
 Investigational product administration at 08:00 ± 1 h; 
 Blood sample collection for pharmacokinetic analysis 
at pre-dose on each day 
 Vital signs measurement pre-dose (before blood 
sampling and within 30 min of investigational 
product administration) 
 AEs and concomitant medications check 
Days 10 - 13 
Standardized breakfast, 
(after 
PK 
sampling), 
lunch, and dinner.  
 
 
 
 


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Study schedule, continued 
 
Period 2 
Cohorts 1 and 2 - Visit 7 
Days 14 - 17 
Day 14 
 Investigational product administration at 08:00 ± 1 h; 
 Vital signs measurement at pre-dose (before blood 
sampling and within 30 min of investigational product 
administration) and 2 h post-dose (± 15 min) 
 
Day 14 - Day 17 
 Blood sample collection for pharmacokinetic analysis 
at: pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 
48 and 72 h post-dose 
 AEs and concomitant medications check 
Day 14 
Standardized lunch at 
approximately 5 h post-
dose. 
Standardized 
dinner at approximately 
13 h post-dose.  
Days 15-16 
Standardized breakfast 
(after 
PK 
sampling), 
lunch and dinner. 
Day 17 
Standardized breakfast 
(after 
PK 
sampling), 
lunch, and dinner.
Period 2 
Cohorts 1 and 2 - Visit 8 
Day 18 
Day 18 
 Blood sample collection for pharmacokinetic analysis 
at 96 h post-dose  
 Vital signs measurement at 96 h post-dose (± 15 min) 
from Day 14 
 AEs and concomitant medications check 
 
 Final visit assessments (see below) and discharge 
Day 18 
Standardized breakfast 
(after PK sampling). 
 
Subjects 
will 
be 
discharged after final 
visit assessments (see 
Final visit/ETV below) 
Final Visit/ETV 
Day 18. At 
ETV in case 
of early 
termination 
The following final assessments will be performed after 
the 96-h time-point assessments (day 18) or at ETV in 
case of early discontinuation: 
 Physical examination (body weight, physical 
abnormalities)  
 ECG recording  
 Laboratory analyses: haematology, blood chemistry, 
urinalysis 
 Urine pregnancy test (women) 
Vital signs assessments performed at 96 h post-dose 
(± 15 min) on day 18 will be considered as the final 
assessment. Vital signs will also be measured at ETV, in 
case of early discontinuation. 
AEs and concomitant medications will also be checked at 
final visit/ETV. AEs will be captured up to the end of study 
visit. 
 
In case of clinically significant results at the final visit, the 
subjects will be followed-up by the investigator until the 
normalisation of the concerned clinical parameter(s) 
Upon 
leaving, 
the 
subjects will be instructed 
to contact immediately 
the investigator in case of 
occurrence of any adverse 
reactions 
 
 
 


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9.2 
Diet, lifestyle and study restrictions 
 
During the study, the subjects will be confined at the clinical centre from the evening preceding 
the first administration (study day -1) until the morning of day 18.  
 
Subjects will be discharged from the study after final assessments (Final visit or ETV). 
 
The subjects will not take any food or drinks (except water) for at least 10 h (i.e. overnight) 
before investigational product administration. On days 1, 8 and 14, subjects will remain under 
fasting conditions up to 5 h post-dose.  
Standardized meals will be served at the clinical centre according to the schedule below: 
 
 
Day -1: standardized dinner; 
 
Day 1, Day 8, Day 14: standardized lunch at approximately 5 h post-dose, standardized 
dinner at approximately 13 h post-dose;  
 
Day 2 to Day 5, Day 9 to Day 13, and Days 15 to 17: standardized breakfast (after PK 
sampling), lunch and dinner; 
 
Day 6 and Day 7: standardized breakfast, lunch and dinner; 
 
Day 18: standardized breakfast (after PK sampling). 
 
Water will be allowed as desired, except for 1 h before and 1 h after investigational product 
administration. Coffee, tea or food containing xanthines (i.e. coke, chocolate, etc.), alcohol and 
grapefruit will be forbidden during confinement starting 48 h before the first administration 
until the end of the study. Smoking is not allowed for the whole study duration. 
 
Routine ambulant daily activities will be strongly recommended. Hazardous, strenuous or 
athletic activities will not be permitted. 


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10 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
10.1 
Physical examination 
 
Full physical examinations will be performed at screening and final visit/ETV. Date of the 
physical examination, overall investigator’s interpretation (as normal or abnormal and, if 
abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be reported in the individual CRFs. 
All clinically significant abnormalities after the screening visit will be recorded as AEs. 
 
10.1.1 
Body weight 
 
Body weight will be recorded at screening and final visit/ETV. 
Subjects will be weighed (kg) lightly clothed without shoes. Height will be measured at 
screening only and Body Mass Index (BMI) will be recorded. BMI will be calculated as weight 
[kg]/(height [m] x height [m]). 
 
10.1.2 
Vital signs 
 
Subjects' blood pressure and heart rate will be measured by the investigator or his deputy after 
5 min at rest (sitting/supine position) at the following times:  
 at screening 
 on day 1, day 8 and day 14: at pre-dose (before blood sampling and within 30 min of 
investigational product administration) and 2 h post-dose (± 15 min) 
 on day 5 and day 18: at 96 h post-dose (± 15 min) 
 on days 10-13: at pre-dose (before blood sampling and within 30 min of investigational 
product administration) 
 at ETV (if applicable). 
 
10.1.3 
ECGs 
 
12-Leads ECGs will be performed (supine position) at screening and final visit/ETV. 
 
Date/time of the ECG recording, overall investigator's interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be reported in the individual CRFs. All clinically significant 
abnormalities after the screening visit will be recorded as AEs. Hard copies of the ECGs will 
be attached as source document at site. 
 
10.2 
Clinical laboratory assays 
 
Samples of blood and urine will be collected. The following laboratory analyses will be 
performed at the screening visit: 
 
HAEMATOLOGY 


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Leukocytes and leukocyte differential count (percentage values and absolute values), 
erythrocytes, haemoglobin (conv. units), haematocrit, MCV, MCH, MCHC, thrombocytes. 
 
BLOOD CHEMISTRY 
Electrolytes: sodium, potassium, calcium, chloride, inorganic phosphorus 
Enzymes: alkaline phosphatase, γ-GT, AST, ALT 
Substrates/metabolites: total bilirubin, creatinine, glucose, urea or BUN, uric acid, total 
cholesterol, triglycerides 
Proteins: total proteins 
 
Serum pregnancy test (women). 
 
URINE ANALYSIS 
Urinalysis: pH, specific gravity, appearance, colour, nitrites, proteins, glucose, urobilinogen, 
bilirubin, ketones, leukocytes, erythrocytes, epithelial cells, crystals, cylinders.  
 
SERUM VIROLOGY  
Hepatitis B (HBs antigen), Hepatitis C (HCV antibodies), HIV 1/2 (HIV Ag/Ab combo).  
 
A urine drug test will be performed at the clinical centre at screening, using a urine multi-drug 
kit. The following drugs will be assessed: cocaine, amphetamine, morphine, cannabis, 
benzodiazepines, barbital.  
 
A serum pregnancy test will be performed by the laboratory at screening, as listed above. Urine 
pregnancy test will be performed on day -1 of each study period at the clinical centre and at the 
final visit/ETV.  
 
The same analyses, with the exception of urine drug test and virology, will be performed at the 
final visit/ETV. 
 
Date/time of samples collection, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
findings (if any) will be reported in the individual eCRFs. All clinically significant 
abnormalities after the screening visit will be recorded as AEs. 
 
10.3 
Sampling for pharmacokinetic analysis 
 
10.3.1 
Venous blood sampling 
 
Venous blood samples (up to 10 mL) will be collected from a forearm vein at the following 
times:  
 
 At pre-dose (0 h), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h post-dose after 
the first single dose (days 1-5) and the last multiple dose (days 14-18) 
 At pre-dose on days 10-13 
 At pre-dose (0 h) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose after the first 
multiple dose (days 8-9) 
 


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Actual sampling times for each subject will be recorded in the individual CRFs. The actual 
sampling times should not exceed the recommended tolerance ranges presented in the following 
table. Any deviation outside the recommended ranges will be verified through Data 
Clarification Forms and, if confirmed, will be reported as protocol deviation, although it will 
not automatically lead to the exclusion of the concerned subjects from the PK set. 
 
Table 10.3.1.1 
Tolerance ranges for the scheduled sampling times 
Sampling time 
Tolerance range 
Pre-dose (0) 
Within 30 minutes before  
investigational product administration
0.5 h (30 min)
± 1 min
1, 1.5 h
± 3 min
2, 3, 4 h
± 5 min
6, 8, 12, 16, 24 h 
± 10 min
36, 48 h
± 30 min
72, 96 h  
± 60 min
 
Blood samples for PK analysis will be collected using an indwelling catheter with switch valve. 
The cannula will be rinsed, after each sampling, with about 1 mL of sterile saline solution. The 
first 2 mL of blood will be discarded at each collection time. 
 
The remaining 6 mL will be collected from the catheter into blood collection tube (Li-heparin). 
Samples handling and processing is described in study specific lab manual.  
 
10.3.2 
Analytics  
 
The concentration of safinamide in plasma samples will be determined at a certified analytical 
laboratory (to be designated). Analyses will be performed according to the general Principles 
of “OECD Good Laboratory Practices for testing of chemicals" C(81) 30 (final) and GCP. 
 
The method validation report and the analytical report will be attached to the final report. 
 
10.3.3 
Labelling, storage and transport of samples 
 
10.3.3.1 
Samples labelling 
 
Labels and labelling process are described in the study specific lab manual.  
 
10.3.3.2 
Samples storage and transport 
 
During the study the samples will be stored at ≤- 70° C. At the end of each collection day, 
aliquots 1 and 2 will be stored in separate freezers. 
 
All aliquots 1, packed in sufficient dry ice, will be shipped by an authorised courier from the 
clinical centre (China) to the analytical laboratory.  
 
 


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11 
ASSIGNMENT OF STUDY TREATMENT 
 
11.1 
Randomisation 
 
Randomisation will be used to minimize bias in the assignment of subjects to treatment cohorts, 
to increase the likelihood that known and unknown subject attributes (e.g., demographic and 
baseline characteristics) will be evenly balanced across treatment cohorts. 
The randomisation schedule will be computer-generated by the CRO biostatistician using SAS®. 
The randomisation schedule will be attached to the final clinical study report. 
 
11.2 
Treatment allocation 
 
Subjects will be randomised to 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), according 
to the study randomised, parallel-group design. 
 
On day -1, Period 1, subjects will be assigned a randomisation number, which will be used to 
assign the study treatment according to the randomisation schedule, as detailed above. 
Subjects who prematurely discontinue participation after randomisation will not be replaced. 
 
11.3 
Blinding 
 
This is an open study. No masking procedure will be applied.  
The open label design is considered appropriate for the primary objective of pharmacokinetic 
characterization, because PK properties and assessments are not prone to bias of observation 
by the investigators or the subjects. 


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12 
EVALUATION PARAMETERS 
 
12.1 
Study variables 
 
12.1.1 
Primary variables 
 
The following safinamide PK parameters will be determined on day 1 (after the first dose), on 
day 8 (after the first multiple dose) and on day 14 (after the last dose): 
 
After single dose and first multiple dose (day 1 and day 8) 
 Cmax, tmax, AUC0-t, and AUC0-24h 
 
After single dose only (day 1): 
 Kel, t1/2, AUC0-, Vd/F, Cl/F and MRT 
 
After multiple dose (day 14): 
 Cmax_ss, tmax_ss, Cmin_ss, AUC0-t,ss, AUC0-24h,ss, Cave_ss, Racc, DF%, Vd,ss/F and Cl,ss/F 
 
12.1.2 
Secondary variables 
 
 Treatment emergent adverse events (TEAEs), vital signs (blood pressure, heart rate), 
body weight, physical examinations, clinical laboratory parameters, ECG. 
 
12.2 
Pharmacokinetic assessments 
 
12.2.1 
Pharmacokinetic parameters 
 
The following safinamide PK parameters will be measured and/or calculated with a Non-
Compartmental Analysis (NCA) using Phoenix WinNonlin v6.3 (or higher). 
 
After single dose and first multiple dose (day 1 and day 8): 
Cmax:
Maximum safinamide plasma concentration
tmax:
Time to achieve Cmax
AUC0-t: 
Area under the concentration-time curve from single dose administration to the 
last quantifiable concentration time t
AUC0-24h: 
Area under the concentration-time curve in the tau interval (from single dose 
administration to 24 h post dose)
 
After single dose (day 1): 
Kel: 
Apparent terminal elimination rate constant, calculated, if feasible, from the 
slope of a log-linear regression using at least 3 last concentration > LLOQ 
points
t1/2:
Apparent terminal elimination half-life, calculated, if feasible, as ln2/Kel
AUC0-: 
Area under the concentration-time curve extrapolated to infinity, calculated, if 
feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration
Vd/F: 
Apparent volume of distribution associated with the terminal slope, calculated, 
if feasible, as Dose/(AUC0-∞*Kel)


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Cl/F: 
Apparent total body clearance, calculated, if feasible, as Dose/AUC0-∞ 
MRT: 
Mean residence time, calculated, if feasible, as AUMC0-∞/AUC0-∞, were 
AUMC0-∞ is area under the moment concentration-time curve extrapolated to 
infinity
 
The sampling schedule is considered adequate if the ratio AUC0-t/AUC0- equals or exceeds a 
factor of 0.8 (i.e. if %AUCextra is <20%) for more than 80% of the individual PK profiles. This 
assures that AUC0-t covers a sufficient percentage of the theoretical total extent of exposure.  
 
The quality of log-linear regression (and, consequently, the reliability of the extrapolated PK 
parameters) should be demonstrated by a determination coefficient R2 ≥ 0.8. Individual 
extrapolated parameters, when considered unreliable, will be reported as NC (not calculated).  
 
After multiple dose (day 14): 
Cmax_ss:
Maximum safinamide plasma concentration at steady state
tmax_ss:
Time to achieve Cmax-ss
AUC0-t,ss: 
Area under the concentration-time curve at steady state from the last dose 
administration to the last quantifiable concentration time t
AUC0-24h,ss: Area under the concentration-time curve at steady state in the tau interval (from 
the last dose administration to 24 h post dose)
Cave_ss: 
Average safinamide plasma concentration at steady state, calculated as AUC0-
24h,ss /tau (24 h)
Racc:
Accumulation ratio, calculated as AUC0-24h,ss/ AUC0-24h
DF%: 
Peak-trough fluctuation over one dosing interval at steady-state, calculated as 
(Cmax,ss - Cmin,ss)/Cave,ss*100
Vd,/Fss 
apparent volume of distribution at steady-state associated with the terminal 
slope, calculated, if feasible, as Dose/( AUC0-24h,ss*Kel)
Cl,/Fss 
apparent total body clearance at steady-state, calculated, if feasible, as Dose/ 
AUC0-24h,ss
 
12.3 
Safety assessments 
 
Safety and general tolerability of the investigational products will be based on TEAEs, physical 
examinations, including body weight, vital signs, ECGs and routine haematology, blood 
chemistry and urinalysis laboratory tests. 
 


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13 
STATISTICAL METHODS 
 
The data documented in this study and the parameters measured will be evaluated using classic 
descriptive statistics, i.e. geometric mean, geometric CV (%) (PK data only), arithmetic mean, 
SD, CV (%), minimum, median and maximum values for quantitative variables, and 
frequencies for qualitative variables. 
 
Not available data will be evaluated as “missing values”. The statistical analysis of demographic 
and safety data will be performed using Statistical Analysis Software (SAS®) Version 9.3 or 
higher. 
The pharmacokinetic parameters will be calculated using the actual recoded sampling times and 
non-compartmental methods with Phoenix WinNonlin (Version 6.3 or higher). 
 
13.1 
Analysis Sets 
 
13.1.1 
Definitions 
 
A subject will be defined as screened after the signature of the informed consent, regardless of 
the completion of all the screening procedures. 
A subject will be defined as eligible if he/she meets all the inclusion criteria and not meet any 
exclusion criteria. Otherwise he/she will be defined as a screen failure.  
 
A subject will be defined as enrolled in the study if he/she is included into the interventional 
phase of the study. The enrolment will be performed through randomised allocation to a 
treatment cohort. An eligible but not enrolled subject will be defined as a reserve. 
A subject will be defined as randomised in the study when he/she is assigned to a randomised 
treatment cohort. 
 
The following analysis sets will be considered: 
 
 Randomised set: all randomised subjects. This analysis set will be used for demographic, 
baseline and background characteristics. 
 Safety set: 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.  
 PK set: all randomised subjects who fulfil the study protocol requirements in terms of 
investigational medicinal products intake and have evaluable PK data readouts, with no 
major deviations that may affect the PK results. This analysis set will be used for the PK 
analysis. 
 
Each subject will be coded as valid or not valid for the Randomised set, Safety set and PK set. 
Subjects will be evaluated according to the treatment they actually receive. 
 
 


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13.1.2 
Reasons for exclusion from the PK set 
 
Reasons for the exclusion of subjects from the PK set are the following: 
 
Before bioanalysis 
 vomiting and diarrhoea after drug intake which could render the plasma concentration-time 
profile unreliable 
 intake of concomitant medications which could render the plasma concentration-time 
profile unreliable 
 AEs which could render the plasma concentration-time profile unreliable 
 administration errors which could render the plasma concentration-time profile unreliable 
 other events which could render the plasma concentration-time profile unreliable 
If one of these events occurs, it will be noted in the CRF as the study is being conducted. 
 
After bioanalysis 
 
Exclusion of subjects on the basis of pharmacokinetic reasons is possible only for: 
 subjects with non-zero baseline concentrations > 5% of Cmax for single dose and first 
multiple dose (day 1 and day 8) 
The samples from the subjects excluded from the PK set should still be assayed and the results 
listed. Subjects should not be excluded from the PK set if the AUC0-t covers less than 80% of 
the AUC0-∞. 
Any data excluded will be discussed in the CSR. 
 
13.2 
Sample size and power considerations 
 
Twelve (12) healthy male and female Chinese volunteers / cohort (24 in total) will be included 
in the study in order to have at least 8 completers / cohort. Drop-out subjects will not be replaced. 
Since no hypothesis will be tested, no formal sample size calculation has been performed. The 
sample size of this study has been determined in agreement with the guidance issued by the 
Chinese Food and Drug Administration (CFDA) for clinical pharmacokinetic studies (1). 
 
13.3 
Demographic, baseline and background characteristics 
 
Demographic and background characteristics will be examined according to qualitative or 
quantitative data. Qualitative data will be summarised in contingency tables. Quantitative data 
will be summarised using classic descriptive statistics. The baseline will be the last pre-dose 
measurement. 
 
13.4 
Analysis of pharmacokinetic parameters 
 
A descriptive PK will be presented. The results will be displayed and summarised in tables and 
figures. Individual and mean curves (+SD at nominal times), indicating inter-subject variability, 
will be plotted. Data below the lower limit of quantification (BLQ) will be 


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considered as 0 in the calculations and presented as BLQ in listings and tables. As a 
consequence of BLQ (i.e. 0) values, calculated geometric means (if requested) could be null. 
For this reason, in the presence of any null value, the geometric mean will be reported as not 
calculated (NC). 
 
13.5 
Safety and tolerability evaluation 
 
13.5.1 
Adverse events 
 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT), 
using the Medical Dictionary for Regulatory Activities (MedDRA). 
AEs will be classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs), 
according to the period of occurrence, as follows:  
 PTAEs: all AEs occurring before the first dose of investigational product and not 
worsening after the first dose of investigational product.  
 TEAEs: all AEs occurring or worsening after the first dose of investigational product 
 
Individual PTAEs and TEAEs will be listed in subject data listings. No summary table will be 
provided for PTAEs. TEAEs will be summarised by treatment and overall. The number and 
percentage of subjects with any TEAE and the number of TEAEs will be tabulated by SOC and 
PT, seriousness, relationship with investigational product and severity.  
 
13.5.2 
Physical examination 
 
Date of the physical examination, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be listed. 
 
13.5.3 
Laboratory data  
 
Date/time of samples collection, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
findings (if any) will be listed. All laboratory results will be listed and a table of all the abnormal 
values will be presented. 
 
13.5.4 
Vital signs 
 
Vital signs values will be listed and summarised by descriptive statistics. 
 
13.5.5 
Body weight  
 
Body weight values will be listed and summarised by descriptive statistics. 
 
 


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13.5.6 
ECG 
 
Date/time of ECG recording, overall investigator’s interpretation (as normal or abnormal and, 
if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be listed. Hard copies of the ECGs will be attached as source 
document at site.  


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14 
DEFINITION AND HANDLING OF AEs AND SAEs 
 
14.1 
Applicable SOPs 
 
AEs definition, classification and management will follow the CRO’s SOPs, based upon 
applicable local and international regulations. The full SOPs or an operative summary will be 
made available in the CRO. 
 
A brief summary of AE definition, classification and management is reported below. 
 
14.2 
Definition of Adverse Event (AE) 
 
An Adverse Event is “any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment”. 
AEs include: 
 worsening (change in nature, severity or frequency) of conditions present at the onset 
of the trial 
 patient/subject deterioration due to the primary illness 
 intercurrent illnesses 
 drug interactions 
 events related or possibly related to concomitant medications 
 abnormal laboratory values, as well as significant shifts from baseline within the range 
of normal, which the investigator considers to be clinically significant. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not considered related to the investigational 
medicinal product. 
 
14.3 
Definition of Adverse Drug Reaction (ADR) 
 
An Adverse Reaction is “any untoward and unintended response to an investigational 
medicinal product related to any dose administered”. 
All AEs judged by either the reporting investigator or the sponsor as having a reasonable causal 
relationship to a medicinal product qualify as adverse reactions. The expression reasonable 
causal relationship means to convey in general that there is evidence or matter to suggest a 
causal relationship. 
 
 Unexpected Adverse Drug Reaction 
 
An unexpected ADR is: “An adverse reaction, the nature, or severity of which is not consistent 
with the applicable product information (Reference Safety Information [RSI]).  
 
 Reference Safety Information (RSI): in order to assess whether an adverse reaction is 
expected, the SmPC will be used. 


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14.4 
Definition of Serious Adverse Events or Serious Adverse Drug Reaction 
 
A Serious Adverse Event (SAE) is: “any untoward medical occurrence or effect that at any 
dose: 
 results in death 
 is life-threatening (i.e. the subject was at risk of death at the time of the event/reaction; it 
does not refer to an event/reaction which hypothetically might have caused death if it were 
more severe) 
 requires inpatient hospitalization or prolongation of existing hospitalization 
 results in persistent or significant disability/incapacity (where disability is defined as a 
permanent or substantial disruption of ability to carry out normal life functions, either 
reported or defined as per clinical judgement) 
 is a congenital anomaly/birth defect 
 is an important medical event that may not result in death, be life-threatening, or require 
hospitalization but, according to appropriate medical judgment, it may jeopardize the 
subject and may require medical or surgical intervention to prevent any of the outcomes 
listed in the definition above.  Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, and blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.  
 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse event. 
 
A Serious Adverse Drug Reaction (SADR) is an ADR that meets also the definition of SAE.  
 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is an ADR that is both 
unexpected (not consistent with the applicable product information, e.g. SmPC) and also meets 
the definition of a SAE. 
 
A non-serious adverse event is any adverse event that does not meet the criteria listed above for 
a serious adverse event. 
 
 
14.5 
Definition of Severity of Adverse Events 
 
The term “severe” is used to describe the intensity (severity) of a specific event: 
- 
Mild: causing no limitation of usual activities; the subject may experience slight 
discomfort. 
- 
Moderate: causing some limitation of usual activities; the subject may experience 
annoying discomfort. 
- 
Severe: causing inability to carry out usual activities; the subject may experience 
intolerable discomfort or pain. 
 
14.6 
Definition of Adverse Event causality 
 


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Causality shall be determined according to the definition of ADR given in 14.3. 
 
All AE judged by either the investigator or the sponsor as having a reasonable suspected causal 
relationship to an investigational medicinal product qualify as adverse reactions. The causality 
assessment given by the investigator should not be downgraded by the sponsor. 
 
The following binary decision for causality will be used: 
 Reasonable possibility that the IMP caused the event 
 No reasonable possibility that the IMP caused the event 
Features supportive of an association include: 
 temporal plausibility 
 pharmacological properties of the drug or of the substance class 
 course of the adverse event after dechallenge and, if applicable, after rechallenge 
 specific tests indicating involvement of the drug in the occurrence/worsening of the 
adverse event  
 alternative explanations 
 
14.7 
Adverse Events recording 
 
Each AE occurring to a subject, either spontaneously revealed by the subject or observed by 
the investigator, whether believed by the investigator to be related or unrelated to the IMP, must 
be recorded on the AE information page of the CRF (for SAEs information must be recorded 
also on the “Serious Adverse Event Form”).  
The Investigator will also perform an evaluation with respect to seriousness and causality 
(relationship of any AE to IMP) of the AEs. and record it on the appropriate section of the CRF 
and on the “Serious Adverse Event Form” (if appropriate).  
 
14.8 
AEs monitoring window 
 
 Start of monitoring: from immediately after the signature of the informed consent 
 End of monitoring: up to final study visit/ETV (observation window)  
An AE occurring after the final visit/ETV and coming to knowledge of the investigator (e.g. 
during a follow-up assessment or by spontaneous reporting by study subjects) must be recorded 
only if it is an ADR, according to the investigator’s judgment. 
 
14.9 
Adverse Events reporting 
 
The official language for reporting is English. The investigator and clinical staff of the present 
study are familiar with English language. 
 
The investigator must report to the CRO all AEs which occur during the study, regardless of 
their relationship to the IMP. Protocol specific AEs or laboratory abnormalities critical to safety 


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evaluations are to be identified in the protocol and reported to the sponsor according to reporting 
requirements and within the time periods specified. 
 
All AEs are recorded by the investigator on the AE information page of the CRF. 
 
In addition, SAE will have to be reported according to the following detailed procedure. 
 
14.9.1 
SAEs reporting 
 
The investigator must report the SAEs to the CRO no later than 24 hours from when he/she 
becomes aware of the SAE, by Electronic Data Capture (preferred method), or e-mailing as 
scanned attachment (back up plan) or by faxing the “Serious Adverse Event Form” (back up 
plan) to the CRO,  as stated in the "List of CRO/ personnel" in § 14.13 of this protocol. 
 
The standards of confidentiality must always be maintained and any relevant national 
legislation on data protection must be followed. 
 
Another copy of the “Serious Adverse Event Form” will be sent to the Medical Affairs/Clinical 
Operations for the Sponsor’s file and another copy will be retained by the Investigator for the 
Investigator’s file. 
 
 
If the investigator becomes aware of any SAE occurred to a subject within the follow-up 
window established in the protocol, he/she will report the SAE as above. The SAE will be also 
reported in the CRF. 
 
If outside the follow-up window established in the protocol the investigator becomes aware of 
a SAE, if the investigator judges that the SAE is related to the study drug, it should be reported 
to the Sponsor. The Investigator might use the “Serious Adverse Event Form” via email or fax, 
but the SAE must not to be reported in the CRF, as it is not an event occurred within the study 
period. 
 
The investigator must report all SAEs that occur to the subjects to National Medical Products 
Administration/Local Ethics Committee/Provincial Food and Drug Administration/National 
Health and Family Planning Commission immediately no later than 24hours from when he/she 
becomes aware of SAE. Any SAEs that happen to the subjects outside the follow-up window 
should be reported by investigator to National Medical Products Administration/Local Ethics 
Committee/Provincial Food and Drug Administration/National Health and Family Planning 
Commission immediately. 
 
14.10 
Follow-up for Adverse Events 
 
A follow-up “Serious Adverse Event Form” will be filled in if important follow-up information 
(i.e. diagnosis, outcome, causality assessment, results of specific investigations) is made 
available after submission of the initial AE Form for immediate reporting. Follow-up “Serious 
Adverse Event Form” will be reported to the Sponsor as above-described, under Section 14.9.1. 
 


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In any case of an AE that, in the opinion of the investigator, requires the subject’s 
discontinuation, follow-up information relating to the subject’s subsequent course must be 
collected until the event has subsided or the condition stabilised or when the subject is lost to 
follow up or death. 
 
When follow-up data on non-serious AE are collected, information should be reported under 
“Comments” in the Final report of the CRF. 
 
14.11 
SUSARs management 
 
The clock for initial expedited reporting starts as soon as the information containing the 
minimum reporting criteria has been received by the CRO/sponsor (day 0).  
Fatal and life-threatening SUSARs, should be reported to Competent Authority as soon as 
possible and in any case within 7 days and to Ethics Committee per the requirement. 
If the initial report is incomplete, e.g. not all the information/assessments were available, a 
complete report should be sent within an additional 8 days. Complete follow-up report should 
be sent within 15 calendar days. 
SUSARs which are not fatal and not life-threatening are to be reported to Competent Authority 
within 15 days and to Ethics Committee per the requirement. 
The minimum information to be reported includes: 
 Sponsor study number 
 One identifiable coded subject 
 One identifiable reporter 
 One SUSAR 
 One suspect IMP (including active substance name, code) 
 A causality assessment. 
 
14.12 
Other events qualified for expedited reporting 
 
Other safety issues also qualify for expedited reporting may be sent to Competent authority 
when they might materially alter the current benefit-risk assessment of a medicinal product or 
would be sufficient to consider changes in the medicinal product administration or in the overall 
conduct of the trial, for instance: 
 single case reports of an expected serious adverse reaction with an unexpected outcome 
(e.g. a fatal outcome) 
 an increase in the rate of occurrence of an expected serious adverse reaction, which is 
judged to be clinically important. 
 post-study SUSARs that occur after the subject has completed a clinical trial and are 
reported to the investigator by the subject. 
 new events relating to the conduct of the trial or the development of the medicinal 
product likely to affect the safety of the subjects, such as : 
 a SAE which could be associated with the trial procedures and which could modify 
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 a significant hazard to the subject population such as lack of efficacy of a medicinal 
product used for the treatment of a life-threatening disease 
 a major safety finding from a newly completed animal study (such as carcinogenicity) 
or from other clinical trials. 
 
14.13 
SAEs: contacts 
 
The investigator will report any SAE to the CRO. The CRO’s details for SAEs are the 
following: 
Email: 
 
 
The sponsor’s details for SAEs are the following: 
Phone: 
 
Fax: 
 
Email: 
 
 
14.14 
Pregnancy 
 
Subjects must be instructed that known or suspected pregnancy occurring during the study 
should be confirmed and reported to the Investigator, who must then withdraw the subject from 
the study without delay. The Investigator should also be notified of pregnancy occurring during 
the study but confirmed after its completion. In the event that a subject is subsequently found 
to be pregnant after inclusion in the study, then any pregnancy will be followed up to the end 
of pregnancy or pregnancy termination and the status of mother and child will be reported to 
the Sponsor after delivery through the Pregnancy Report Form provided by the Sponsor. The 
Investigator will send pregnancy reports to DSU within the timeframes of SAEs, with follow-
up information to be actively sought for the outcome of pregnancy.  
- 
Part I of the Form is completed at the time of awareness of foetal exposure during 
pregnancy.  
- 
Part II of the Form is filled in when information on pregnancy outcome becomes available. 
If pregnancy results in abnormal outcome (spontaneous miscarriage, stillbirth and congenital 
anomalies) will be considered as SAE. If the investigator considers this to be due to the IMP, 
this will be treated as an expedited ADR report. 
 
 
PPD
PPD
PPD
PPD


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15 
DATA MANAGEMENT PROCEDURES 
 
15.1 
Data collection – CRFs 
 
The investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the eCRFs. He/she must also check that the data reported in the eCRFs correspond 
to those in the subject’s source documents.  
ECG and laboratory results must be printed and signed by the Investigator and kept as source 
data on site after entering outcome into the eCRF. 
All other data has to be documented in the subject file as source data first and then entered into 
the eCRF.  
Data must be entered into eCRFs in English by the designated site personnel as soon as possible 
after a subject visit, and monitors will have access to data recorded. These data will be reviewed 
versus source documents by trial monitors for completeness and acceptability during 
monitoring visits.  
If data correction is required for an eCRF after initial entry, the site personnel can make 
necessary corrections on their own or as a response to an automated query by the eCRF system. 
Monitor and Clinical Data Manager review the eCRF for accuracy and can also generate queries 
to the investigational staff for resolution.  
Any correction to the eCRFs' entries must be carried out by the Investigator or a designated 
member of staff. Corrections are recorded in an audit trail that records the old information, the 
new information, and identification of the person making the changes, date of correction made 
and reason for change. In the interests of completeness of data acquisition, the questions which 
are repeated in each section of the eCRFs should be answered in full, even if there are no 
changes from a previous examination. A reasonable explanation must be given by the 
Investigator for all missing data. The Investigator or his/her designees named in the clinical 
staff list will review the eCRF for accuracy and completeness. The Investigator must 
electronically sign and date the eCRF pages as indicated. 
 
15.2 
Database management 
 
The CRO will update and verify the database and create the final SAS data sets. The final data 
file will be transferred to the sponsor in the agreed format with all the other study documentation. 
 
15.2.1 
Coding dictionaries 
 
Medical/surgical history and underlying diseases, clinically significant physical examination 
abnormalities, AEs and previous and concomitant medications will be coded. 
Information on coding dictionaries will be provided in a Data Management Plan. 
 


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16 
STUDY MONITORING, QUALITY CONTROL AND 
QUALITY ASSURANCE 
 
16.1 
Monitoring 
 
The monitoring visits will be conducted by personnel of the CRO, PAREXEL.  
 
Monitoring activities, including monitoring purpose, selection and qualifications of monitors, 
extent and nature of monitoring, monitoring procedures, monitoring reports will comply with 
ICH-GCP chapter 5.18 requirements, CFDA-GCP and the monitoring plan. 
 
Adequate time and availability for monitoring activities should be ensured by the investigator 
and key study personnel. 
 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the investigator will assure support to the monitor at all times. 
 
The investigator agrees, by written consent to this protocol, to fully co-operate with compliance 
checks by allowing authorised individuals to have access to all the study documentation. In 
addition to the monitoring activities performed by the study monitor, the sponsor could perform 
some quality control activities to verify the compliance with the study procedures and the ICH-
GCP and CFDA-GCP guidelines 
 
16.2 
Quality Control and Quality Assurance  
 
The CRO has implemented and maintains a Quality System that includes quality controls and 
audits at different study steps with written SOPs to ensure that the study is conducted in 
compliance with the protocol and all effective amendments, ICH-GCP and CFDA-GCP, and 
the applicable regulatory requirement(s) and that data have been reliably and correctly 
generated, recorded, processed and reported, in agreement with the ALCOAC principles 
(Attributable-Legible-Contemporaneous-Original-Accurate-Complete). 
 
The clinical site(s) is responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, documented 
(recorded), and reported in compliance with the protocol, ICH-GCP, CFDA GCP and any 
applicable regulatory requirement(s). 
 
This protocol has been audited by the Sponsor QA.   
 
The CROs and the sponsor will be responsible for their respective activities. 
 
The sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a CRO, 
but the ultimate responsibility for the quality and integrity of the trial data always resides with 
the sponsor. 
 
 


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16.3 
Applicable SOPs 
 
The sponsor, the clinical centre and the CRO will follow their respective SOPs in the conduct 
of the respective activities, unless otherwise stated in written agreements. SOPs will be made 
available for Sponsor review, if required. 
 
16.4 
Data access 
 
The investigator and the CRO(s) will ensure that all source data, medical records, CRFs and all 
other documentation that is relevant to this study will be made accessible for monitoring 
activities, audits, IEC review, and regulatory inspections. 
 
16.5 
Audits and inspections 
 
The sponsors, independent bodies acting on behalf of the sponsor and the CRO have the right 
to perform audits according to ICH-GCP and CFDA responsibilities. 
 
The study may also be inspected by regulatory authorities.  
 
The investigator(s) and the CRO(s) agree, by written consent to this protocol, to fully co-operate 
and support audits and inspections compliance checks by allowing authorised individuals to 
have access to all the study documentation. 
 
 
 


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17 
ETHICAL CONSIDERATIONS 
 
17.1 
Ethics and Good Clinical Practice (GCP) 
 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
 
The approval of the study protocol by the relevant Ethics Committee will be obtained before 
the start of the study. 
Study notification to the Competent Authorities will be performed according to the current local 
regulations. 
 
The present clinical study will be carried out according to the current revision of Good Clinical 
Practice (GCP), ICH topic E6 (R2), CFDA Reg No. 25 “Good Clinical Practice (GCP) Mar 23, 
2016 and the applicable local law requirements. 
 
17.2 
Informed consent 
 
Before being enrolled into the clinical study, the subjects must have expressed their consent to 
participate, after the investigator has explained to them, clearly and in details, the scope, the 
procedures and the possible consequences of the clinical study. Information will be given in 
both oral and written form. The information sheet and informed consent form will be prepared 
in the local language by the CRO and must be approved by the EC and regulatory authorities. 
The document will include all the elements required by law according to the ICH-GCP 
recommendations.  
In addition to the standard requirements that physicians are currently obliged to observe when 
providing information, the following points must also be covered: 
 a description of the aims of the study and how it will be organised 
 the type of treatment (information on the IMP(s) and treatment procedures, as applicable) 
 any potential negative effects attributable to the study product or treatment 
 the freedom to ask for further information at any time 
 the subjects’ right to withdraw from the clinical study at any time without giving reasons 
and without jeopardising their further course of medical treatment  
 the existence of a subject insurance cover and obligations following from this cover 
 
Adequate time and opportunity to satisfy questions will be given to the subjects and the time 
will be recorded. 
 
The investigator will be supplied with an adequate number of blank informed consent forms to 
be used. The forms will be signed and dated by both the investigator and the subject.  
A copy of the signed form will be given to the subject. 
 
To ensure medical confidentiality and data protection, the signed informed consent forms will 
be stored in the investigator's study file according to the regulatory requirements. The 
investigator will allow inspection of the forms by authorised representatives of the sponsor, EC 


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members and regulatory authorities. He/she will confirm, by signing and dating the forms, that 
informed consent has been obtained. 
 
17.3 
Insurance policy 
 
An insurance cover has been issued in favour of the subjects participating in this clinical study. 
The insurance is in compliance with the local regulation and with the requirements of the Health 
Authorities. 
 
17.4 
Withdrawal of subjects 
 
It will be documented whether or not each subject completed the clinical study. If, for a subject, 
study treatment or observations are discontinued, the primary reason for discontinuation will 
be recorded. 
 
17.4.1 
Primary reason for discontinuation 
 
 Adverse event: Any (significant) adverse event that in the opinion of the investigator or 
concerned subject is not compatible with study continuation. For the definition of AE, 
please refer to § 14. 
 death: the absence of life or state of being dead 
 lost to follow-up: the loss or lack of continuation of a subject to follow-up 
 non-compliance with study drug: an indication that a subject has not agreed with or 
followed the instructions related to the study medication 
 physician decision: a position, opinion or judgment reached after consideration by a 
physician with reference to the subject 
 pregnancy: pregnancy is the state or condition of having a developing embryo or foetus in 
the body (uterus), after union of an ovum and spermatozoon, during the period from 
conception to birth 
 protocol deviation: an event or decision that stands in contrast to the guidelines set out by 
the protocol 
 study terminated by sponsor: an indication that a clinical study was stopped by its sponsor 
 technical problems: a problem with some technical aspect of a clinical study, usually 
related to an instrument 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 
 other: different than the ones previously specified 
 
17.4.2 
Discontinuation procedures 
 
For any subject discontinuing the study, the investigator will:  
 ask the subject to undergo, as far as possible, a final medical visit (ETV) to examine the 
subject's health conditions and perform the required blood sampling for the laboratory 


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assays. This examination will verify that all values tested at screening have remained within 
a clinically acceptable range (i.e. not clinically significant changes compared to screening) 
 arrange for alternative medical care of the withdrawn subject, if necessary 
 record the subject decision about the use of collected biological samples 
 report in the CRF date and time of the last dose administration, and date and primary reason 
of study discontinuation 
 record in the CRF any follow-up, if the subject is withdrawn for an AE 
 
Discontinued subjects will not be replaced.  
 
17.5 
Study termination 
 
The study will be considered terminated at the date of the last visit of the last subject or upon 
completion of any follow-up procedure described in the protocol. The investigator and the 
sponsor have the right to discontinue the study at any time for reasonable medical and/or 
administrative reasons. As far as possible, this should occur after mutual consultation. Reasons 
for discontinuation have to be documented appropriately. 


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18 
ADMINISTRATIVE PROCEDURES 
 
18.1 
Material supplied to the clinical centre 
 
Beside the investigational products, the following study material will be supplied to the clinical 
centre: 
 final version of the study protocol 
 access to the eCRF 
 copy of the SmPC relative to the investigational products 
 informed consent forms 
 investigator site file 
 laboratory supplies 
Moreover, before the start of the study, the investigator(s) will be provided with the following 
documents: ICH guidelines, confidentiality agreement (if applicable), protocol amendments (if 
any), declaration of Helsinki, insurance statement, SAE forms, financial agreement (if 
applicable), confidential subject identification code list form, drug accountability forms, 
investigator and study staff list form. 
 
18.2 
Protocol amendments 
 
In order to obtain interpretable results, neither the investigator nor the sponsor will alter the 
study conditions agreed upon and set out in this protocol. Amendments should be made by 
mutual agreement between the investigator and the sponsor. Any amendment must be set out 
in writing, giving the reasons, and being signed by all concerned parties. The amendment 
becomes then part of the protocol. 
 
All substantial amendments will be sent to the EC and concerned Competent Authorities, as 
appropriate. The amendment will be applicable only when it is approved, unless the changes 
consist of urgent safety measures to protect study subjects. 
 
Non-substantial amendments will be notified according to the current local regulations. 
 
18.3 
Study documentation and record keeping 
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the sponsor in the CRFs and in all required reports. 
 
The investigator must keep source documents for each subject in the study. Information present 
on the CRFs must be traceable to these source documents, which are generally stored in the 
subject's medical file. The source documents should contain all demographic and medical 
information, including laboratory data, ECGs, etc., and the original signed informed consent 
forms. 
 
Data reported on the CRF that are derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 


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The investigator and the sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirement(s).  
 
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are not 
limited to, study protocol, amendments, submission and approval of EC, raw data of subjects 
including lab tests and ECG tracing, insurance contracts, certificate of analysis of the IMP(s), 
drug accountability records, signed informed consent forms, confidential subjects identification 
code, CRFs, curricula vitae of the investigator and other participants in the study, study staff 
lists and responsibilities, monitoring reports and final study report. 
 
The investigator and the sponsor should take measures to prevent accidental or premature 
destruction of these documents. 
 
Study documents must be retained by the investigator and the sponsor as long as needed to 
comply with ICH-GCP, CFDA GCP national and international regulations. By signing the 
protocol, the investigator and the sponsor agree to adhere to these requirements. 
 
18.4 
Study subjects’ recruitment 
 
The CRO and its clinical site have detailed SOPs on the recruitment process. 
 
18.5 
Confidentiality and data protection 
 
By signing this protocol, the investigator agrees to keep all the information provided by the 
sponsor in strict confidentiality and to request the same confidentiality from his/her staff. Study 
documents provided by the sponsor (protocols, CRFs and other materials) will be stored 
appropriately to ensure confidentiality. The information provided by the sponsor to the 
investigator cannot be disclosed to others without direct written authorisation from the sponsor, 
except for the extent necessary to obtain the informed consent from the subjects wishing to 
participate in the study. 
 
Subjects data collected in the eCRFs during the study will be documented in an anonymous 
way. If, as an exception, for safety or regulatory reasons identification of a subject becomes 
necessary, the monitor, the sponsor and the investigator will be bound to keep this information 
confidential. 
 
18.6 
Publication policy 
 
The Investigator agrees to inform Zambon in advance about his/her intention to divulge any 
data, results concerning the Confidential Information and/or the study patient to this Agreement. 
As a consequence hereof, the Investigator hereby undertakes to submit to Zambon, at least with 
a sixty (60) days (30 in case of abstracts) prior written notice, the text and or the content of the 
concerned publication, divulgation as to allow Zambon to assess properly that such proposed 
publication respects and/or is not in conflict with Zambon’s rights to preserve and protect its 


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intellectual property rights and any confidentiality imposed to Zambon by the prevailing rules 
of the country where the study is conducted. 
Furthermore, without any prejudice to the Investigator’s right to divulge and save for what 
stated hereinabove, the Investigator intends to seek Zambon opinion and advice on and prior to 
the intended publication and/or disclosure, in consideration also of the contractual relationship 
in force between Zambon and Investigator and the nature of the study hereto. 
 
 


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19 
STUDY RESPONSIBLE PERSONS 
 
19.1 
Sponsor 
 
Zambon S.p.A., via Lillo del Duca 10, 20091 Bresso (Milan), Italy 
Phone: 
 
Fax: 
 
 
Protocol Review Committee Chairman  
 
 
Medical Expert 
 
 
19.2 
Institutes performing the study 
 
19.2.1 
Clinical centre 
 
"Denomination"  Address XXXXXXX, "Zip" "City", China 
Phone: 
+00.nnnnnnnnn 
Fax: 
+00.nnnnnnnnn 
Email: 
"Email"@"Specify".com 
 
Principal investigator 
"SpecifyName", MD 
 
19.3 
Drug assay 
 
Analytical Facility for PK/drug assay: 
 
United-Power Pharma Tech Co., Ltd. (UP-Pharma) 
Building 30, Lane 908, Ziping Road, Pudong New Area, Shanghai, P.R.China 
ZIP Code: 201318 
 
Analytical facilities and procedures are in compliance with the general principles of GLP 
regulations. 
 
19.4 
Co-ordination, data analysis & reporting 
 
PAREXEL International (IRL) Limited (“PAREXEL”), a corporation organized under the 
laws of Ireland with a registered address at 70 Sir John Rogerson’s Quay, Dublin 2, Ireland. 
 
19.5 
Project Management and Monitoring 
 
PAREXEL International (IRL) Limited (“PAREXEL”), a corporation organized under the 
laws of Ireland with a registered address at 70 Sir John Rogerson’s Quay, Dublin 2, Ireland. 
 
PPD
PPD
PPD
PPD


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20 
REFERENCES 
 
1. CFDA Guidance 
2. EMA Commission Implementing Decision C (2015) 1390 (final)  – Xadago (safinamide). 24 February 2015 
3. Summary of Product Characteristics (SmPC) – Xadago 50 mg, 100 mg film-coated tablets 
4. Caccia C, Maj R, Calabresi M, Maestroni S, Faravelli L, Curatolo L, Salvati P, Fariello RG. Safinamide: from 
molecular targets to a new anti-Parkinson drug. Neurology. 2006 Oct 10;67(7 Suppl 2):S18-23. 
5. Schapira AH. Monoamine oxidase B inhibitors for the treatment of Parkinson's disease: a review of 
symptomatic and potential disease-modifying effects. CNS Drugs. 2011 Dec 1;25(12):1061-71 
6. Salvati P, Maj R, Caccia C, Cervini MA, Fornaretto MG, Lamberti E, Pevarello P, Skeen GA, White HS, 
Wolf HH, Faravelli L, Mazzanti M, Mancinelli E, Varasi M, Fariello RG. Biochemical and 
electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound. J 
Pharmacol Exp Ther. 1999 Mar;288(3):1151-1159. 
7. Pevarello P, Amici R, Bonsignori A, Caccia C, Amici R, McArthur RA, Fariello RG, Salvati P, Varasi M. 
Sodium channel activity and sigma binding of 2-aminopropanamide anticonvulsivants. Bioorg Med Chem 
Lett. 1999 Sep 6;9(17):2521-4. 
8. Binda C, Milczek EM, Bonivento D, Wang J, Mattevi A, Edmondson DE. Lights and shadows on monoamine 
oxidase inhibition in neuroprotective pharmacological therapies. Curr Top Med Chem. 2011 
Nov;11(22):2788-96. Review. 
9. Schapira AH. Safinamide in the treatment of Parkinson's disease. Expert Opin Pharmacother. 2010 
Sep;11(13):2261-8 
10. Onofrj M, Bonanni L, Thomas A. An expert opinion on safinamide in Parkinson's disease. Expert Opin 
Investig Drugs. 2008 Jul;17(7):1115-25 
11. Marzo A, Dal Bo L, Monti NC, Crivelli F, Ismaili S, Caccia C, Cattaneo C, Fariello RG. Pharmacokinetics 
and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity. 
Pharmacol Res 2004; 50(1):77-85 
12. Leuratti C, Sardina M, Ventura P, Assandri A, Müller M, Brunner M. Disposition and metabolism of 
safinamide, a novel drug for Parkinson's disease, in healthy male volunteers. Pharmacology. 2013;92(3-
4):207-16 
13. Marquet A, Kupas K, Johne A, Astruc B, Patat A, Krösser S, Kovar A. The effect of safinamide, a novel drug 
for Parkinson's disease, on pressor response to oral tyramine: a randomized, double-blind, clinical trial. Clin 
Pharmacol Ther. 2012 Oct;92(4):450-7  
14. Di Stefano AFD, Rusca A. Pressor response to oral tyramine during co-administration with safinamide in 
healthy volunteers. Naunyn-Schmiedeberg's Arch Pharmacol 2011; 384:505-515 
15. Cattaneo C, Caccia C, Marzo A, Maj R, Fariello RG. Pressor response to intravenous tyramine in healthy 
subjects after safinamide, a novel neuroprotectant with selective, reversible monoamine oxidase B inhibition. 
Clin Neuropharmacol. 2003 Jul-Aug;26(4):213-7. 
16. Guidelines on GMP, published by the Commission in The rules governing medicinal products in the European 
Community, Volume 4 
17. U.S. Department of Health and Human Services and U.S. Department of Agriculture, Nutrition and your 
health: 2015-2020 Dietary Guidelines, Appendix 9 
18. Safinamide Investigator’s Brochure, Edition Number 4, dated 13 February 2018.  
 
 
 
 
 


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21 
APPENDIX 1 
 
ACTIVITIES 
 
Period 1 
Screening
Single Dose  
Visit
V1
V2
V3
V4
Day 
Day -14/-2
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Informed consent 
x
Demography
x
Lifestyle 
x
Medical and surgical history  
x
Physical examination3
x
Prior and concomitant medications 
x
x
x
x
x
x
x
Height 
x
Body Weight3 
x
Laboratory analysis4 
x
Virology 
x
Serum pregnancy test (women) 
x
Urine multi-drug kit test 
x
x
Blood pressure and heart rate5 
x
x
x
Alcohol breath test 
x
Urine pregnancy test (women) 
x
ECG6 
x
Inclusion/exclusion criteria 
x
x
Subject eligibility
x
x
Enrolment and randomisation
x
Confinement 
x
x
x
x
x
x
Investigational product 
administration 
 
 
x7  
 
 
 
 
Blood sampling for PK analysis 
x8 
x8
x8
x8
x8
Standardized meals11  
x
x
x
x
x
x
Adverse event monitoring12 
x
x
x
x
x
x
x
 
 




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1. 
Early termination visit (ETV) 
2. 
Final visit on day 18  
3. 
Physical examination, including body weight, at screening and final visit/ETV 
4. 
Laboratory analyses at screening and final visit/ETV  
5. 
At pre-dose (before blood sampling and within 30 min of investigational product administration), at 2 h (± 15 min) and 96 h (± 15 min) after day 1 single dose and after day 14 
last multiple dose. At pre-dose (before blood sampling and within 30 min of investigational product administration) and 2 h (± 15 min) after the day 8 first multiple dose. At 
pre-dose (before blood sampling and within 30 min of investigational product administration) on day 10 to day 13. 
6. 
At screening and final visit/ETV  
7. 
On day 1 (Period 1) and once daily from day 8 to day 14 (Period 2), at 8 00 ± 1 h 
8. 
At pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 36, 48, 72 and 96 h post-dose after the first single dose (day 1) and the last multiple dose (day 14);  
9. 
At pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose after the first multiple dose (day 8) 
10. At pre-dose (0) on each day (day 10-13) 
11. Day -1  standardized dinner; 
Day 1, Day 8, Day 14  standardized lunch at approximately 5 h post-dose, standardized dinner at approximately 13 h post-dose;  
 
 
Day 2 to Day 5, Day 9 to Day 13, and Days 15 to 17  standardized breakfast (after PK sampling), lunch and dinner; 
 
 
Day 6 and Day 7  standardized breakfast, lunch, and dinner; 
Day 18  standardized breakfast (after PK sampling) 
12. Adverse events monitored starting at the screening visit, immediately after informed consent, up to the final visit/ETV 
 

SAP_001.pdf: 
 
 
 
A PHASE I, PHARMACOKINETICS, SAFETY AND TOLERABILITY 
STUDY OF SINGLE AND MULTIPLE ORAL DOSES OF SAFINAMIDE 
IN HEALTHY ADULT CHINESE VOLUNTEERS 
 
 
 
ClinicalTrials.gov Identifier: NCT03887221 
 
 
 
 
 
Statistical Analysis Plan Version 1.0: 12 December 2018 
Statistical Analysis Plan version 2.0: 10 October 2019 
 


PAREXEL International 
Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
CONFIDENTIAL 
Project Document Version No. 1.0 
Project Document Effective Date: <12Dec2018> 
                                                                                                             Page 1 of 31 
 
 PAREXEL International 
Zambon SpA 
Z7219J03 
 A PHASE I, PHARMACOKINETICS, SAFETY AND TOLERABILITY STUDY OF SINGLE 
AND MULTIPLE ORAL DOSES OF SAFINAMIDE IN HEALTHY ADULT CHINESE 
SUBJECTS    
Statistical Analysis Plan 
Version: 1.0 
PAREXEL Project Number: 
 
 
 
CCI
CCI






PAREXEL International 
Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
CONFIDENTIAL 
Project Document Version No. 1.0 
Project Document Effective Date: <12Dec2018> 
                                                                                                             Page 4 of 31 
TABLE OF CONTENTS 
 
1 
INTRODUCTION .................................................................................................... 10 
2 
STUDY OBJECTIVES ............................................................................................. 10 
2.1 
Primary Objective ..................................................................................................... 10 
2.2 
Secondary Objective ................................................................................................. 10 
3 
INVESTIGATIONAL PLAN.................................................................................... 11 
3.1 
Overall Study Design and Plan .................................................................................. 11 
3.2 
Endpoints and Associated Variables .......................................................................... 11 
3.2.1 
Efficacy Variables ................................................................................................ 11 
3.2.2 
Pharmacokinetic Variables ................................................................................... 11 
3.2.3 
Safety Variables ................................................................................................... 15 
3.2.3.1 Adverse Events .................................................................................................... 15 
3.2.3.2 Clinical Laboratory Tests...................................................................................... 16 
3.2.3.3 Vital Signs ........................................................................................................... 17 
3.2.3.4 12-Leads ECGs .................................................................................................... 17 
3.2.3.5 Physical Examination ........................................................................................... 17 
3.2.3.6 Prior/Concomitant Medication .............................................................................. 17 
4 
STATISTICAL METHODS...................................................................................... 17 
4.1 
Data Quality Assurance............................................................................................. 17 
4.2 
General Presentation Considerations.......................................................................... 18 
4.3 
Software Considerations ........................................................................................... 19 
4.4 
Study Subjects .......................................................................................................... 19 
4.4.1 
Disposition of Subjects ......................................................................................... 19 
4.4.2 
Protocol Deviations .............................................................................................. 19 
4.5 
Analysis Sets ............................................................................................................ 20 
4.5.1 
Randomized Set ................................................................................................... 20 
4.5.2 
Safety Set............................................................................................................. 20 
4.5.3 
Pharmacokinetic Set ............................................................................................. 20 
4.6 
Demographics and Baseline Characteristics ............................................................... 21 
4.7 
Medical History and Concomitant Illnesses ............................................................... 21 
4.8 
Prior and Concomitant Medications........................................................................... 21 
4.9 
Treatment Exposure / Compliance ............................................................................. 22 
4.10 Pharmacokinetics Evaluation..................................................................................... 22 
4.10.1 
Pharmacokinetics Concentrations.......................................................................... 22 
4.10.1.1 Handling of Values Below the Limit of Quantification (BLQ) ............................... 23 
4.10.1.2 Pharmacokinetic Parameters ................................................................................. 23 
4.11 Safety Evaluation...................................................................................................... 24 
4.11.1 
Adverse Events .................................................................................................... 24 
4.11.2 
Deaths, Serious Adverse Events, and Other Significant Adverse Events ................. 26 
4.11.3 
Clinical Laboratory Evaluation ............................................................................. 26 
4.11.4 
Vital Signs, Physical Findings and Other Observations Related to Safety ............... 27 
4.12 Determination of Sample Size ................................................................................... 28 
4.13 Changes in the Conduct of the Study or Planned Analysis .......................................... 28 
CCI


PAREXEL International 
Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
CONFIDENTIAL 
Project Document Version No. 1.0 
Project Document Effective Date: <12Dec2018> 
                                                                                                            Page 5 of 31 
5 
REFERENCES ......................................................................................................... 28 
6 
APPENDICES.......................................................................................................... 29 
 
 
CCI


PAREXEL International 
Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
CONFIDENTIAL 
Project Document Version No. 1.0 
Project Document Effective Date: <12Dec2018> 
                                                                                                            Page 6 of 31 
REVISION HISTORY 
 
 
Version No. 
Effective Date 
Summary of Change(s) 
1.0 
12 Dec 2018 
New Document 
 
 
CCI








PAREXEL International 
Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
CONFIDENTIAL 
Project Document Version No. 1.0 
Project Document Effective Date: <12Dec2018> 
                                                                                                            Page 10 of 31 
1 
INTRODUCTION 
The present study will be part of safinamide registration package in China and was designed 
according to CFDA guideline recommendations. Safinamide has been granted marketing 
authorization in EU (2015), US (2017) and Switzerland (2015).   
In the present study, safinamide pharmacokinetic profile, safety and tolerability after single dose 
and at steady state will be investigated for the first time in Chinese healthy male and female 
volunteers. 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing 
study data and outlines the statistical programming specifications for the Tables, Listings and 
Figures (TLFs). It describes the variables and populations, anticipated data transformations and 
manipulations and other details of the analyses not provided in the Clinical Study Protocol (CSP). 
The analyses described in this SAP are based upon the following study documents: 
• Study Protocol, Version 1.0 (December 10, 2018) 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• To evaluate plasma safinamide pharmacokinetic parameters after single and multiple dose 
administration of the investigational medicinal products (IMP) 
 
2.2 
Secondary Objective 
• To collect safety and tolerability data after single and multiple dose administration of the 
IMP 
 
CCI


PAREXEL International 
Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
CONFIDENTIAL 
Project Document Version No. 1.0 
Project Document Effective Date: <12Dec2018> 
                                                                                                            Page 11 of 31 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
Phase I, single center, single and multiple-dose, 
open-label, randomized, parallel-group, 
pharmacokinetics, safety and tolerability clinical study. 
The study population will consist of 24 adult healthy male and female subjects (12 / cohort). 
Subjects will be randomized to 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), according to 
the study randomized, parallel-group design, as follows: 
Cohort 
Period 1 - single dose 
Day 1 
Washout 
Period 2 - Multiple doses 
Days 8 - 14 
Cohort 1 
50 mg po 
7 days 
50 mg po o.d for 7 days 
Cohort 2 
100 mg po 
100 mg po o.d. for 7 days 
 
 
3.2 
Endpoints and Associated Variables 
3.2.1 Efficacy Variables 
NA 
 
3.2.2 Pharmacokinetic Variables 
Unless otherwise stated, derivation of Pharmacokinetic (PK) parameters will be the responsibility 
of Qualitative Clinical Development (QCD), PAREXEL International.  The following PK 
parameters will be determined for Investigational Medicinal Product (IMP) in plasma following 
single dose and multiple dose administration: 
CCI


PAREXEL International 
Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
CONFIDENTIAL 
Project Document Version No. 1.0 
Project Document Effective Date: <12Dec2018> 
                                                                                                            Page 12 of 31 
Table 1 
Pharmacokinetic Parameters after Single Dose Administration 
Parameter 
Definition 
Cmax 
Maximum observed concentration 
tmax 
Time corresponding to occurrence of Cmax 
t½ 
Apparent terminal elimination half life 
Kel 
Terminal elimination rate constant 
AUC(0-t) 
AUC from time zero to the last quantifiable concentration 
AUC(0-inf) 
AUC from time zero extrapolated to infinity 
%AUCex 
Percentage of AUC(0-inf) obtained by extrapolation 
CL/F 
Apparent clearance following oral administration 
Vz/F 
Apparent volume of distribution during terminal phase 
 
Table 2 
Pharmacokinetic Parameters after Multiple Dose Administration 
Parameter 
Definition 
Cmax,ss 
Maximum observed concentration at steady state 
Cmin,ss 
Minimum observed concentration at steady state 
tmax,ss 
Time corresponding to occurrence of Cmax,ss at steady state 
t½,ss 
Apparent terminal elimination half-life at steady state 
Kel.ss 
Terminal elimination rate constant at steady state 
AUC(0-τ),ss 
AUC over the dosing interval at steady state 
CL/F, ss 
Apparent clearance following oral administration at steady state 
Vz /F,ss 
Apparent volume of distribution during terminal phase at steady state 
Cavg,ss 
Average concentration at steady-state 
DF% 
Peak trough fluctuation 
Racc 
Accumulation ratio 
 
 
 
 
 
CCI


PAREXEL International 
Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
CONFIDENTIAL 
Project Document Version No. 1.0 
Project Document Effective Date: <12Dec2018> 
                                                                                                            Page 13 of 31 
Pharmacokinetic Parameter Calculation Methods 
PK parameters will be calculated by non-compartmental analysis methods from the concentration-
time data using WinNonlin (WNL) Professional (Version 6.3 or higher) following these 
guidelines: 
• Actual sampling times relative to dosing rather than nominal times will be used in the 
calculation of all derived PK parameters. 
• There will be no imputation of missing data. Any subjects with missing concentration data 
will be included in the PK analysis set provided that at least one PK parameter can be 
reliably calculated. 
• Single dose: All below the limit of quantification (BLQ) values pre-dose and in the 
absorption phase prior to the first quantifiable concentration will be substituted by zeros. 
Thereafter BLQ values between evaluable concentrations will be substituted by missing 
before the calculation of the PK variables. Terminal BLQ values will be disregarded. 
• Multiple dose: For Day 1, all BLQ values pre-dose and in the absorption phase prior to the 
first quantifiable concentration will be substituted by zeros. For subsequent dosing days 
not separated by a washout, BLQ values pre-dose, in the absorption phase, and between 
evaluable concentrations will be substituted by missing, before the calculation of the PK 
variables. Terminal BLQ values will be disregarded. 
PK parameters will be estimated according to the following guidelines: 
For single dose 
• Cmax will be obtained directly from the concentration-time data. 
• tmax is the time at which Cmax is observed. 
• Kel will be estimated at terminal phase by linear regression after log-transformation of the 
concentrations: 
 Only those data points that are judged to describe the terminal log-linear decline will be 
used in the regression.  
CCI


PAREXEL International 
Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
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Project Document Version No. 1.0 
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 A minimum number of three data points in the terminal phase will be used in calculating 
Kel with the line of regression starting at any post-Cmax data point (Cmax should not be part 
of the regression slope) and including Clast, tlast. 
 The adjusted correlation coefficient (R2 adjusted) in general should be greater than 0.80. 
Any value less than 0.80 may be used at the PK Scientist’s best knowledge and judgment. 
 An appropriate number of decimal places should be used for Kel to enable the reported 
value of t½ to be calculated. 
• t1/2 will be calculated as ln2/ Kel. 
• AUC is calculated as follows: 
 The linear trapezoidal method will be employed for all incremental trapezoids arising from 
increasing concentrations and the logarithmic trapezoidal method will be used for those 
arising from decreasing concentrations. 
 AUC(0-t)=
. 
 AUC(0-inf) =
＋
= AUC(0-t)＋Ct/Kell. 
 Ct is last observed quantifiable concentration. 
• %AUCex will be calculated as (1－[AUC(0-t)/AUC(0-inf)] )×100. 
• CL/F will be calculated as dose/AUC(0-inf), parent drug only. 
• Vz/F will be calculated as CL/F/λZ, parent drug only. 
For multiple dose 
• Cmax,ss at steady state will be obtained directly from the concentration-time data. 
• Cmin,ss at steady state will be obtained directly from the concentration-time data. 
• tmax,ss time at which Cmax,ss occurs at steady state. 
• t½,ss will be calculated as ln2/ Kel,ss. 
• Kel,ss will be estimated at terminal phase by linear regression 
 Only those data points that are judged to describe the terminal log-linear decline will be 
used in the regression.  

 t
0
dt
t
C )
(

 t
0
dt
t
C )
(


t
dt
t
C
)
(
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PAREXEL International 
Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
CONFIDENTIAL 
Project Document Version No. 1.0 
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 A minimum number of three data points in the terminal phase will be used in calculating 
Kel,ss with the line of regression starting at any post-Cmax,ss data point (Cmax,ss should not be 
part of the regression slope) and including Clast, tlast. 
 The adjusted correlation coefficient (R2 adj) in general should be greater than 0.80. Any 
value less than 0.80 may be used at the PK Scientist’s best knowledge and judgment. 
 An appropriate number of decimal places should be used for Kel,ss to enable the reported 
value of t½,ss to be calculated. 
• AUC0-τ,ss       Area under the concentration-time curve over the dosing interval will be 
calculated using linear trapezoidal method; all incremental trapezoids arising from 
increasing concentrations and the logarithmic trapezoidal method will be used for 
those arising from decreasing concentrations. 
• CL /F,ss         Apparent clearance following oral administration at steady state for the parent 
drug calculated as dose/ AUC(0-τ). 
• Vz /F,ss         Apparent volume of distribution during terminal phase at steady state for the 
parent drug calculated as CL/F,ss / λZ,ss. 
• Cavg,ss            Average steady-state concentration calculated as AUC(0 τ),ss/τ. 
 
The following PK parameters will also be derived using Statistical Analysis Software (SAS®) 
(version 9.3 or higher). 
• DF%          Peak trough fluctuation calculated as 100* (Cmax,ss - Cmin,ss)/ Cavg,ss.  
• Racc                     Accumulation ratio calculated as: 
Cmax (last dose interval)/ Cmax (first dose interval). 
AUC(0-τ),ss (last dose interval)/ AUC(0-τ),ss (first dose interval). 
 
3.2.3 Safety Variables 
3.2.3.1 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
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(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal 
product. 
All AEs will be coded using the latest available version of MedDRA. 
A treatment-emergent adverse event (TEAE) is defined as an AE that begins or that worsens in 
severity after at least one dose of the study drug has been administered. 
Any AEs with incomplete start and end dates/times will be treated as follows: 
• Adverse events with unknown start and/or end times (but where the date is known) will be 
imputed with a time of 00:00 h for the tabulations but will be shown as NK:NK in the 
listings (where NK = Not Known). 
• Adverse events with completely unknown start dates will be considered as treatment-
emergent for the tabulations and will be shown as NK in the listings. 
 
3.2.3.2 Clinical Laboratory Tests 
The following safety laboratory parameters will be measured: 
• Hematology: Leukocytes and leukocyte differential count (percentage values and absolute 
values), 
erythrocytes, hemoglobin, 
hemoglobin, 
hematocrit, 
MCV, MCH, MCHC, 
thrombocytes. 
• Biochemistry: sodium, 
potassium, calcium, chloride, inorganic phosphorus, alkaline 
phosphatase, γ-GT, AST, ALT, total bilirubin, creatinine, glucose, urea BUN, uric acid, total 
cholesterol, triglycerides, total proteins.  
• Urinalysis: stick (pH, specific weight, appearance, color, nitrites, proteins, glucose, 
urobilinogen, 
bilirubin, ketones, hematic pigments, leukocytes), sediment (leukocytes, 
erythrocytes, flat cells, round cells, crystals, cylinders, mucus, bacteria)   
• Serology: Hepatitis B (HBs antigen), Hepatitis C (HCV antibodies), HIV 1/2 (HIV Ag/Ab 
combo). 
• Drugs of abuse: urine multi-drug 
kit (cocaine, amphetamine, morphine, 
cannabis, 
benzodiazepines, barbital)  
• Pregnancy test: only for female (serum, urine) 
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Overall investigator’s interpretation (as normal or abnormal and, if abnormal, clinically significant 
(NS) or not clinically significant (NCS)) and clinically significant findings (if any) will be reported 
in the individual eCRFs. All CS abnormalities after the screening visit will be recorded as AEs. 
 
3.2.3.3 Vital Signs 
 
The following vital signs measurements will be obtained: 
• Systolic blood pressure (SBP) [mmHg] 
• Diastolic blood pressure (DBP) [mmHg] 
• Heart rate (bpm) 
 
3.2.3.4 12-Leads ECGs 
The ECG recording will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, NCS’ or 
‘Abnormal, CS’. 
 
3.2.3.5 Physical Examination 
Full physical examinations will be performed, overall investigator’s interpretation (as normal or 
abnormal and, if abnormal, CS or NCS) and CS abnormalities (if any) will be reported in the 
individual CRFs. 
All CS abnormalities after the screening visit will be recorded as AEs. 
 
3.2.3.6 Prior/Concomitant Medication 
Prior and concomitant medication will be coded using the latest version of World Health 
Organization-Drug Dictionary (WHO-DD) and will be classified by Anatomical Therapeutic 
Chemical (ATC) categories. 
 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard PAREXEL procedures. 
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Z7219J03                                                                                                                                Statistical Analysis Plan 
 
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4.2 
General Presentation Considerations 
‘Baseline’ is defined as the last available pre-treatment assessment. ‘End of Study’ is defined as 
the last available post-treatment assessment.  ‘Treatment Day’ will be calculated relative to the 
date of randomization i.e. Treatment Day = Assessment Date -Randomization Date + 1. ‘Week 1’ 
will be defined as the mean of the Day 1 to Day 7 values, ‘Week 2’ will be defined as the mean of 
the Day 8 to Day 14 values and so on.   
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, 
minimum, maximum and number of observations, unless otherwise stated.  
Continuous data that are expected to be skewed will be presented in terms of the maximum, upper 
quartile, median, lower quartile, minimum and number of observations.  The minimum and 
maximum will be reported to the same number of decimal places as the raw data recorded in the 
database.  The mean, median, lower quartile and upper quartile will be reported to one more 
decimal place than the raw data recorded in the database.  The SD will be reported to two more 
decimal places than the raw data recorded in the database.  In general, the maximum number of 
decimal places reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at the 
relevant time point (n), frequency counts and percentages.  Any planned collapsing of categories 
will be detailed in the SAP text and the data displays.   
Percentages will be presented to one decimal place. Percentages will not be presented for zero 
counts.  Percentages will be calculated using n as the denominator.  If sample sizes are small, the 
data displays will show the percentages, but any textual report will describe frequencies only.   
Changes from baseline in categorical data will be summarized using shift tables where appropriate. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places.  P-
values less than 0.001 will be presented as “<0.001”. 
Confidence intervals will be presented to one more decimal place than the raw data. 
 
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4.3 
Software Considerations 
All report outputs will be produced using SAS® version 9.4 or a later version in a secure and 
validated environment.  
PK analyses will be produced using Phoenix® WinNonLin (WNL) version 6.3 or a later version 
in a secure and validated environment.  
All report outputs will be provided to the Sponsor in RTF format.   
 
 
4.4 
Study Subjects 
4.4.1 Disposition of Subjects 
A clear accounting of the disposition of all subjects who enter the study will be provided, from 
screening to study completion. 
• A summary of the number of subjects screened for entry into the study and the number and 
percentage of subjects excluded prior to randomization by major reason and overall. 
• A summary of the number of subjects randomized, the number and percentage of subjects 
treated (with at least one dose of study medication) and the number and percentage of 
subjects withdrawing from study treatment, withdrawing from the study and completing 
each period of the study by treatment group and overall.  Withdrawals from the study and 
from study treatment should also be summarized by major reason. 
By-subject listings of eligibility details, randomization details (including whether the blind was 
broken at discontinuation), visit dates and withdrawal/study completion details (including reason 
for discontinuation and duration of treatment prior to discontinuation) should be provided. 
 
4.4.2 Protocol Deviations 
All protocol deviations will be recorded by the Investigator and will be listed by subject. All 
protocol deviations will be discussed between PAREXEL and the Sponsor during the clean file 
meeting before database lock in order to determine whether these may warrant exclusion of a 
subject from the statistical analyses. 
• A summary of the number and percentage of subjects with a major (decided by sponsor) 
protocol deviation by treatment group and overall 
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A by-subject listing of major protocol deviations should be provided. 
 
 
4.5 
Analysis Sets 
4.5.1 Randomized Set 
The randomized set includes all subjects randomized. This analysis set will be used for 
demographic, baseline and background characteristics. 
 
4.5.2 Safety Set 
The safety set includes all subjects who receive at least 1 dose of IMP. Safety analyses will be 
based on the treatment actually received, not on the treatment to which the subject was randomized. 
The safety summaries and analyses will be based on the Safety Set.   
 
4.5.3 Pharmacokinetic Set 
The PK Set will include all subjects who have received at least one dose of IMP with at least one 
primary PK parameter evaluable and without any major protocol deviation thought to interfere 
with the absorption, distribution, metabolism, and excretion of the compound to be measured. Any 
data excluded will be discussed at data review meeting before PK parameters are available. 
Data may/will be excluded (depending on the protocol and IMP under study) from PK analysis 
(concentrations listed only) if any of the following criteria are fulfilled: 
• Concomitant medication, which could render the plasma concentration time profile 
unreliable  
• The pre-dose concentration is greater than 5% of the corresponding Cmax in any given 
treatment period. 
• Subject vomits within 2 x the reported median t max for the analyte (oral studies only). 
• Subject has moderate or severe diarrhea within 2 x the reported median tmax for the analyte 
(oral studies only). 
• Other events which could render the plasma concentration-time profile unreliable (such as 
AEs, administration errors etc.). 
 
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Z7219J03                                                                                                                                Statistical Analysis Plan 
 
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4.6 
Demographics and Baseline Characteristics 
The summaries and listings provided include the following: 
• demographic variables (age, sex, ethnic origin, race, height and weight, Body mass index 
(BMI)) by treatment group and overall 
• other possibly relevant variables (drug, alcohol, and smoking history) by treatment group 
and overall 
Age will be calculated as the number of complete years between a subject's birth date and the date 
of informed consent. 
 
 
4.7 
Medical History and Concomitant Illnesses 
All medical history and concomitant illness will be coded using the latest available version of the 
Medical Dictionary for Regulatory Activities (MedDRA). 
All medical history and concomitant illness will be summarized by System Organ Class (SOC) 
and Preferred Term (PT) for each cohort/period and listed using the safety set. 
 
4.8 
Prior and Concomitant Medications 
Medication start and stop dates will be compared to the date of first dose of study medication to 
allow medications to be classified as either Prior only, both Prior and Concomitant, or Concomitant 
only.  Medications starting after the completion/withdrawal date will be listed but will not be 
classified or summarized. 
Medications that start and stop prior to the date of first dose of study medication will be classified 
as Prior only.  If a medication starts before the date of first dose of study medication and stops on 
or after the date of first dose of study medication, then the medication will be classified as both 
Prior and Concomitant.  Medications will be classified as Concomitant only if they have a start 
date on or after the date of first dose of study medication. 
If medication start and/or stop dates are missing or partial, the dates will be compared as far as 
possible with the date of first dose of study medication.  Medications will be assumed to be 
Concomitant only, unless there is clear evidence (through comparison of partial dates) to suggest 
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Z7219J03                                                                                                                                Statistical Analysis Plan 
 
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that the medication started prior to the first dose of study medication.  If there is clear evidence to 
suggest that the medication started prior to the first dose of study medication, the medication will 
be assumed to be both Prior and Concomitant, unless there is clear evidence to suggest that the 
medication stopped prior to the first dose of study medication.  If there is clear evidence to suggest 
that the medication stopped prior to the first dose of study medication, the medication will be 
assumed to be Prior only. 
Prior and concomitant medication will be coded using the latest version of World Health 
Organization-Drug Dictionary (WHO-DD) and will be classified by Anatomical Therapeutic 
Chemical (ATC) categories. 
All prior/concomitant medications will be summarized by ATC4 and Preferred Term (PT) for each 
cohort/period and listed using the safety set. 
 
 
4.9 
Treatment Exposure / Compliance 
Per ICH E3: When the dose in each [subject] can vary, the actual doses received by [subjects] 
should be shown and individual [subject's] doses should be [presented in a listing].  
Study treatment will be administered under the supervision of investigator site personnel. The date 
and time of IMP administration will be listed by subject using the safety set. 
 
 
4.10 Pharmacokinetics Evaluation 
4.10.1 Pharmacokinetics Concentrations 
Pharmacokinetic concentration data for will be listed by subject including actual sampling times 
relative to cohort/period based on PK set. Plasma concentrations below the lower limit of 
quantification (LLOQ) will be presented as BLQ in the listings. Plasma concentrations will be 
summarized by dose cohort, period, and nominal timepoint. The following descriptive statistics 
will be presented for plasma concentrations obtained at each nominal time point: n, arithmetic 
mean, SD, coefficient of variation (CV%), geometric mean, geometric CV% (calculated as:  
gCV% =SQRT(exp(s2)-1)*100; where s is the standard deviation of the log-transformed values), 
median, minimum and maximum values. 
The following rules will be followed with regards to the number of decimal places and presentation 
of data in the tables and listings of concentration data:  
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Z7219J03                                                                                                                                Statistical Analysis Plan 
 
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• Source data shall be used in all derived PK concentrations without prior rounding  
• The mean, standard deviation (SD), geometric mean and median will be tabulated to one 
more significant digit compared to the source data, but with a maximum of four significant 
digits.  
• Minimum and maximum values will be tabulated to the same precision as the source data, 
but with a maximum of four significant digits.  
• Geometric coefficient of variation (CV) % and coefficient of variation (CV%) will be 
presented to one decimal place.  
Individual plasma concentration versus actual times will be plotted by cohort/period in linear and 
semi-logarithmic scale. Mean plasma concentrations versus nominal times will also be presented 
in linear and semi-logarithmic scale. 
  
4.10.1.1 Handling of Values Below the Limit of Quantification (BLQ) 
Graphical Presentation 
For graphs of arithmetic means all BLQ concentrations will be substituted by zeros.  For graphs 
of geometric means, BLQ concentration values at pre-dose, at all time points up to the first 
quantifiable concentration, between quantifiable concentrations and after the last quantifiable  
concentration will be substituted by zero, hence geometric means are not defined and disregarded 
from displays.  
Handling of values below the limit of quantification (BLQ) in listings and for the calculation of 
descriptive statistics at each time point: 
• All concentrations below the limit of quantification (BLQ) or missing data will be labeled 
as such in the concentration data listings. Missing samples will be reported as no sample 
("NS") and excluded from analysis. Values that are BLQ will be substituted with zero for 
the calculation of descriptive statistics of concentration by time point.   
 
4.10.1.2 Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by non-compartmental analysis methods from the 
concentration-time data using Phoenix® WinNonlin® (Version 6.3) or higher. Please refer to 
section 3.2.2. 
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Statistical Analysis Plan for Early Phase Studies 
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Z7219J03                                                                                                                                Statistical Analysis Plan 
 
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Pharmacokinetic parameters will be listed by subject and summarized by cohort and period. 
Descriptive statistics for calculated PK parameters will include: n, arithmetic mean, SD, CV%, 
geometric mean, geometric CV%, median, minimum and maximum values. For tmax, only median, 
minimum and maximum values will be presented. No descriptive statistics will be determined 
when fewer than three individual PK parameters are available. 
The following rules will be followed with regards to the number of decimal places and presentation 
of data in the tables and listings for PK parameters:  
• Individual PK parameters will be presented to four significant digits, with the exception of 
tmax, which will be presented to two decimal places.  
• Parameters derived directly from source data (e.g. Cmax,) shall be reported with the same 
precision as the source data (if this is not four significant digits).  
• The mean, geometric mean, median and SD values will be reported to four significant 
digits, all other descriptive statistics will be reported to three significant digits except for 
CV% which will be presented to one decimal place.  
• For tmax the minimum and maximum will be presented to two decimals places and all other 
descriptive statistics will be presented to three decimal places.  
 
 
4.11 Safety Evaluation 
All safety summaries and analyses will be based upon the Safety Set as defined in Section 4.5. 
4.11.1 Adverse Events 
An AE is any untoward medical occurrence in a study subject administered an IMP which does 
not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an IMP, whether or not considered 
related to the IMP. Adverse events may include the onset of new illness and the exacerbation of 
pre-existing conditions. 
Other untoward events occurring in the framework of a clinical study will be recorded as AEs, e.g. 
those occurring during treatment-free periods (including Screening or post-treatment Follow-up 
periods), in association with study-related procedures and assessments. 
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Z7219J03                                                                                                                                Statistical Analysis Plan 
 
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Concomitant illnesses, which existed before entry into the clinical study, will not be considered 
AEs unless they worsen during the treatment period. Pre-existing conditions will be recorded as 
part of the subject’s medical history. 
A treatment-emergent adverse event (TEAE) is defined as an AE that begins or that worsens in 
severity after at least one dose of the study drug has been administered. 
Any AEs with incomplete start and end dates/times will be treated as follows: 
Adverse events with unknown start and/or end times (but where the date is known) will be imputed 
with a time of 00:00 h for the tabulations but will be shown as NK: NK in the listings (where NK 
= Not Known). 
Adverse events with completely unknown start dates will be considered as treatment-emergent for 
the tabulations and will be shown as NK in the listings. Partially complete AE dates will not be 
imputed in the listings and the available day, month and year components will be used to determine 
if an adverse event is treatment- emergent taking the first dosing date and end of study date as 
references.  
 
Adverse events will be coded using the latest available version of the Medical Dictionary for 
Regulatory Activities (MedDRA).   
AEs will be summarized on a per-subject basis and per-event basis. A per-subject basis means that 
even if a subject reported the same event repeatedly (i.e., events mapped to the same PT) during 
the trial period, the event will be counted only once. A per-event basis will report the number of 
events. 
• A summary of the number and percentage of subjects reporting a treatment-emergent 
adverse event by SOC, and PT 
• A summary of the number and percentage of subjects reporting a treatment-emergent 
adverse event by PT  
• A summary of the most common treatment-emergent adverse events by PT (reported by > 
5% of subjects in any treatment).  
• A summary of the number and percentage of subjects reporting a treatment-emergent 
adverse event by severity, SOC and PT 
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Statistical Analysis Plan for Early Phase Studies 
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Z7219J03                                                                                                                                Statistical Analysis Plan 
 
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• A summary of the number and percentage of subjects reporting a treatment-emergent 
adverse event by causality, SOC and PT 
For each subject and each adverse event, the worst severity recorded will be attributed and used in 
the by-severity summaries.  Similarly, the worst causality (most related to treatment) will be 
attributed and used in the by-causality summaries.   
 
A by-subject listing of all adverse events (including non-treatment-emergent events) will be 
provided. This listing will include: subject identifier, age, sex, race, first dosing date/time, adverse 
event (SOC, PT, and verbatim term), date of onset, date of resolution, duration, severity, causality, 
seriousness, action taken, and outcome.  
 
4.11.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
The following listings will be produced: 
• Withdrawals/Discontinuation due to AEs (if applicable). 
• SAEs (if applicable). 
• Death (if applicable). 
listings by subject will include: subject identifier, age, sex, race, first dosing date/time, adverse 
event (SOC, PT, and verbatim term), date of onset, date of resolution, duration, severity, causality, 
seriousness, action taken, and outcome. 
 
4.11.3 Clinical Laboratory Evaluation 
For by-visit summaries, the last non-missing assessment (including repeat assessments) recorded 
at each visit will be summarized. If visit windows are to be used, the non-missing assessment 
closest to the mid-point of the visit window will be summarized (including repeat and unscheduled 
assessments).  For across visit summaries (e.g. maximum post-baseline value), scheduled, 
unscheduled and repeat assessments will be considered. 
Overall investigator’s interpretation (as normal or abnormal and, if abnormal, CS or NCS and 
clinically significant findings (if any) will be reported in the individual eCRFs. All CS 
abnormalities after the screening visit will be recorded as AEs. 
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Z7219J03                                                                                                                                Statistical Analysis Plan 
 
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Following summaries will be produced: 
• A summary of value and changes from baseline for each laboratory parameter by time point 
• A summary of the number and percentage of subjects experiencing low, normal or high 
values at baseline and at post-baseline time points, for selected laboratory parameter (shift 
table)  
A by-subject listing of all laboratory data should be provided, with abnormal values highlighted, 
and including: subject identifier, age, sex, race, weight and visit.  Laboratory reference ranges 
should also be listed.  
Laboratory values (hematology, biochemistry and urinalysis) will be listed by subject and time 
point including changes from baseline (with the exception of urinalysis).  
All values outside the clinical reference ranges will be flagged in the data listings. The abnormal 
values will be flagged with ‘L’ for values below the lower limit of the clinical reference range and 
‘H’ for values above the upper limit of the clinical reference range and included in the listings. 
The Investigator will assess the values outside the clinical reference range and these will be 
reported as abnormal NCS or abnormal CS.  
 
4.11.4 Vital Signs, Physical Findings and Other Observations Related to Safety 
Vital Signs 
Vital signs data will be listed by subject including changes from baseline. The baseline for the vital 
signs measurements will be the last pre-dose measurement within each period. 
Descriptive statistics will be presented by each cohort/period for both individual values (N, mean, 
SD, median, minimum, maximum) and changes from baseline. 
 
12-Leads ECG 
All ECG parameters obtained from the ECG measurement will be listed by subject for study time 
point including changes from baseline. The baseline for the ECG measurements the last pre-dose 
measurement within each period. 
Descriptive statistics (for non-categorical data) will be presented by each cohort/period for both 
individual values (N, mean, SD, median, minimum, maximum) and changes from baseline. 
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Z7219J03                                                                                                                                Statistical Analysis Plan 
 
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Qualitative data will be summarized using frequency counts in each category for each scheduled 
time point. 
 
Physical Examination 
The results of the physical examination will be listed by subject and study time point. 
 
4.12 Determination of Sample Size 
12 healthy male and female Chinese subjects / cohort (24 in total) will be included in the study in 
order to have at least 8 completers / cohort. Drop-out subjects will not be replaced. 
Since no hypothesis will be tested, no formal sample size calculation has been performed. The 
sample size of this study has been determined in agreement with the guidance issued by the 
Chinese Food and Drug Administration (CFDA) for clinical pharmacokinetic studies. 
 
 
4.13 Changes in the Conduct of the Study or Planned Analysis 
NA 
 
5 
REFERENCES 
[1] CFDA Guidance 
[2] SAS® Version 9.4 of the SAS System for Personal Computers. Copyright © 2002-2003. SAS 
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
[3] Phoenix®WinNonlin® Professional Software Version 6.3 https://www.certara.com 
 
 
 
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Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
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6 
APPENDICES 
 
STUDY SCHEDULE 
 
ACTIVITIES 
 
Period 1 
Screening 
Single Dose  
Visit 
V1 
V2 
V3 
V4 
Day 
Day -14/-2 
Day -1 
Day 1 Day 2 Day 3 Day 4 Day 5 
Informed consent 
x 
 
 
 
 
 
 
Demography 
x 
 
 
 
 
 
 
Lifestyle 
x 
 
 
 
 
 
 
Medical and surgical history  
x 
 
 
 
 
 
 
Physical examination3 
x 
 
 
 
 
 
 
Prior and concomitant medications 
x 
x 
x 
x 
x 
x 
x 
Height 
x 
 
 
 
 
 
 
Body Weight3 
x 
 
 
 
 
 
 
Laboratory analysis4 
x 
 
 
 
 
 
 
Virology 
x 
 
 
 
 
 
 
Serum pregnancy test (women) 
x 
 
 
 
 
 
 
Urine multi-drug kit test 
x 
x 
 
 
 
 
 
Blood pressure and heart rate5 
x 
 
x 
x 
x 
 
 
Alcohol breath test 
 
x 
 
 
 
 
 
Urine pregnancy test (women) 
 
x 
 
 
 
 
 
ECG6 
x 
 
 
 
 
 
 
Inclusion/exclusion criteria  
x 
x 
 
 
 
 
 
Subject eligibility 
x 
x 
 
 
 
 
 
Enrolment and 
randomisation 
 
x 
 
 
 
 
 
Confinement 
 
x 
x 
x 
 
 
 
Discharge 
 
 
 
 
x 
 
 
Ambulatory visits 
 
 
 
 
 
x 
 
Investigational product 
administration 
 
 
x7  
 
 
 
 
Blood sampling for PK analysis 
 
 
x8 
x8 
x8 
x8 
x8 
Standardised meals11  
 
x 
x 
x 
x 
 
 
Adverse event monitoring12 
x 
x 
x 
x 
x 
x 
x 
 
 
 
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PAREXEL International 
Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
CONFIDENTIAL 
Project Document Version No. 1.0 
Project Document Effective Date: <12Dec2018> 
                                                                                                            Page 30 of 31 
ACTIVITIES 
Period 2 
 
Final visit /ETV1 
 
Multiple Dose 
Visit 
V5 
V6 
V7 
V8 
Day 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
12 
Day 
13 
Day 
14 
Day 
15 
Day 
16 
Day 
17 
Day 
18 
Day 182 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
 
 
 
 
 
 
 
 
 
 
 
 
Lifestyle 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history  
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination3 
 
 
 
 
 
 
 
 
 
 
 
x 
Prior and concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight3 
 
 
 
 
 
 
 
 
 
 
 
x 
Laboratory analysis4 
 
 
 
 
 
 
 
 
 
 
 
x 
Virology 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (women) 
 
 
 
 
 
 
 
 
 
 
 
 
Urine multi-drug kit test 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure and heart rate5 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Alcohol breath test 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (women) 
 
 
 
 
 
 
 
 
 
 
 
 
ECG6 
 
 
 
 
 
 
 
 
 
 
 
x 
Inclusion/exclusion criteria  
 
 
 
 
 
 
 
 
 
 
 
 
Subject eligibility 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment and randomisation 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement 
x 
x 
 
 
 
 
x 
x 
x 
x 
 
 
Discharge 
 
x 
 
 
 
 
 
 
 
x 
 
 
Ambulatory visits 
 
 
x 
x 
x 
x 
 
 
 
 
x 
 
Investigational product 
administration 
x7 
x7 
x7 
x7 
x7 
x7 
x7  
 
 
 
 
 
Blood sampling for PK analysis x9 
x9 
x10 
x10 
x10 
x10 
x8 
x8 
x8 
x8 
x8 
 
Standardised meals11  
x 
x 
 
 
 
 
x 
x 
x 
 
 
 
Adverse event monitoring12 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
1. 
Early termination visit (ETV) 
2. 
Final visit on day 18  
3. 
Physical examination, including body weight, at screening and final visit/ETV 
4. 
Laboratory analyses at screening and final visit/ETV  
5. 
At pre-dose, at 2 h and 96 h after day 1 single dose and day 14 last multiple dose. At pre-dose, 2 h and 24 h after the 
day 8 first multiple dose. Before blood sampling and investigational product administration during ambulatory visits 
6. 
At screening and final visit/ETV  
7. 
On day 1 (Period 1) and once daily from day 8 to day 14 (Period 2), at 8:00 ± 1 h 
8. 
At pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 36, 48, 72 and 96 h post-dose after the first single dose (day 1) and 
the last multiple dose (day 14);  
9. 
At pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose after the first multiple dose (day 8) 
10. At pre-dose (0) on each day (day 10-13) 
11. Day -1: standardised dinner; 
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PAREXEL International 
Statistical Analysis Plan for Early Phase Studies 
Zambon SpA 
 
Z7219J03                                                                                                                                Statistical Analysis Plan 
 
CONFIDENTIAL 
Project Document Version No. 1.0 
Project Document Effective Date: <12Dec2018> 
                                                                                                            Page 31 of 31 
Day 1, Day 8, Day 14: standardised lunch at approximately 5 h post-dose,  standardised dinner at approximately 13 h 
post-dose;  
                Day 2, Day 9 and Days 15/16: standardised breakfast, lunch and dinner 
12. Adverse events monitored starting at the screening visit, immediately after informed consent, up to the final visit/ETV 
 
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International’s electronic signature policies and procedures and in compliance with applicable regulations. 
 
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Title:  
 
Date: Wednesday, 12 December 2018, 11:38 PM   GMT Standard Time 
Meaning: Document contents approved. 
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Title:  
 
Date: Thursday, 13 December 2018, 01:29 PM   GMT Standard Time 
Meaning: Document contents approved. 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 4 of 32 
TABLE OF CONTENTS 
 
1 
INTRODUCTION ........................................................................................................... 10 
2 
STUDY OBJECTIVES ................................................................................................... 11 
2.1 
Primary Objective ............................................................................................................ 11 
2.2 
Secondary Objective ........................................................................................................ 11 
3 
INVESTIGATIONAL PLAN ......................................................................................... 11 
3.1 
Overall Study Design and Plan........................................................................................ 11 
3.2 
Endpoints and Associated Variables ............................................................................... 11 
3.2.1 
Efficacy Variables ...................................................................................................... 11 
3.2.2 
Pharmacokinetic Variables ......................................................................................... 12 
3.2.3 
Safety Variables .......................................................................................................... 16 
3.2.3.1 Adverse Events ........................................................................................................... 16 
3.2.3.2 Clinical Laboratory Tests ........................................................................................... 17 
3.2.3.3 Vital Signs .................................................................................................................. 17 
3.2.3.4 Body Weight ............................................................................................................... 17 
3.2.3.5 12-Leads Electrocardiograms (ECGs) ........................................................................ 18 
3.2.3.6 Physical Examination ................................................................................................. 18 
4 
STATISTICAL METHODS ........................................................................................... 18 
4.1 
Data Quality Assurance ................................................................................................... 18 
4.2 
General Presentation Considerations ............................................................................... 18 
4.3 
Software Considerations .................................................................................................. 19 
4.4 
Study Subjects ................................................................................................................. 19 
4.4.1 
Disposition of Subjects ............................................................................................... 19 
4.4.2 
Protocol Deviations .................................................................................................... 21 
4.5 
Analysis Sets ................................................................................................................... 21 
4.5.1 
Randomized Set .......................................................................................................... 21 
4.5.2 
Safety Set .................................................................................................................... 21 
4.5.3 
Pharmacokinetic Set ................................................................................................... 22 
4.6 
Demographics and Baseline Characteristics ................................................................... 23 
4.7 
Medical and Surgical History .......................................................................................... 23 
4.8 
Prior and Concomitant Medications ................................................................................ 23 
4.9 
Treatment Exposure / Compliance .................................................................................. 24 
4.10 Pharmacokinetics Evaluation .......................................................................................... 24 
4.10.1 
Pharmacokinetics Concentrations ............................................................................... 24 
4.10.1.1 Handling of Values Below the Limit of Quantification (BLQ) .................................. 25 
4.10.2 
Pharmacokinetic Parameters ....................................................................................... 25 
4.11 Safety Evaluation............................................................................................................. 26 
4.11.1 
Adverse Events ........................................................................................................... 26 
4.11.2 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .................. 27 
4.11.3 
Clinical Laboratory Evaluation ................................................................................... 28 
4.11.4 
Vital Signs, Physical Findings and Other Observations Related to Safety ................ 28 
4.12 Determination of Sample Size ......................................................................................... 29 
4.13 Changes in the Conduct of the Study or Planned Analysis ............................................. 29 
5 
REFERENCES ................................................................................................................ 29 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 5 of 32 
6 
APPENDICES ................................................................................................................. 30 
 
 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 6 of 32 
REVISION HISTORY 
 
 
Version No.
Effective Date
Summary of Change(s)
1.0
12 Dec 2018
New Document
1.1 
NA 
Updates per finalized protocol amendment and finalized 
eCRF. (The first version was based on draft protocol and not 
based on eCRF so that the analyses described were not 
comprehensive)
1.2
NA
Address internal review comments
1.3
NA
Address sponsor review comments
1.4 
NA 
Updates per draft shells after sponsor review; 
Simplified the definition for prior and concomitant 
medications.
1.5
NA
Address internal review comments
1.6 
NA 
Address sponsor comments: added one period (pre-
treatment). And minor updates from shells comments.
2.0
10 Oct 2019
Please refer to changes in 1.1-1.6 
 
 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 7 of 32 
 
LIST OF ABBREVIATIONS 
 
List and define all acronyms and abbreviations used in the document here.  Abbreviations should 
be spelled out in full and the abbreviation indicated in parentheses at first appearance in the text.  
Abbreviations should appear in alphabetical order. 
 
Abbreviation / Acronym 
Definition / Expansion 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the concentration-time curve 
AUC(0-inf)  
AUC from time zero extrapolated to infinity 
AUC(0-t)  
AUC from time zero to the last quantifiable concentration 
AUC(0-24h) 
AUC from time zero to 24h after administration 
AUC(0-24h),ss 
AUC from time zero to 24h after administration at steady state 
AUC%extrap 
Percentage of AUCinf that is due to extrapolation beyond tlast 
BLQ 
Below the lower limit of quantification 
BMI 
Body Mass Index 
Bpm 
Beats per minute 
Cave,ss 
Average concentration at steady state  
CFDA 
Chinese Food and Drug Administration 
CI 
Confidence interval 
Clast 
Last quantifiable concentration at tlast 
CLR 
Renal clearance 
CL/F 
Apparent clearance following oral administration 
CL/F,ss 
Apparent clearance following oral administration at steady state 
CRF 
Case Report Form 
CSP 
Clinical Study Protocol 
Cmax 
Maximum observed concentration 
Cmax,ss 
Maximum observed concentration at steady state 
Cmin 
Minimum observed concentration in the dosing interval 
Cmin,ss 
Minimum observed concentration at steady state 
CS 
Clinically significant 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 8 of 32 
Abbreviation / Acronym 
Definition / Expansion 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
DF% 
Peak-trough fluctuation over one dosing interval at steady-state 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
ETV 
Early termination visit 
-GT 
-Glutamyl transpeptidase 
HBsAg 
Hepatitis B surface antigen 
HCG 
human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IMP 
Investigational Medicinal Product 
LLOQ 
Lower limit of quantification 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Metabolic ratio 
MRT(0-inf) 
Mean residence time extrapolated to infinity 
MRT(0-inf),ss 
Mean residence time at steady state extrapolated to infinity 
NA 
Not available 
NCS 
Not clinically significant 
NK 
Not known 
OTC 
Over the counter 
PK 
Pharmacokinetic 
Racc 
Accumulation ratio 
RBC 
Red Blood Cells 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 9 of 32 
Abbreviation / Acronym 
Definition / Expansion 
SBP 
Systolic blood pressure 
SD 
Standard deviation or single dose 
SE 
Standard error of the mean 
SOC 
System Organ Class 
t½ 
Apparent terminal elimination half-life  
t½,ss 
Apparent terminal elimination half-life at steady state 
tlast 
Time of last quantifiable concentration 
TEAE 
Treatment-emergent adverse event 
tmax 
Time corresponding to occurrence of Cmax 
tmax,ss 
Time corresponding to occurrence of Cmax,ss at steady state 
Vd/F 
Apparent volume of distribution during terminal phase 
Vd /F,ss 
Apparent volume of distribution during terminal phase at steady 
state 
WHODrug Global 
World Health Organization Drug Global 
Kel 
Terminal elimination rate constant 
Kel ,ss 
Terminal elimination rate constant at steady state 
%AUCex 
Percentage of AUC(0-inf) obtained by extrapolation 
 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 10 of 32 
1 
INTRODUCTION 
The present study will be part of safinamide registration package in China and was designed 
according to Chinese Food and Drug Administration (CFDA) guideline recommendations [1]. 
Safinamide has been granted marketing authorization in EU (2015), US (2017) and Switzerland 
(2015).   
The 
-aminoamide derivative safinamide [(S)-(+)-2-[4-(3-fluorobenzyloxy) benzylamino] 
propanamide], developed as methane sulfonate salt, is an original anticonvulsant and antiparkinson 
agent which has been granted marketing authorization in 9 EU Member States (i.e. Germany, Italy, 
Spain, Portugal, United Kingdom, Belgium, The Netherlands, Sweden and Denmark), in Norway 
and in Switzerland under the brand name of Xadago®, 50 and 100 mg, film-coated tablets [2], for 
the 
sease (PD) as add-on therapy to a 
stable dose of Levodopa (L-dopa) alone or in combination with other PD medicinal product in 
mid-to late-stage fluctuating patients [3]. 
In the present study, safinamide pharmacokinetic profile, safety and tolerability after single dose 
and at steady state will be investigated for the first time in Chinese healthy male and female 
volunteers. 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing 
study data and outlines the statistical programming specifications for the Tables, Listings and 
Figures (TLFs). It describes the variables and populations, anticipated data transformations and 
manipulations and other details of the analyses not provided in the Clinical Study Protocol (CSP). 
The analyses described in this SAP are based upon the following study documents: 
 Study Protocol, Version 2.0 (April 18, 2019) 
 electronic Case Report Form (eCRF), Version 1.0 (May 7, 2019) 
The SAP will be finalized prior to database lock and describes the statistical analysis as it is 
foreseen when the study is being planned. If circumstances should arise during the study rendering 
this analysis inappropriate, or if improved methods of analysis should arise, updates to the analyses 
may be made. Post database lock modifications will be documented as Statistical Analysis 
Modification Requests. 
 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 11 of 32 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 To evaluate plasma safinamide pharmacokinetic parameters after single and multiple dose 
administration of the investigational products. 
 
2.2 
Secondary Objective 
 To collect safety and tolerability data after single and multiple dose administration of the 
investigational products. 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase I, single center, single and multiple-dose, open-label, randomized, parallel-group, 
pharmacokinetics, safety and tolerability study. 
The study population will consist of 24 adult healthy male and female subjects (12 per cohort). 
Subjects will be randomized to 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), according to 
the study randomized, parallel-group design, as follows: 
Cohort 
Period 1 - single dose 
Day 1 
Washout 
Period 2 - Multiple doses 
Days 8 - 14 
Cohort 1 
50 mg po 
7 days 
50 mg po o.d for 7 days 
Cohort 2 
100 mg po 
100 mg po o.d. for 7 days 
 
 
3.2 
Endpoints and Associated Variables 
3.2.1 Efficacy Variables 
Not applicable. 
 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 12 of 32 
3.2.2 Pharmacokinetic Variables 
Unless otherwise stated, derivation of Pharmacokinetic (PK) parameters will be the responsibility 
of Qualitative Clinical Development (QCD), PAREXEL International.  The following PK 
parameters will be determined for Investigational Medicinal Product (IMP) in plasma following 
single dose and multiple dose administration: 
Table 1 
Pharmacokinetic Parameters after Single Dose Administration 
Parameter 
Definition 
Cmax [1] 
Maximum observed concentration 
tmax  [1] 
Time corresponding to occurrence of Cmax 
t½ 
Apparent terminal elimination half life 
Clast/Ct 
Last quantifiable concentration 
AUMC 
Area under the first moment of the concentration-time curve  
Kel 
Terminal elimination rate constant 
AUC(0-t) [1] 
AUC from time zero to the last quantifiable concentration 
AUC(0-24) [1] 
AUC over the dosing interval (24 hours) 
AUC(0-inf) 
AUC from time zero extrapolated to infinity 
%AUCex 
Percentage of AUC(0-inf) obtained by extrapolation 
MRT 
AUMC/AUC 
CL/F 
Apparent clearance following oral administration 
Vd/F 
Apparent volume of distribution during terminal phase 
[1] These parameters will also be calculated after first multiple dose (day 8). 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 13 of 32 
Table 2 
Pharmacokinetic Parameters after Multiple Dose Administration 
Parameter 
Definition 
Cmax,ss 
Maximum observed concentration at steady state 
Cmin,ss 
Minimum observed concentration at steady state 
tmax,ss 
Time corresponding to occurrence of Cmax,ss at steady state 
Kel.ss 
Terminal elimination rate constant at steady state 
AUC(0-t),ss 
AUC to last observed concentration at steady state 
AUC(0-
 
AUC over the dosing interval at steady state 
CL/F, ss 
Apparent clearance following oral administration at steady state 
Vd /F,ss 
Apparent volume of distribution during terminal phase at steady state 
Cave,ss 
Average concentration at steady-state 
DF% 
Peak trough fluctuation 
Racc,AUC 
Accumulation ratio, based on AUC 
Racc,Cmax 
Accumulation ratio, based on Cmax 
 
 
 
Pharmacokinetic Parameter Calculation Methods 
PK parameters will be calculated by non-compartmental analysis methods from the concentration-
time data using WinNonlin (WNL) Professional (Version 8.0) following these guidelines: 
 Actual sampling times relative to dosing rather than nominal times will be used in the 
calculation of all derived PK parameters. 
 There will be no imputation of missing data. Any subjects with missing concentration data 
will be included in the PK analysis set provided that at least one PK parameter can be 
reliably calculated. 
 Single dose: All below the limit of quantification (BLQ) values pre-dose and in the 
absorption phase prior to the first quantifiable concentration will be substituted by zeros. 
Thereafter BLQ values between evaluable concentrations will be substituted by missing 
before the calculation of the PK variables. Terminal BLQ values will be disregarded. 
CCI




PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 15 of 32 
 CL/F will be calculated as dose/AUC(0-inf), parent drug only. 
 Vd/F will be calculated as (CL/F)/Kel, parent drug only. 
For multiple dose 
 Cmax,ss at steady state will be obtained directly from the concentration-time data. 
 Cmin,ss at steady state will be obtained directly from the concentration-time data. 
 tmax,ss time at which Cmax,ss occurs at steady state. 
 Kel,ss will be estimated at terminal phase by linear regression 
 Only those data points that are judged to describe the terminal log-linear decline will be 
used in the regression.  
 A minimum number of three data points in the terminal phase will be used in calculating 
Kel,ss with the line of regression starting at any post-Cmax,ss data point (Cmax,ss should not be 
part of the regression slope) and including Clast, tlast. 
 The adjusted correlation coefficient (R2 adj) in general should be greater than 0.80. Any 
valu
 
 An appropriate number of decimal places should be used for Kel,ss to enable the reported 
value of t½,ss to be calculatedAUC0-24,ss        
 
Area under the concentration-time curve over the dosing interval will be calculated using 
linear trapezoidal method; all incremental trapezoids arising from increasing concentrations 
and the logarithmic trapezoidal method will be used for those arising from decreasing 
concentrations. 
 CL /F,ss         Apparent clearance following oral administration at steady state for the parent 
drug calculated as dose/ AUC(0-24,ss). 
 Vd /F,ss         Apparent volume of distribution during terminal phase at steady state for the 
parent drug calculated as (CL/F,ss )/ Kelss. 
 Cavg,ss            Average steady-state concentration calculated as AUC
/  
 
The following PK parameters will also be derived using Statistical Analysis Software (SAS®) 
(version 9.3 or higher). 
CCI


PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 16 of 32 
 DF%          Peak trough fluctuation calculated as 100* (Cmax,ss - Cmin,ss)/ Cavg,ss.  
 Racc,AUC  and Racc,Cmax                       Accumulation ratio calculated as: 
                               Cmax (last dose interval)/ Cmax (first dose interval). 
                               AUC(0-
 (last dose interval)/ AUC(0-24) (first dose interval). 
 
3.2.3 Safety Variables 
3.2.3.1 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a study subject 
administered an IMP and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an IMP, 
whether or not considered related to the medicinal product. Adverse events may include the onset 
of new illness and the exacerbation of pre-existing conditions. 
Other untoward events occurring in the framework of a clinical study will be recorded as AEs, e.g. 
those occurring during treatment-free periods (including Screening or post-treatment Follow-up 
periods), in association with study-related procedures and assessments. 
Concomitant illnesses, which existed before entry into the clinical study, will not be considered 
AEs unless they worsen during the treatment period. Pre-existing conditions will be recorded as 
cal history. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 
22.0. 
AEs will be classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs) 
according to the period of occurrence. A PTAE is defined as an AE occurring before the first dose 
of investigational product and not worsening after the first dose of investigational product. A 
TEAE is defined as an AE that occurring or worsening after the first dose of investigational 
product. Where dates are missing or partially missing, adverse events will be assumed to be 
treatment-emergent, unless there is clear evidence (through comparison of partial dates) to suggest 
that the adverse event started or worsen in severity prior to the first dose of study treatment. 
Any AEs with incomplete start and end dates/times will be treated as follows:  
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 17 of 32 
Adverse events with completely unknown start dates will be considered as treatment-emergent for 
the tabulations and will be shown as NK in the listings (where NK = Not Known). Partially 
complete AE dates will not be imputed in the listings and the available day, month and year 
components will be used to determine if an adverse event is treatment-emergent taking the first 
dosing date and end of study date as references. 
The severity of an AE will be evaluated by the investigator and recorded in the eCRF as Mild, 
Moderate, or Severe. The investigator will also perform an evaluation with respect to seriousness 
and causality (relationship of any AE to IMP, whether believed by the investigator to be related or 
unrelated to the IMP) of the AEs and record it on the appropriate section of the eCRF. 
 
3.2.3.2 Clinical Laboratory Tests 
The following safety laboratory parameters will be measured: 
 Hematology: Leukocytes and leukocyte differential count (percentage values and absolute 
values), erythrocytes, hemoglobin, hematocrit, MCV, MCH, MCHC, thrombocytes. 
 Biochemistry: sodium, potassium, calcium, chloride, inorganic phosphorus, alkaline 
-GT, AST, ALT, total bilirubin, creatinine, glucose, urea or BUN, uric acid, total 
cholesterol, triglycerides, total proteins.  
 Urinalysis: pH, specific gravity, appearance, color, nitrites, proteins, glucose, urobilinogen, 
bilirubin, ketones, leukocytes, erythrocytes, epithelial cells, crystals, cylinders.  
 
[NS] or not clinically significant [NCS]) and clinically significant findings (if any) will be reported 
in the individual eCRFs. All CS abnormalities after the screening visit will be recorded as AEs. 
 
3.2.3.3 Vital Signs 
 
The following vital signs measurements will be obtained: 
 Systolic blood pressure (SBP) [mmHg] 
 Diastolic blood pressure (DBP) [mmHg] 
 Heart rate (beats/min) 
 
3.2.3.4 Body Weight 
 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 18 of 32 
3.2.3.5 12-Leads Electrocardiograms (ECGs) 
 
All CS abnormalities after the screening visit will be recorded as AEs. 
 
3.2.3.6 Physical Examination 
abnormal and, if abnormal, CS or NCS) and CS abnormalities (if any) will be reported in the 
individual eCRFs. 
All CS abnormalities after the screening visit will be recorded as AEs. 
 
 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in  accordance with standard PAREXEL procedures. 
 
 
4.2 
General Presentation Considerations 
Each cohort has three periods (pre-treatment period, single dose period (Day 1) and multiple doses 
period (Day 8 to Day 18)) with a washout duration of 7 days between single dose period and 
multiple dose period. Period will be displayed for subject listings where applicable. Baseline  is 
defined as the last available assessment prior to the first dose of study treatment (per period when 
pre-dose assessment is available for both of the single dose and multiple dose periods). 
-
Study 
relative to the  first dose date of study treatment i.e. Study Day = Assessment Date -First Dose 
Date + 1 (+ 1 if assessment date is on or after the first dose date).  
Continuous data will be summarized in terms of the mean, standard deviation (SD), coefficient of 
variation (CV) (%), median, minimum, maximum and number of observations, unless otherwise 
stated.  
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 19 of 32 
Continuous data that are expected to be skewed will be presented in terms of the maximum, upper 
quartile, median, lower quartile, minimum and number of observations. The minimum and 
maximum will be reported to the same number of decimal places as the raw data recorded in the 
database. The mean, median, lower quartile and upper quartile will be reported to one more 
decimal place than the raw data recorded in the database. The SD will be reported to two more 
decimal places than the raw data recorded in the database. The CV(%) will be presented to one 
decimal place. In general, the maximum number of decimal places reported shall be four for any 
summary statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at the 
relevant time point (n), frequency counts and percentages. Any planned collapsing of categories 
will be detailed in the SAP text and the data displays.   
Percentages will be presented to one decimal place. Percentages will not be presented for zero 
counts. Percentages will be calculated using the number of subjects included in the corresponding 
set of subjects that is indicated in the title of the tables as the denominator. If sample sizes are 
small, the data displays will show the percentages, but any textual report will describe frequencies 
only.   
Changes from baseline in categorical data will be summarized using shift tables where appropriate. 
 
4.3 
Software Considerations 
All report outputs will be produced using SAS® version 9.3 or a later version [4] in a secure and 
validated environment.  
The PK parameters will be produced using Phoenix® WinNonLin (WNL) version 8.0 [5] in a 
secure and validated environment.  
All report outputs will be provided to the Sponsor in RTF and/or PDF format.   
 
 
4.4 
Study Subjects 
4.4.1 Disposition of Subjects 
A subject will be defined as screened after the signature of the informed consent, regardless of the 
completion of all the screening procedures. A subject will be defined as eligible if he/she meets all 
the inclusion criteria and not meet any exclusion criteria. Otherwise he/she will be defined as a 
CCI


PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 20 of 32 
screen failure. A subject will be defined as enrolled in the study if he/she is included into the 
interventional phase of the study. The enrollment will be performed through randomized allocation 
to a treatment cohort. An eligible but not enrolled subject will be defined as a reserve. A subject 
will be defined as randomized in the study when he/she is assigned to a randomized treatment 
cohort. A clear accounting of the disposition of all subjects who enter the study will be provided, 
from screening to study completion. 
 A summary of the number of subjects screened for entry into the study and the number and 
percentage of eligible subjects, screen failure subjects (including the reason for screen 
failure), enrolled subjects, and randomized subjects. 
 A summary of the number of subjects randomized, the number and percentage of subjects 
treated (with at least one dose of study medication) and the number and percentage of 
subjects withdrawing from study treatment and withdrawing from the study by treatment 
cohort and overall. Withdrawals from the study and from study treatment should also be 
summarized by major reason. Primary reason of study discontinuation or study treatment 
discontinuation will be documented as one of the following: 
 Adverse event 
 Death 
 Lost to follow-up 
 Non-compliance with study drug 
 Physician decision 
 Pregnancy 
 Protocol deviation 
 Study terminated by sponsor 
 Technical problem 
 Withdrawal by subject 
 Other 
By-subject listings of eligibility details, randomization details and study treatment/study 
discontinuation/completion details (including reason for discontinuation) will be provided. 
 
CCI


PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 21 of 32 
4.4.2 Protocol Deviations 
All protocol deviations will be recorded by the Investigator. Major protocol deviations are defined 
as those deviations from the protocol 
safety, well-being, and/or on the validity of the data for analysis. The impact of major protocol 
deviations will be investigated by assessing the robustness of the study results and conclusions to 
the choice of analysis set, both including and excluding data potentially affected by major protocol 
deviations. 
Major protocol deviations and any action to be taken regarding the exclusion of subjects or affected 
data from specific analyses are defined in the project-specific Protocol Deviation Specification and 
approved by Sponsor. All major protocol deviations will be discussed between PAREXEL and the 
Sponsor during the data review meeting shortly before database lock in order to determine whether 
these may warrant exclusion of a subject from the statistical analyses. Results and population 
assignments will be summarized in a meeting minute/report and will be signed off by all relevant 
scientific experts. 
 A summary of the number and percentage of subjects with a major (approved by sponsor) 
protocol deviation by treatment cohort and overall 
A by-subject listing of major protocol deviations should be provided. 
 
 
4.5 
Analysis Sets 
The number and percentage of subjects within each analysis set will be summarized based on all 
enrolled subjects. A by-subject listing, including the reasons of being excluded from a specific 
analysis set, will also be provided. 
 
4.5.1 Randomized Set 
The randomized set includes all subjects randomized. This analysis set will be used for the analysis 
of demographic, baseline and background characteristics. If a subject is allocated to the incorrect 
treatment cohort as per the study randomization list, the subject will be summarized and analyzed 
 cohort. 
 
4.5.2 Safety Set 
The safety set includes all randomized subjects who receive at least one dose of IMP. Safety 
analyses will be based on the treatment cohort actually received, not on the treatment cohort to 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 22 of 32 
which the subject was randomized. The safety summaries and analyses will be based on the Safety 
Set.   
 
4.5.3 Pharmacokinetic Set 
The PK Set will include all randomized subjects who fulfil the study protocol requirements in 
terms of IMP intake and have evaluable PK data readouts, with no major deviations that may affect 
the PK results. Any data excluded will be discussed at data review meeting before database lock. 
PK analyses will be based on the treatment cohort actually received, not on the treatment cohort 
to which the subject was randomized. The PK summaries and analyses will be based on the PK 
set. 
Subjects may/will be excluded (depending on the protocol and IMP under study) from PK set if 
any of the following criteria are fulfilled: 
Before statistical analysis 
 Vomiting and diarrhea after drug intake which could render the plasma concentration-time 
profile unreliable.  
 Intake of concomitant medications which could render the plasma concentration-time 
profile unreliable. 
 AEs which could render the plasma concentration-time profile unreliable. 
 Administration errors which could render the plasma concentration-time profile unreliable. 
 Other events which could render the plasma concentration-time profile unreliable. 
After bioanalysis 
Subjects can be excluded from PK set only for the reason below: 
 Subject with non-zero baseline concentrations > 5% of Cmax for single dose and first 
multiple dose (day 1 and day 8). 
The samples from the subjects excluded from the PK set should still be assayed and the results 
listed. Subjects should not be excluded from the PK set if the AUC0-t covers less than 80% of the 
AUC0- . 
 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 23 of 32 
4.6 
Demographics and Baseline Characteristics 
The summaries and listings that will be provided include the following: 
 demographic variables (age, sex, ethnicity, height, weight, and body mass index [BMI]) by 
treatment cohort and overall 
 other possibly relevant variables (drug, alcohol, caffeine, and smoking history) by 
treatment cohort and overall 
 other baseline characteristics (virology, pregnancy test, urine drug test, alcohol breath test) 
 
4.7 
Medical and Surgical History 
All medical and surgical history will be coded using the MedDRA version 22.0. 
All medical and surgical history will be summarized by System Organ Class (SOC) and Preferred 
Term (PT) for each treatment cohort and listed by subject using the safety set. 
 
4.8 
Prior and Concomitant Medications 
Medication start and stop dates will be compared to the date of first dose of study medication to 
allow medications to be classified as either Prior, or Concomitant.  
Medications that start and stop prior to the date of first dose of study medication will be classified 
as Prior. If a medication stops on or after the date of first dose of study medication, then the 
medication will be classified as Concomitant. 
If medication start and/or stop dates are missing or partial, the dates will be compared as far as 
possible with the date of first dose of study medication. Medications will be assumed to be 
Concomitant, unless there is clear evidence (through comparison of partial dates) to suggest that 
the medication stopped prior to the first dose of study medication. If there is clear evidence to 
suggest that the medication stopped prior to the first dose of study medication, the medication will 
be assumed to be Prior. 
Prior and concomitant medication will be coded using the WHODrug Global Version Mar 2019 
or later and will be classified by Anatomical Therapeutic Chemical (ATC) categories. 
All prior/concomitant medications will be summarized by ATC level 3 term and PT for each 
treatment cohort and listed by subject using the safety set. 
CCI


PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 24 of 32 
Information of concomitant procedures, including any surgical, therapeutic or diagnostic 
procedures, will only be collected for adverse events and serious adverse events, and will be coded 
using the MedDRA version 22.0. All concomitant procedures will be summarized by SOC and PT 
for each cohort and listed by subject based on the safety set. 
 
4.9 
Treatment Exposure / Compliance 
Study treatment will be administered under the supervision of investigator site personnel. The date 
and time of IMP administration will be listed by subject using the safety set. 
 
 
4.10 Pharmacokinetics Evaluation 
4.10.1 Pharmacokinetics Concentrations 
Pharmacokinetic concentration data for will be listed by subject including nominal sampling times 
relative to cohort/period/day based on PK set. Plasma concentrations below the lower limit of 
quantification (LLOQ) will be presented as BLQ in the listings. Plasma concentrations will be 
summarized by dose cohort, period, day and nominal timepoint. The following descriptive 
statistics will be presented for plasma concentrations obtained at each nominal time point: n, 
arithmetic mean, SD, coefficient of variation (CV%), geometric mean, geometric CV% (calculated 
as:  gCV% =SQRT(exp(s2)-1)*100; where s is the standard deviation of the log-transformed 
values), median, minimum and maximum values. 
The following rules will be followed with regards to the number of decimal places and presentation 
of data in the tables and listings of concentration data:  
 Source data shall be used in all PK concentrations without prior rounding  
 The mean, standard deviation (SD), geometric mean and median will be tabulated to one 
more significant digit compared to the source data, but with a maximum of four significant 
digits.  
 Minimum and maximum values will be tabulated to the same precision as the source data, 
but with a maximum of four significant digits.  
 Geometric coefficient of variation (gCV) % and coefficient of variation (CV%) will be 
presented to one decimal place.  
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                             Page 25 of 32 
Individual plasma concentration versus actual times will be plotted by cohort/period/day in linear 
and semi-logarithmic scale. Mean plasma concentrations (±SD) versus nominal times will also be 
presented in linear and semi-logarithmic scale. 
  
4.10.1.1 Handling of Values Below the Limit of Quantification (BLQ) 
Graphical Presentation 
For graphs of arithmetic means all BLQ concentrations will be substituted by zeros.  For graphs 
of geometric means, BLQ concentration values at pre-dose, at all timepoints up to the first 
quantifiable concentration, between quantifiable concentrations and after the last quantifiable 
concentration will be substituted by zero, hence geometric means are not defined and disregarded 
from displays.  
Handling of values below the limit of quantification (BLQ) in listings and for the calculation of 
descriptive statistics at each time point: 
 All concentrations below the limit of quantification (BLQ) or missing data will be labeled 
as such in the concentration data listings. Missing samples will be reported as no sample 
("NS") and excluded from analysis. Values that are BLQ will be substituted with zero for 
the calculation of descriptive statistics of concentration by time point.   
 
4.10.2 Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by non-compartmental analysis methods from the 
concentration-time data using Phoenix® WinNonlin® (Version 8.0). Please refer to section 3.2.2. 
Pharmacokinetic parameters will be listed by subject and summarized by cohort, period, and day. 
Descriptive statistics for calculated PK parameters will include: n, arithmetic mean, SD, CV%, 
geometric mean, geometric CV%, median, minimum and maximum values. For tmax, only median, 
minimum and maximum values will be presented. No descriptive statistics will be determined 
when fewer than three individual PK parameters are available. 
The following rules will be followed with regards to the number of decimal places and presentation 
of data in the tables and listings for PK parameters:  
 Individual PK parameters will be presented to four significant digits, with the exception of 
tmax, which will be presented to two decimal places.  
CCI


PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 26 of 32 
 Parameters derived directly from source data (e.g. Cmax,) shall be reported with the same 
precision as the source data (if this is not four significant digits).  
 The mean, geometric mean, median and SD values will be reported to four significant 
digits, all other descriptive statistics will be reported to three significant digits except for 
CV% which will be presented to one decimal place.  
 For tmax the minimum and maximum will be presented to two decimals places and all other 
descriptive statistics will be presented to three decimal places.  
 
 
4.11 Safety Evaluation 
All safety summaries and analyses will be based upon the Safety Set as defined in Section 4.5. 
4.11.1 Adverse Events 
All AE data will be listed individually by subject. Only TEAEs will be included in the summary 
tables. Any PTAEs will be included in the data listings but will not be included in the summary 
tables of AEs. 
AEs will be summarized on per-subject basis and per-event basis. A per-subject basis means that 
even if a subject reported the same event repeatedly (i.e., events mapped to the same PT) during 
the trial period, the event will be counted only once. A per-event basis will report the number of 
events. 
An overview table will be summarized for the following categories: 
 Any TEAEs 
 Any TEAEs related to study drug 
 Any severe TEAEs 
 Any severe TEAEs related to study drug 
 Any TEAEs leading to drug interruption 
 Any TEAEs leading to drug withdrawal 
 Any TEAEs with outcome of death 
 Any TEAEs with outcome of death, related to study drug 
 Any SAEs (including events with outcome of death) 
CCI


PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 27 of 32 
 Any SAEs (including events with outcome of death), related to study drug 
 Any SAEs leading to drug withdrawal 
The following summaries will be produced: 
 A summary of TEAEs by SOC, and PT 
 A summary of TEAEs by PT  
 A summary of the most common TEAEs by PT (reported by > 5% of subjects in any 
treatment cohort).  
 A summary of TEAEs by seriousness, SOC and PT 
 A summary of TEAEs by severity, SOC and PT 
 A summary of TEAEs by causality, SOC and PT 
AE summaries will be displayed by period (single dose and multiple dose) and ordered in terms of 
decreasing frequency in total column for SOC and PT within SOC, and then  alphabetically by 
SOC and PT within SOC. For each subject and each adverse event, the worst severity recorded 
will be attributed and used in the by-severity summary. Similarly, the worst seriousness will be 
attributed and used in the by seriousness summary, the worst causality (most related to treatment) 
will be attributed and used in the by-causality summary. If severity, seriousness or causality is 
missing, no imputation will be applied.   
 
A by-subject listing of all adverse events (including non-treatment-emergent events) will be 
provided. This listing will include: subject identifier, age, sex, ethnicity, treatment cohort, period, 
adverse event (SOC, PT, and verbatim term), start date, end date, severity, causality, seriousness, 
action taken, and outcome.  
 
4.11.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
Other significant adverse events are those adverse events reported as leading to drug interruption, 
drug withdrawal, or study discontinuation.  
The following by-subject listings will be produced (if applicable): 
 A listing of AEs leading to drug interruption 
 A listing of AEs leading to drug withdrawal 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 28 of 32 
 A listing of AEs leading to study discontinuation 
 A listing of SAEs 
 A listing of all deaths 
Listings should follow the format described for AEs in Section 4.11.1 if appropriate. 
 
4.11.3 Clinical Laboratory Evaluation 
Summaries will be presented for the overall interpretation of the laboratory data. The number and 
percentages of subjects within each if the interpretation categories (Normal, Abnormal Not 
Clinically Significant, Abnormal Clinically Significant) will be summarized in these tables.  
By-subject listings of all laboratory data will be provided including: subject identifier, age, sex, 
ethnicity, weight and visit. Laboratory reference ranges should also be listed. All values outside 
the clinical reference ranges will be flagged in the data listings. The abnormal values will be 
above the upper limit of the clinical reference range and included in the listings. 
 
4.11.4 Vital Signs, Physical Findings and Other Observations Related to Safety 
Vital Signs 
Vital signs data will be listed by subject. Descriptive statistics of individual values will be 
presented by treatment cohort at scheduled visit/time point. 
 
Body Weight 
Body weight values will be summarized descriptively by treatment cohort at schedule visit. 
Corresponding data will be listed by subject. 
 
12-Leads ECG 
rpretation for ECG will be listed by subject and study time point. 
 
Physical Examination 
The results of the physical examination will be listed by subject and study time point. 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 29 of 32 
 
4.12 Determination of Sample Size 
Twelve healthy male and female Chinese subjects / cohort (24 in total) will be included in the 
study in order to have at least 8 completers / cohort. Drop-out subjects will not be replaced. 
Since no hypothesis will be tested, no formal sample size calculation has been performed. The 
sample size of this study has been determined in agreement with the guidance issued by the CFDA 
for clinical pharmacokinetic studies. 
 
 
4.13 Changes in the Conduct of the Study or Planned Analysis 
NA 
 
5 
REFERENCES 
[1] CFDA Guidance 
[2] EMA Commission Implementing Decision C (2015) 1390 (final)   Xadago (safinamide). 24 
February 2015 
[3] Summary of Product Characteristics (SmPC)  Xadago 50 mg, 100 mg film-coated tablets 
[4] SAS® Version 9.3 of the SAS System for Personal Computers. Copyright © 2002-2003. SAS 
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
[5] Phoenix®WinNonlin® Professional Software Version 8.0 https://www.certara.com 
 
 
 
CCI


PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 30 of 32 
6 
APPENDICES 
 STUDY SCHEDULE 
 
ACTIVITIES 
 
Period 1 
Screening 
Single Dose  
Visit 
V1 
V2 
V3 
V4 
Day 
Day -14/-2 
Day -1 
Day 1/3 
Day 4/5 
Informed consent 
x
Demography 
x
Lifestyle 
x
Medical and surgical history  
x
Physical examination3 
x
Prior and concomitant medications 
x
x
x
x
Height 
x
Body Weight3 
x
Laboratory analysis4 
x
Virology 
x
Serum pregnancy test (women) 
x
Urine multi-drug kit test 
x
x
Blood pressure and heart rate5 
x 
 
x (Day 1: pre-
dose, 2 hours 
post-dose)
x (Day 5: 96 
hours after Day 
1)
Alcohol breath test 
x
Urine pregnancy test (women) 
 
x 
 
 
ECG6 
x 
 
 
 
Inclusion/exclusion criteria  
x 
x 
 
 
Subject eligibility 
x 
x 
 
 
Enrolment and randomisation 
 
x 
 
 
Confinement 
 
x 
x 
 
Discharge 
 
 
x (Day 3) 
 
Ambulatory visits 
 
 
 
x 
Investigational product administration 
 
 
x7 (Day 1) 
 
Blood sampling for PK analysis 
 
 
x8 
x8 
Standardized meals11  
 
x 
x 
 
Adverse event monitoring12 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
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PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 31 of 32 
ACTIVITIES 
Period 2 
Final visit/ETV1
 
Multiple Dose 
 
Visit 
V5 
V6 
V7 
V8 
 
Day 
Day 8/9 
Day 10/13
Day 14/17
Day 18 
Day 182 
Informed consent 
Demography 
Lifestyle 
Medical and surgical history  
Physical examination3 
 
x 
Prior and concomitant medications 
x
x
x
x
x
Height 
Body Weight3 
x
Laboratory analysis4 
 
x 
Virology 
Serum pregnancy test (women) 
Urine multi-drug kit test 
Blood pressure and heart rate5 
x (Day 8: 
pre-dose, 2 
hours post-
dose)
x 
x (Day 14: 
pre-dose, 2 
hours post-
dose)
x (Day 18: 
96 hours 
after Day 
14)
x 
Alcohol breath test 
Urine pregnancy test (women) 
x
ECG6 
x
Inclusion/exclusion criteria  
 
 
 
 
 
Subject eligibility 
 
 
 
 
 
Enrolment and randomisation 
 
 
 
 
 
Confinement 
x 
 
x 
 
 
Discharge 
x (Day 9) 
 
x (Day 17)
 
 
Ambulatory visits 
 
x 
 
x 
 
Investigational product administration 
x7 
x7 
x7 (Day 14)
 
 
Blood sampling for PK analysis 
x9 
x10 
x8 
x8 
 
Standardized meals11  
x 
 
x 
 
 
Adverse event monitoring12 
x 
x 
x 
x 
x 
 
 
CCI


PAREXEL International 
 
Zambon SpA 
Z7219J03                                                                                                                     
Statistical Analysis Plan 
CONFIDENTIAL 
Project Document Version No. 2.0 
Project Document Effective Date: 10 Oct 19 
                                                                                                            Page 32 of 32 
 
1. 
Early termination visit (ETV) 
2. 
Final visit on day 18  
3. 
Physical examination, including body weight, at screening and final visit/ETV 
4. 
Laboratory analyses at screening and final visit/ETV  
5. 
At pre-dose, at 2 h and 96 h after day 1 single dose and day 14 last multiple dose. At pre-dose and 2 h after the day 8 
first multiple dose. Before blood sampling and investigational product administration during ambulatory visits 
6. 
At screening and final visit/ETV  
7. 
On day 1 (Period 1) and once daily from day 8 to day 14 (Period 2), at 8:00 ± 1 h 
8. 
At pre-dose (0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 36, 48, 72 and 96 h post-dose after the first single dose (day 1) and 
the last multiple dose (day 14);  
9. 
At pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose after the first multiple dose (day 8) 
10. At pre-dose (0) on each day (day 10-13) 
11. Day -1: standardised dinner; 
Day 1, Day 8, Day 14: standardized lunch at approximately 5 h post-dose,  standardized dinner at approximately 13 h 
post-dose;  
                Day 2 and Days 15/16: standardized breakfast, lunch and dinner 
               Day 3, Day 9 and Day 17: standardized breakfast 
12. Adverse events monitored starting at the screening visit, immediately after informed consent, up to the final visit/ETV 
 
 
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