Clinical trial NCT03841604
Conditions: Idiopathic Parkinson Disease
Keywords: Parkinson disease Safinamide
Sponsor: Zambon SpA
Start date: 2019-04-09; Completion date: 2021-05-03
Enrollment: 94 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary objective:

• To evaluate the potential efficacy of safinamide 100 mg once daily (OD), compared with placebo, as add-on therapy for PD-related chronic pain

Secondary objectives:

* Percentage of pain responders
* Clinical Global Impression for pain
* Patient Global Impression for pain
* Reduction in use of pain drugs
* Mood
* Motor and non-motor symptoms

Safety Objectives:

• Safety and tolerability

Detailed description:
This is a Phase IV, international, multicentre, randomised, double-blind, placebo controlled study in idiopathic Parkinson's disease (IPD) patients, experiencing motor fluctuations and PD-related chronic pain while on stable doses of levodopa (L-Dopa), to Evaluate the Efficacy and Safety of Safinamide 100 mg Once Daily, as Add-On Therapy.

The study consisted of:

* A screening period of up to 1 to 2 weeks.
* A treatment period of 16 weeks.
* A telephone follow-up call at 1 week after the end of treatment. Eligible subjects were randomly assigned in a ratio of 2:1 to receive either safinamide (50 mg or 100 mg) or matching placebo. At Day 1, eligible subjects entered the treatment period to receive safinamide 50 mg (from Day 1 to Day 7) and then 100 mg (from Day 8 onwards) orally OD. After completion of all baseline assessments, subjects received the first dose of study drug at the study center and, thereafter, study drug was to be taken at home each morning along with their first morning dose of L-DOPA and other (if any) PD medications. On Day 8, the dose of study drug was increased, at home, to 100 mg OD. Each subject received treatment for 16 weeks, with visits at Week 0/Day 1 (baseline) and at Weeks 4, 8, and 16 (or early termination). From Day 1 onwards, subjects recorded the use of as-needed (PRN) medications along with indicating the worst pain they experienced on a daily basis.

Arms: arm 1: Safinamide methanesulfonate film coated tablets once daily, 50 mg and 100 mg. Safinamide methanesulfonate 50 mg and 100 mg tablets was administered orally, OD, with or without food, at breakfast time when the subject was taking their morning dose of L-DOPA.

Subjects received study drug 50 mg (from Day 1 to Day 7) and then 100 mg (from Day 8 onwards). The dose of 100 mg/day (titrated from 50 mg/day after 1 week) was selected based on the results of previous studies in patients with PD and from the results of a post hoc analysis that investigated the effects of safinamide on pain. arm 2: Safinamide methanesulfonate matching placebo film coated tablets once daily. The matching placebo was administered orally, OD, in tablets, with or without food, at breakfast time when the subject was taking their morning dose of L-DOPA.
Interventions: intervention 1: Safinamide Methanesulfonate intervention 2: Safinamide methanesulfonate matching placebo
Intervention descriptions: intervention 1: 50 mg, 100 mg intervention 2: 50 mg, 100 mg

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Title Page 
Protocol Title: 
A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF SAFINAMIDE 100 MG ONCE DAILY, 
AS ADD-ON THERAPY, IN IDIOPATHIC PARKINSON'S DISEASE (PD) PATIENTS 
WITH MOTOR FLUCTUATIONS AND PD RELATED CHRONIC PAIN 
Protocol Number: 
Z7219M01 
Amendment Number: 
2 -AUS GER ITA ESP 
Compound: 
Safinamide 
Short Title: 
Effect of Safinamide on Parkinson's Disease Related Chronic Pain 
Sponsor Name: 
Zambon SpA 
Legal Registered Address: 
Via Lillo del Duca 10, 20091 Bresso, Milan, Italy 
Regulatory Agency Identifying Number(s)-EUDRACT number : 
2017-002426-20 
Approval Date: 
27th October 2020 
© 2018 Zambon SpA 


CONFIDENTIAL 
Sponsor Signatory: 
Charlotte Keywood 
Open R&D Global Head 
Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
{J-/LToGb 
Date 
Medical Monitor Name and Contact Information will be provided separately 
© 2018 Zambon SpA 
2 


CONFIDENTIAL 
Protocol Z7219M0 1 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Investigator Signature Page 
I have read this protocol. 
I agree to comply with the current International Council for Harmonization Guidelines for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved. 
I will immediately disclose it in writing to the sponsor if any person who is involved in the study 
is debarred or if any proceeding for debarment is pending or, to the best of my knowledge, 
threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the Health Authority/Ethics 
Committee/Institutional Review Board. 
I agree to ensure that this information will not be used for any purpose other than the evaluation 
or conduct of the clinical study without the prior written consent of the sponsor. 
Investigator Signatory: 
Name: 
Date: 
Title: 
Affiliation: 
© 2018 Zambon SpA 
3 


CONFIDENTIAL 
Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Protocol Amendment Summary of Change History 
This amendment is considered to be substantial based on the criteria set forth in Article 1 0(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
Protocol Version 
Version 1.0; 30 July 2018 
Version 2.0 
Amendment 1.0, 10 October 2019 
Version 3.0 
Amendment 2.0, 27 October2020 
© 2018 Zambon SpA 
4 
Key Changes 
Original protocol version 
Eligibility criteria revised 
Screening failure allowed 
Reference Safety Information explicated 
Ambiguities in the text have been amended for 
clarification purposes 
For additional information, please refer to the 
Summary 
of 
Key 
Changes 
document 
associated with this protocol version. 
Sample size reassessed 
Statistical analyses better clarified 
Reference to the measures taken during 
COVID-19 outbreak added 
For additional information, please refer to the 
Summary 
of 
Key 
Changes 
document 
associated with this protocol version. 


CONFIDENTIAL 
Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Table of Contents 
Title Page .......................................................................................................................................... 
1 
Investigator Signature Page ......................................................................................................... 
3 
Protocol Amendment Summary of Change History ....................................................................... 4 
Table of Contents .......................................................................................................................... 
5 
1. 
Protocol Summary ......................................................................................................... 
8 
1.1. 
Synopsis ........................................................................................................................... 8 
1.2. 
Schema ........................................................................................................................... 10 
1.3. 
Schedule of Activities (SoA) ......................................................................................... 11 
2. 
Introduction ................................................................................................................... 
14 
2.1. 
Study Rationale .............................................................................................................. 14 
2.2. 
Background .................................................................................................................... 14 
2.3. 
Benefit/Risk Assessment ............................................................................................... 15 
3. 
Objectives and Endpoints ............................................................................................ 
16 
4. 
Study Design ................................................................................................................. 
17 
4.1. 
Overall Design ............................................................................................................... 17 
4.2. 
Scientific Rationale for Study Design ............................................................................ 17 
4.3. 
Justification for Dose ..................................................................................................... 17 
4.4. 
End of Study Definition ................................................................................................. 18 
5. 
Study Population .......................................................................................................... 
19 
5 .1. 
Inclusion Criteria ........................................................................................................... 19 
5.2. 
Exclusion Criteria .......................................................................................................... 20 
5.3. 
Lifestyle Considerations ................................................................................................ 21 
5.4. 
Screen Failures ............................................................................................................... 21 
6. 
Study Intervention ....................................................................................................... 
22 
6.1. 
Study Intervention(s) Administered ............................................................................... 22 
6.2. 
Preparation/Handling/Storage/ Accountability ............................................................... 23 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................... 24 
6.4. 
Study Intervention Compliance ..................................................................................... 25 
6.5. 
Concomitant Therapy ..................................................................................................... 25 
6.5.1. 
Rescue Medicine ............................................................................................................ 25 
6.5.2. 
Excluded Medicine ......................................................................................................... 26 
6.5.3. 
Pennitted Medication ..................................................................................................... 26 
6.6. 
Dose Modification ......................................................................................................... 26 
6.7. 
Intervention after the End of the Study .......................................................................... 26 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ....................................................................................... 
27 
7 .1. 
Discontinuation of Study Intervention ........................................................................... 27 
© 2018 Zambon SpA 
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CONFIDENTIAL 
Protocol Z7219M01 
Version: 3.0 
7.2. 
7.3. 
8. 
8.1. 
8.1.1. 
8.2. 
8.2.1. 
8.2.2. 
8.2.3. 
8.2.4. 
8.2.5. 
8.3. 
8.3.1. 
8.3.2. 
8.3.3. 
8.3.4. 
8.3.5. 
8.3.6. 
8.4. 
8.5. 
8.6. 
8.7. 
8.8. 
8.9. 
9. 
9.1. 
9.2. 
9.3. 
9.4. 
9.4.1. 
9.4.2. 
9.4.3. 
9.5. 
9.5.1. 
10. 
10.1. 
10.1.1. 
10.1.2. 
10.1.3. 
10.1.4. 
10.1.5. 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Participant Discontinuation/Withdrawal 
from the Study ............................................... 27 
Lost to Follow Up .......................................................................................................... 
27 
Study Assessments and Procedures ............................................................................ 29 
Efficacy Assessments ..................................................................................................... 
32 
Pain Assessments ........................................................................................................... 
32 
Safety Assessments ........................................................................................................ 
33 
Physical Examinations ................................................................................................... 
33 
Vital Signs ...................................................................................................................... 
33 
Cognitive Impairn1ent .................................................................................................... 
33 
Clinical Safety Laboratory Assessments ........................................................................ 
34 
Suicidal Risk Monitoring ............................................................................................... 
34 
Adverse Events and Serious Adverse Events ................................................................ 
34 
Time Period and Frequency for Collecting AE and SAE 
Infonnation ..................................................................................................................... 
34 
Method of Detecting 
Es and AE .............................................................................. 
35 
Follow-up of AEs and SAEs .......................................................................................... 
35 
Regulat01y Reporting Requirements for SAEs .............................................................. 
35 
Pregnancy ....................................................................................................................... 
36 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs ............................................................................................ 
36 
Treatment of Overdose ......................... : ......................................................................... 
36 
Pharmacokinetics ........................................................................................................... 
36 
Pharn1acodynamics ........................................................................................................ 
3 7 
Genetics .......................................................................................................................... 
37 
B iomarkers ..................................................................................................................... 
3 7 
Health Economics .......................................................................................................... 
37 
Statistical Considerations ............................................................................................ 
38 
Statistical Hypotheses .................................................................................................... 
38 
Sample Size Determination ............................................................................................ 
38 
Populations for Analyses ............................................................................................... 
39 
Statistical Analyses ........................................................................................................ 
40 
Efficacy Analyses ........................................................................................................... 
41 
Safety Analyses .............................................................................................................. 
42 
Baseline Descriptive Analyses ....................................................................................... 
42 
Interim Analyses ............................................................................................................ 
43 
Data Monitoring Committee (DMC) ............................................................................. 
43 
Supporting Documentation and Operational Considerations ................................. 44 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................ 
44 
Regulatory and Ethical Considerations .......................................................................... 
44 
Financial Disclosure ....................................................................................................... 
44 
Infonned Consent Process ............................................................................................. 
44 
Data Protection ............................................................................................................... 
45 
Committees Structure ..................................................................................................... 
45 
© 2018 Zambon SpA 
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Protocol Z7219M01 
Version: 3.0 
10.1.6. 
10.1.7. 
10.l.8. 
10.1.9. 
10.1.10. 
10.2. 
10.3. 
L0.4. 
10.5. 
10.6. 
11. 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Dissemination of Clinical Study Data ............................................................................ 
45 
Data Quality Assurance .................................................................................................. 
45 
Source Documents ......................................................................................................... 
46 
Study and Site Closure ................................................................................................... 
46 
Publication Policy .......................................................................................................... 
47 
Appendix 2: Clinical Laboratory Tests .......................................................................... 
48 
Appendix 3: Adverse 
vents: Definition and Pr cedures for 
Recording, Evaluating, Follow-up, and Reporting ........................................................ 
50 
Appendix 4: C ntraceptive Guidanc and Collecti n of 
Pregnancy Info1111ation ................................................................................................... 
55 
Appendix 9: Abbreviation ............................................................................................ 
58 
Appendix 10: Contingency Plan .................................................................................... 
61 
References ..................................................................................................................... 
65 
© 2018 Zambon SpA 
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CONFIDENTIAL 
Protocol Z7219M0I 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
1. 
1.1. 
Protocol Summary 
Synopsis 
Protocol Title: 
A randomised, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of 
safinamide 100 mg once daily, as add-on therapy, in idiopathic Parkinson's Disease (IPD) patients 
with motor fluctuations and PD related chronic pain 
Short Title: 
Pain Study 
Rationale: 
To study the effect of safinamide on PD related chronic pain, a frequent non-motor symptom of 
IPD. 
Oh' 
f 
1.1ec 1ves an d E d 
. t 
n .pom s 
Objectives 
Endpoints 
Primary 
• To evaluate the potential efficacy of 
• The change from baseline to week 16 
safinamide 100 mg once daily, 
in pain severity ("average worst pain 
compared to placebo, as add-on 
experienced in the last 7 days"), as 
therapy, for PD related chronic pain. 
assessed by an I I-point Numerical 
Rating Scale (NRS). 
Secondary 
• The percentage of pain responders 
• Participants with reduction in pain 
severity of ::::2 points ("average worst 
pain experienced in the last 7 days"), 
at week 16 as assessed by an 11-point 
NRS, compared to baseline. 
• Clinical Global Impression for pain 
• The CGI-S score for pain at week 16. 
• The change from baseline to week 16 
in the CGI-C score for pain. 
• The change from baseline to week 16 
• Patient Global Impression for pain 
in the PGI-C score for pain. 
© 2018 Zambon SpA 
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CONFIDENTIAL 
Protocol Z7219M0 1 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
• 
Reduction of pain drugs 
• 
Mood 
• 
Motor and non-motor Symptoms 
• 
Safety & Tolerability 
Overall Design: 
• 
The percentage of reduction in number 
of 
concomitant 
pain 
drugs 
from 
baseline to week 16. 
• 
The number of patients with at least 
one intake of PRN pain medication. 
• 
Amount of PRN pain medications. 
• 
The change from baseline to week 16 
in the HADS score. 
• 
The change from baseline to week 16 
in the MDS-UPDRS (total score and 
subscores) during the "ON" phase. 
• 
Descriptive 
This is a Phase IV, international, multicentre, randomised, double-blind, placebo controlled study 
in IPD patients, experiencing motor fluctuations and PD related chronic pain while on stable doses 
of levodopa (L-Dopa). 
Participants will be randomized 2: 1 to receive either active or placebo. 
Number of Participants: 
Up to 132 participants will be screened to achieve approximately 105 randomly assigned to study 
intervention and 84 evaluable participants for an estimated total of 56 and 28 evaluable participants 
in the active and placebo group respectively. 
Intervention Groups and Duration: 
Study participation will be up to a maximum duration of 19 weeks and will comprise a screening 
period (1 to 2 weeks) and a treatment period (16 weeks). A telephone follow-up call will be 
performed 1 week after the end of treatment. 
At baseline (Visit 2, Day 1), eligible participants will enter the treatment period and will receive 
study medication 50 mg (from Day 1 to Day 7) and then 100 mg (from Day 8 onwards), to be 
taken orally once daily (od). Following completion of all baseline assessments, they will receive 
the first dose of study medication at the study center. Thereafter, study drug will be taken, at home, 
each morning along with their first morning dose of L-Dopa and other (if any) PD medications. 
On Day 8 the dose of study drug will be increased, at home, to 100 mg od. Each subject will receive 
treatment for 16 weeks, with visits at Week 0/Day 1 (baseline) and at Weeks 4, 8 and 16 ( or early 
termination). 
© 2018 Zambon SpA 
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CONFIDENTIAL 
Protocol Z7219M0 l 
Version: 3.0 
Amendment: 2 - AUS GER ITA ESP 
Date: 27th October 2020 
From day 1 onwards, participant will record the use of PRN medications along with indicating the 
worst pain experienced on a daily basis. 
Data Monitoring Committee: No 
1.2. 
Schema 
Screening 
1 to 2 weeks 
before Day 1 
Active 
Placebo 
Day 1 
Baseline, 
Randomisation to 
Active or Placebo 
(2:1) 
© 2018 Zambon SpA 
16 week treatment period 
Day8 
Uptitration 
from 50 to 100 mg 
10 
Follow up 
Phone Call 
1 week 
after EoT 
Day 112 
End of Treatment 


CONFIDENTIAL 
Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
1.3. 
Schedule of Activities (SoA) 
For detailed description of assessments see Study Assessments and Procedures. 
Visit 
1 
2 
3 
4 
5 
6 
Screening 
Baseline 
Interim 
Interim 
EoT 
Call 
* 
Week4 
Week8 
Week 16 
* 
* 
* 
Day/ 
(up to 14 
Procedure 
days before 
1 
28±3 
56±3 
112 ±3 
119±3 
Notes* 
Day 1) 
After informed 
Informed 
X 
consent 
consent 
signing, enter 
details in 
IWRS to obtain 
screenmg 
number. 
Check prior to 
Eligibility 
X 
X 
randomisation/ 
criteria 
1st dose of 
study 
medication 
Randomisation 
X 
Use IWRS to 
randomise 
Demographics 
X 
Age, sex, 
ethnicity, 
smoking and 
alcohol use 
Medical history 
X 
PD diagnosis, 
Hoehn & Yahr 
staging, etc. 
Vital signs 
X 
X 
X 
Heart rate, 
systolic and 
diastolic blood 
pressure 
© 2018 Zambon SpA 
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CONFIDENTIAL 
Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Visit 
1 
2 
3 
4 
5 
6 
Screening 
Baseline 
Interim 
Interim 
EoT 
Call 
* 
Week4 
Week8 
Week 16 
* 
* 
* 
Day/ 
(up to 14 
Procedure 
days before 
1 
28±3 
56±3 
112 ±3 
119±3 
Notes* 
Day 1) 
Physical 
examination and 
neurological 
X 
X 
examination 
MMSE 
X 
eDiary Issue, 
Training and 
X 
X 
X 
return 
Participant to 
eDiary Review 
X 
X 
X 
X 
complete diary 
for 7 days prior 
to each visit. 
For eligibility: 
NRS Review 
X 
PI checks NRS 
score to confim 
eligibility 
MDS-UPDRS 
X 
X 
X 
X 
CGI-S 
X 
X 
X 
X 
CGI-C 
X 
X 
X 
PGI-C 
X 
X 
X 
HADS 
X 
X 
© 2018 Zambon SpA 
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CONFIDENTIAL 
Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Visit 
1 
2 
3 
4 
5 
6 
Screening 
Baseline 
Interim 
Interim 
EoT 
Call 
* 
Week4 
Week8 
Week 16 
* 
* 
* 
Day/ 
(up to 14 
Procedure 
days before 
1 
28±3 
56±3 
112 ±3 
119±3 
Notes* 
Day 1) 
Blood draw 
X 
X 
For 
Haematology 
& Clinical 
chemistry 
Pregnancy test 
X 
X 
Urine dipstick 
test for 
WOCBP only 
Prior and 
X 
X 
X 
X 
X 
X 
concomitant 
medications 
Adverse events 
X 
X 
X 
X 
X 
X 
Drug Dispense 
X 
X 
X 
Drug 
X 
X 
X 
accountability 
*= COVID- 19 outbreak: in order to ensure the continuity of the study, limiting the subjects' 
exposure to infection and overcoming travel restriction imposed by governments, a 
Contingency Plan has been finalized (see Appendix 10) describing alternative procedures to be 
adopted in the study in order to mitigate the restrictions and keeping participants in the study 
trial ( see Appendix 10 for details) 
© 2018 Zambon SpA 
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Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
2. 
Introduction 
Safinamide is an alpha-aminoamide derivative, structurally unrelated to any other drug for the 
treatment of PD. 
Safinamide has both dopaminergic and non-dopaminergic activities. It is a potent, selective and 
reversible MAO-B inhibitor, a mechanism associated with enhancement of dopaminergic 
transmission in the brain. Safinamide is also a state-dependent inhibitor of voltage-gated sodium 
channels and, at higher concentrations, inhibits calcium channels. These molecular mechanisms 
act in animal models of PD to increase brain dopamine, extend L-Dopa induced ON-time 
(dopaminergic actions) and reduce the severity of L-Dopa induced dyskinesia (non-dopaminergic 
action). 
It is suggested that dopaminergic effects through selective and reversible inhibition of MAO-B, 
and non-dopaminergic 
effects through state dependent inhibition of voltage-gated 
sodium 
channels, are likely to be the principal relevant mechanisms for therapeutic activity in PD. 
Safinamide (50mg and 100mg) has been approved by the European Medicines Agency (EMA) and 
FDA for the treatment of mid- to late-stage fluctuating PD patients as add-on therapy to L-Dopa 
(alone or in combination with other anti-Parkinson drugs). 
2.1. 
Study Rationale 
Pain is a frequent non-motor symptom of PD, often underestimated and inadequately treated, with 
a significant impact on patients' quality of life. 
There 
is growing 
evidence 
that motor complications 
and pain may 
share common 
pathophysiologic mechanisms that include not only dopaminergic but also non-dopaminergic 
systems dysfunction, such as glutamatergic hyperactivity. 
Results from a post-hoe analysis of the pooled data of two Phase III studies (016 and SETTLE) 
indicate that safinamide 100 mg/day significantly reduced in fluctuating PD patients the individual 
use of pain treatments by about 24% and improved two out of three items of the Parkinson's 
Disease Quality of Life Questionnaire (PDQ-39) related to pain (Cattaneo et al. 2017). 
Therefore, drugs that modulate glutamate release, such safinamide, may be a further option for the 
treatment of PD chronic pain. 
2.2. 
Background 
IPD is a neurodegenerative condition characterized by the loss of neuromelanin containing neurons 
in the substantia nigra. Depletion of the dopaminergic neurons of the substantia nigra results in 
dopamine reduction, which is the main biochemical abnormality. 
The main symptoms of IPD are resting tremor, bradykinesia and rigidity. The disease is also 
associated with non motor symptoms such as mood disorders and pain (Chaudhuri et al. 2009). 
The incidence of IPD increases with age, with incidence rates in the general population increasing 
from 0.3 per 1,000 person-years in participants aged 55 to 65 years, to 4.4 per 1,000 person-years 
for those aged 2':85 years (De Lau et al. 2004). 
© 2018 Zambon SpA 
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CONFIDENTIAL 
Protocol Z7219M0 1 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Levodopa (L-Dopa) remains the most effective therapy for IPD, but is associated with treatment 
complications such as motor fluctuations, wearing off phenomena and dyskinesia. As the disease 
progresses, the majority of participants will require therapies combining L-Dopa and with other 
agents which increase local dopamine concentrations or the efficacy of endogenous dopamine, 
such as adjunct dopamine agonists and/or MAO-B inhibitors. The demonstration of an anti-
dyskinetic effect of the glutamate antagonist amantadine opened the door for novel non-
dopaminergic approaches to PD therapy. 
2.3. 
Benefit/Risk Assessment 
The patient in active drug may benefit in reduction of pain medication's intake. 
In terms of risk, safinamide is approved by both EMA and FDA. 
When drawing blood samples, bruising might occur. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of safinamide is 
provided in the Summary of Product Characteristics (SmPC). 
© 2018 Zambon SpA 
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CONFIDENTIAL 
Protocol Z7219M01 
Version: 3.0 
Amendment: 
2 -AUS GER ITA ESP 
Date: 27 th October 2020 
3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate the potential efficacy of 
• The change from baseline to week 16 
safinamide 
100 mg od, compared to 
in pain severity ("average worst pain 
placebo, as add-on therapy, for PD 
experienced in the last 7 days"), as 
related chronic pain. 
assessed by an 11-point Numerical 
Rating Scale (NRS). 
Secondary 
• The percentage of pain responders 
• Participants with reduction in pain 
severity of~2 points ("average worst pain 
experienced in the last 7 days"), at week 
16 as assessed by an I I-point NRS, 
compared to baseline. 
• 
Clinical Global Impression for pain 
• 
The CGI-S score for pain at week 16. 
• The change from baseline to week 16 in 
the CGI-C score for pain. 
• 
Patient Global Impression for pain 
• The change from baseline to week 16 in 
the PGI-C score for pain. 
• 
Reduction of pain drugs 
The percentage of reduction in number of 
• 
concomitant pain drugs from baseline to 
week 16. 
• The number of patients with at least one 
intake of PRN pain medication. 
• Amount of PRN pain medication 
• The change from baseline to week 16 in 
• 
Mood 
the HADS score. 
• The change from baseline to week 16 in 
• Motor and non-motor symptoms 
the MDS-UPDRS (total score and 
subscores) during the "ON" phase. 
• Safety & Tolerability 
• Descriptive 
© 2018 Zambon SpA 
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CONFIDENTIAL 
Protocol Z7219M01 
4. 
4.1. 
Amendment: 2 -AUS GER ITA ESP 
Study Design 
Overall Design 
Version: 3.0 
Date: 27th October 2020 
• 
International, multicentre, randomised, double-blind, placebo-controlled study. 
• 
Two treatment groups, active & placebo, randomized 2: 1. 
• 
Up to 132 participants will be screened, of which approximately 105 will be enrolled, to 
have 84 evaluable participants (56 active: 28 placebo). 
• 
Study consists of two periods, screening (1-2 weeks) and a treatment period (16 weeks), 
with a follow-up call at 1 week after treatment, total duration 19 weeks. 
• 
Study medication consists of active and matching placebo, presented in identical wallets, 
and during the first week of the treatment period participants will start with 50 mg dose for 
1 week, before taking 100 mg which should contribute to maintaining the blind. 
• 
Participants have a diagnosis of IPD (according to United Kingdom Parkinson's Disease 
Society Brain Bank criteria for at least 5 years), Hoehn and Yahr stage between 2-3 
inclusive during the "ON" phase, experiencing motor fluctuations while on stable doses of 
L-Dopa (with or without benserazide/carbidopa, with or without addition of a catechol 0-
methyltransferase (COMT) inhibitor) and may be on stable doses of other PD medications 
(a dopamine agonist, an anticholinergic and/or amantadine), yet are experiencing chronic 
PD related pain. 
4.2. 
Scientific Rationale for Study Design 
The guideline on clinical investigation of medicinal products in the treatment of Parkinson's 
Disease (EMA/CHMP/330418/2012 rev. 2 dated 21 June 2012), paragraph "Symptomatic relief in 
patients with Parkinson's Disease on L-Dopa+", recommends performing placebo-controlled 
double-blind studies, in order to establish unequivocal safety and efficacy data in this patient 
population, as follows: "In patients with some form of advanced PD the test drug may be given as 
adjunctive to L-Dopa+. These patients may suffer from an insufficient control of motor symptoms 
despite treatment with L-Dopa+ or may suffer from dose dependent or non -dose dependent motor 
fluctuations. 
The use of placebo in addition to background standard of care (SoC) therapy in this study is based 
on the ICH Topic E 10 guideline on the "Choice of control group in clinical trials" 
(CPMP/ICH/364/96) and is in accordance with the EMA position for "Use of placebo in clinical 
trials with regard to the revised Declaration of Helsinki" (EMEA/17424/01). 
As for participants who experience periodic worsening of their chronic pain during treatment or 
follow-up periods of the study, they may take PRN medications. 
4.3. 
Justification for Dose 
The dose of 100 mg/day (titrated from 50 mg/day after 1 week) was selected based on the results 
of the previous studies in PD patients and from the results of the post-hoe analysis on the effects 
of safinamide on pain. 
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Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the follow-up phone call after Visit 5 (End of Treatment) which is the last 
scheduled procedure shown in the Schedule of Activities. 
The end of the study is defined as the date of the last visit of the last participant in the study last 
scheduled procedure shown in the Schedule of Activities for the last participant in the trial globally. 
© 2018 Zambon SpA 
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Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 30 years of age or older, at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
Sex 
2. Diagnosed with IPD by using the United Kingdom Parkinson's Disease Society Brain Bank 
criteria for more than 5 years duration. 
3. Receiving treatment with a stable dose of oral L-Dopa (including controlled release [CR], 
immediate 
release 
[IR] 
or 
a 
combination 
of 
CR/IR), 
with 
and 
without 
benserazide/carbidopa, 
with or without addition of a catechol O-methyltransferase 
(COMT) inhibitor and may be receiving concomitant treatment with stable doses of a 
dopamine agonist, an anticholinergic and/or amantadine for at least 4 weeks prior to the 
randomisation (baseline visit). 
4. Hoehn and Y ahr stage between 2-3 (inclusive) during the "ON" phase at the screening 
visit. 
5. Experiencing motor fluctuations following optimum titration of treatment medications and 
within the 4 weeks immediately prior to randomisation. 
6. Experiencing chronic pain (i.e. ongoing for 2:3 months prior to screening visit); the 
Investigator must consider chronic pain directly related to PD and not explained by any 
other health problem ( e.g. peripheral neuropathy, organ disease or arthritis pain) OR 
consider the intensity of chronic pain specifically aggravated by PD. 
7. If taking regular analgesics, the treatment regimen should be stable in the 4 weeks prior to 
the randomisation visit. 
8. Able to maintain an accurate and complete electronic diary with the help of a caregiver. 
9. Male or female 
a. 
Female participants: 
• 
A female participant is eligible to participate if she is not pregnant (see Appendix 4), not 
breastfeeding, and at least one of the following conditions applies: 
1. 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
OR 
© 2018 Zambon SpA 
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Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
11. 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4. 
Informed Consent 
10. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Any form of Parkinsonism other than IPD. 
2. Diagnosis of chronic migraine (> 15 days per month) or cancer pain. 
3. History of bipolar disorder, depression, schizophrenia or other psychotic disorder requiring 
treatment with neuroleptics. 
4. History of dementia or cognitive dysfunction. 
5. Severe, peak dose or biphasic dyskinesia. 
6. Unpredictable or widely swinging fluctuations. 
7. Ophthalmologic history including any of the following conditions: albinism, uveitis, 
retinitis pigmentosa, retinal degeneration, active retinopathy, severe progressive diabetic 
retinopathy, inherited retinopathy or family history of hereditary retinal disease. 
8. Moderate or severe liver failure using the Child-Pugh classification score. 
9. History of drug and/or alcohol abuse within 12 months prior to screening as defined by the 
current edition of the Diagnostic and Statistical Manual of Mental Disorders. 
10. Allergy/sensitivity, intolerance or contraindications to Safinamide. 
Prior/Concomitant Therapy 
11. Treatment with monoamine oxidase inhibitors (MAOis), levodopa infusion, pethidine, 
fluoxetine, fluvoxamine less than 4 weeks prior to the randomisation visit. 
© 2018 Zambon SpA 
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Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Prior/Concurrent Clinical Study Experience 
12. Use of any investigational drug or device within 30 days prior to screening or 5 half-lives, 
whichever is the longest. 
13. Previous treatment with Safinamide in the 9 months before the screening visit 
Diagnostic assessments 
14. Mini-Mental State Exam (MMSE) total score <24 at screening. 
15. NRS score:::; 4 points at randomization visit. 
Other Exclusions 
16. Any clinically significant condition which, in the opinion of the Investigator, would not be 
compatible with study participation or represent a risk for participants while in the study. 
5.3. 
Lifestyle Considerations 
Not applicable, no dietary restrictions. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants 
to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once within six weeks. 
© 2018 Zambon SpA 
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Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1. 
Study Intervention(s) Administered 
Study Intervention 
Active 
Placebo 
Name: 
Dosage formulation: 
Safinamide 
methanesulfonate 
Excipients: 
microcrystalline 
microcrystalline 
cellulose, 
cellulose, 
crospovidone, 
crospovidone, 
colloidal silicone 
colloidal silicone 
dioxide, 
dioxide, 
magnesmm 
magnesmm 
stearate, and for 
stearate, and for 
the coating: 
the coating: 
purified water, 
purified water, 
hypromellose and 
hypromellose and 
polyethylene 
polyethylene 
glycol. Candurin® 
glycol. Candurin® 
pigments are 
pigments are 
included for colour 
included for colour 
modification 
modification 
Unit dose 
50mg, 100 mg 
-
strength( s )/Dosage 
safinamide ( free 
level(s): 
base) 
Route of 
Oral 
Administration 
Dosing instructions: 
Once daily, 
with or without food, at breakfast time 
when taking the morning dose of L-Dopa 
© 2018 Zambon SpA 
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Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Study Intervention and placebo will be 
Packaging and 
provided in PVC/PVDC60/ Al blisters. 
Labeling 
Blister Wallets are used 
Each wallet will be labeled with a 
booklet label 
3 wallets will be placed into a carton: 1 x 
Wallet Visit 2, lx Wallet Visit 3, lx 
Wallet Visit 4 
Each carton will be labeled with a 
booklet label 
Tamper seals applied. 
Manufacturer 
Catalent, 
Zambon S.p.A., 
Schorndorf, 
Vicenza, Italy 
Germany 
in alternative 
Zambon S.p.A., 
Vicenza, Italy 
Primary Packaging 
Catalent, Schorndorf, Germany 
in alternative 
Zambon S.p.A., Vicenza, Italy 
Secondary Packaging 
Almac, Craigavon, United Kingdom 
6.2. 
Preparation/Handling/Storage/ Accountability 
Study medication will be stored on-site in a secure area with access limited to the Investigator and 
authorised study personnel. 
No special procedures for the storage or the safe handling of the study medication are required. 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. * 
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). * 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual. 
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Date: 27th October 2020 
5. The Sponsor and their authorized representatives such as study monitors or auditors as well 
as regulatory inspectors will be permitted, upon request, to audit the supplies, storage and 
dispensing procedures and records in accordance with applicable regulatory requirements 
*= COVID- 19 outbreak: in order to ensure the continuity of the study, limiting the subjects' 
exposure to infection and overcoming travel restriction imposed by governments, a Contingency 
Plan has been finalized describing alternative procedures to be adopted in the study in order to 
mitigate the restrictions and keeping participants in the trial (see Appendix 10 for details) 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
At screening, each participant who has signed an informed consent form and is screened will be 
allocated, by the IWRS, a screening number comprising the prefix 'xx' where xx is the unique site 
number and a 3-digit number representing the sequential order in which they are screened, e.g. 01-
001, 01-002, 02-001 etc. 
Participants who meet all criteria for enrolment will be randomised to double-blind treatment in a 
2: 1 ratio either to safinamide or placebo at visit 2 ( day 1) 
Investigators will be able to randomise participants using a web-based interactive web response 
system (IWRS) which is fully integrated within the eCRF. 
The IWRS will allocate a unique medication kit number which will consist of a 4-digit number 
starting with 1001, 1002, etc. 
Study using 
IWRS 
Blind Break 
(IVRS/IWRS) 
© 2018 Zambon SpA 
All participants will be centrally assigned to randomized study intervention using 
an Interactive Web Response System IWRS). Before the study is initiated, the log 
in information & directions for the IWRS will be provided to each site. 
Study intervention will be dispensed at the study visits summarized in SoA. 
Returned study intervention should not be re-dispensed to the participants. 
The IWRS will be programmed with blind-breaking instructions. 
In case of an emergency, the investigator has the sole responsibility for 
determining ifunblinding ofa participants's treatment assignment is warranted. 
Participant safety must always be the first consideration in making such a 
determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding 
a participant's treatment assignment unless this could delay emergency 
treatment of the participant. If a participant's treatment assignment is unblinded, 
the sponsor must be notified within 24 hours after breaking the blind. The date 
and reason that the blind was broken must be recorded in the source 
documentation and case report form, as applicable. 
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6.4. 
Study Intervention Compliance 
The prescribed dosage, timing and mode of administration of study medication may not be 
changed. 
Study medication accountability and subject compliance will be documented throughout the 
treatment period using study-specific study medication dispensing and return record forms. 
Participants will be asked to return all unused medication. From Visits 3 to 5 (weeks 4 to 16), the 
study medication dispensed at the previous visit will be retrieved by the Investigator and 
compliance assessed by tablet count. 
Non-compliance is defined as taking less than 80% of study medication during any visit-to-visit 
evaluation period. 
Participants exhibiting non-compliance will be reminded about the importance of being compliant 
with the study dosing regimen. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the participant is receiving at the time of enrollment or receives during 
the study will be recorded along with: 
• 
Reason for use. 
• 
Dates of administration including start and end dates. 
• 
Dosage information including dose and frequency. 
In particular, all pain medication taken on a PRN basis ( e.g. paracetamol, up to a maximum of 
4,000mg/day; NSAIDs) will be recorded in the dedicated section of eCRF. 
In addition, patients will continue to use their regular non PRN pain medication, if taken, ( e.g. 
oxycodone, codeine, botulinum toxin, gabapentin, nortriptyline, muscle relaxants, analgesics) 
which should remain stable from the 4 weeks prior to randomization visit and at least for the first 
4 weeks of the study. 
If the patient is using a combination analgesic that contains paracetamol, extreme caution 
must be exercised in the use of PRN medications containing paracetamol, so as not to exceed 
a paracetamol total daily dose of 4000 mg (see section 6.5.2) 
Medical Monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
6.5.1. 
Rescue Medicine 
Not Applicable 
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Protocol Z72 I 9M0 1 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
6.5.2. 
Excluded Medicine 
Treatment with the following drugs is not allowed 4 weeks before randomization, throughout the 
study and up 2 weeks after the last dose of study drug: 
· 
• 
Monoamine oxidase inhibitors (MAOis), 
• 
Levodopa infusion, 
• 
Pethidine, 
• 
Fluvoxamine, 
• 
Fluoxetine, 
• 
Combination analgesic products including paracetamol are permitted, but extreme caution 
must be exercised in the use of PRN medications containing paracetamol so as not to exceed a 
total daily dose of 4000mg paracetamol 
The use of any prohibited concomitant medication is a protocol deviation and should be 
recorded. 
6.5.3. 
Permitted Medication 
Selective serotonin reuptake inhibitors (SSRis) ,other than fluoxetine or fluvoxamine, selective 
serotonin-norepinephrine reuptake inhibitors (SNRis), tricyclic and tetracyclic antidepressants can 
be administered provided they remain at the lowest effective dose and remain stable throughout 
the study 
Dextromethorphan, sympathomimetics, nasal and oral decongestants or cold medicinal products 
containing ephedrine, pseudoephedrine, phenylephrine or phenylpropanolamine are permitted if 
used for treating cough but must be used with caution. 
6.6. 
Dose Modification 
Not applicable. 
6.7. 
Intervention after the End of the Study 
Phone call at one week after Eo T. 
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CONFIDENTIAL 
Protocol Z7219M01 
Version: 3.0 
7. 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Intervention 
Not applicable 
7 .2. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
• 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• 
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
• 
See SoA for data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed. 
• 
Pregnant participants must be withdrawn from the study without delay 
Participants who are withdrawn from the study will not be replaced. 
In the event that a subject discontinues from the study prematurely due to an AE or SAE, they will 
be followed until the event has resolved (returns to normal or baseline values) or has stabilised. 
The reason for withdrawal of a subject from the study must be fully documented in the eCRF as 
well in source documents. 
Any major or critical deviation which may have an impact on study results and or safety of the 
participants should be immediately reported to Sponsor/CRO and notified to Regulatory 
Authorities (EC/CA) according to local regulations. A decision will be taken by the Sponsor, after 
consultation with the medical monitor as to whether or not the subject affected by the departure 
from the protocol, is to continue in the study. A deviation log will be maintained to track actual 
deviations and decisions taken, including all deviations occurred. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
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Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
• 
Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant's last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant's 
medical record. 
© 2018 Zambon SpA 
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Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
8. 
Study Assessments and Procedures 
• 
Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions 
are not allowed. 
• 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• 
All screening evaluations must be completed 
and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to record 
details of all participants screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
• 
Procedures conducted as part of the participant's routine clinical management and obtained 
before signing of the ICF may be utilized for screening or baseline purposes provided the 
procedures met the protocol-specified 
criteria and were performed within the time frame 
defined in the SoA. 
• 
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 20 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. 
• 
Local labs will be used in this study 
Visit 1: Screening visit (7 to 14 days before Dayl) 
The screening visit (Visit 1) should take place at least 7 days prior to Visit 2 to allow sufficient 
time to receive lab results and for subject to complete 7 days' worth of diary data, to fully assess 
eligibility. 
• 
Obtain written informed consent. 
• 
Record details in IWRS (Section 6.3) for screening number allocation. 
• 
Record demographic data, including age, sex, ethnicity, smoking and alcohol use. 
• 
Record of medical history and PD diagnosis, including Hoehn and Y ahr stage. 
• 
Recording of prior medications, concomitant medications (including PRN medication for 
pain) and therapies (Section 6.5). 
• 
Neurological examination. 
• 
MMSE (Section 8.2.3). 
• 
Physical examination (Section 8.2.1). 
• 
Vital signs (heart rate, systolic and diastolic blood pressure) measured after at least 5 
minutes in the supine position (Section 8.2.2). 
• 
Blood sampling for clinical laboratory assessments (haematology and clinical chemistry, 
including liver function tests) (Section 8.2.4 & 10.2). 
• 
Show the subject how to use the electronic diary (Section 8.1.1 ). 
• 
Check of inclusion and exclusion criteria (Sections 5.1 and 5.2). 
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Amendment: 2 - AUS GER IT A ESP 
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• 
Issue electronic diary with instructions for the NRS pain assessment and PRN pain 
medication intake to be completed daily over the seven consecutive days immediately prior 
to the baseline visit (Visit 2). 
• 
When agreeing the visit schedule with the subject, bear in mind that scales & questionnaires 
should be done at approximately the same time of day, preferably at least one hour after 
the usual morning L-Dopa dose (and study medication), when participant is in an optimal 
ON state. 
Visit 2: Baseline visit (Day 1) 
At Visit 2, if subject is eligible, the baseline values will be established, and the first dose of study 
medication will be administered under supervision at the site. 
• 
NRS score of pain intensity> 4 for eligibility, as recorded in the electronic diary. (Section 
8.1.1). 
• 
Check of inclusion and exclusion criteria. If participant is eligible, upon completing the 
data entry in the EDC system the randomization form will appear to randomise subject. 
• 
Vital signs (heart rate, systolic and diastolic blood pressure) measured after at least 5 
minutes in the supine position. 
• 
Urine sampling for urine (dipstick) pregnancy test for women of child-bearing potential 
(WOCB). 
• 
Completion of MDS-UPDRS (part 1B and 11) and HADS by the subject (Section 8.1). 
• 
Completion of MDS-UPDRS (part IA, III and IV) and CGI-S by the rater (Section 8.1). 
• 
Administer subject's first dose of study medication (50 mg) at the study centre. 
• 
Instruct participants to take the study medication, once daily, in the morning, along with 
their usual dose ofL-Dopa. During Week 1 subject will take 50 mg, which will be increased 
up 100 mg at home on Day 8. 
• 
Dispense study medication for the next 28 days. 
• 
Re-issue electronic diary with instructions for the NRS pain assessment to be completed 
daily over the 7 consecutive days immediately prior to the visit at week 4 (Visit 3) and the 
intake of PRN pain medication to be recorded daily according to use. 
• 
Recording of prior medications, of concomitant medications and therapies. 
• 
Recording of AEs (Section 8.3). 
When scheduling Visits 3, 4 and 5, bear in mind that: 
- where possible, the subject should be in an optimal ON state, i.e. at least 1 hour after the morning 
dose L-Dopa and study medication. 
- the questionnaires should be completed at the approximately on the same time of the day as at 
the baseline visit. 
COVID- 19 outbreak: in order to ensure the continuity of the study, limiting the subjects' 
exposure to infection and overcoming travel restriction imposed by governments, a Contingency 
© 2018 Zambon SpA 
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Amendment: 2 - AUS GER IT A ESP 
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Plan has been finalized describing alternative procedures to be adopted in the study in order to 
mitigate the restrictions and keeping participants in the trial ( see Appendix 10 for details). 
Visit 3 & Visit 4: interim visits (Day 28 & Day 56) 
• 
Completion of MDS-UPDRS (part 1B and II), and PGI-C by the subject. 
• 
Completion of MDS-UPDRS (part IA, III and IV), CGI-S and CGI-C by the rater. 
• 
Recording of concomitant medications and therapies. 
• 
Recording of AEs. 
• 
Drug accountability. 
• 
Review and evaluate daily diary (provide additional daily diary training, as required). 
• 
Re-issue electronic diary at weeks 4 and 8, with instructions for the NRS pain assessment 
and the intake of PRN pain medication to be completed daily over the 7 consecutive days 
immediately prior to the next visit (Visits 4 & 5). 
• 
Dispense study medication for next period. 
COVID- 19 outbreak: in order to ensure the continuity of the study, limiting the subjects' exposure 
to infection and overcoming travel restriction imposed by governments, a Contingency Plan has 
been finalized describing alternative procedures to be adopted in the study in order to mitigate the 
restrictions and keeping participants in the trial ( see Appendix 10 for details). 
Visit 5: End of Treatment (Day 112) 
Following completion of 16 weeks' of treatment or in the event of premature discontinuation, the 
following End of Treatment (EOT) assessments and procedures should be performed. 
• 
Neurological & Physical examination. 
• 
Vital signs (heart rate, systolic and diastolic blood pressure measured after at least 5 
minutes in the supine position). 
• 
MDS-UPDRS (part 1B and II), HADS and PGI-C completed by the participant. 
• 
MDS-UPDRS (part IA, III and IV), CGI-S and CGI-C completed by the rater. 
• 
Obtain blood sample for clinical laboratory assessments (haematology and clinical 
chemistry). 
• 
Obtain urine sample only for WOCBP for urine (dipstick) pregnancy test. 
• 
Record any changes or new concomitant medications and therapies. 
• 
Record any AEs. 
• 
Review and evaluate daily e-diary. 
• 
Drug (all used & unused study medication) and final accountability. 
• 
Collect e-diaiy. 
• 
Agree on day & time for the follow up call in one weeks' time. 
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Protocol Z7219M01 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
COVID- 19 outbreak: in order to ensure the continuity of the study, limiting the subjects' 
exposure to infection and overcoming travel restriction imposed by governments, a Contingency 
Plan has been finalized describing alternative procedures to be adopted in the study in order to 
to mitigate the restriction sand keeping participants in the trial (see Appendix 10 for details) 
8.1. 
Efficacy Assessments 
Site personnel who are to be involved in performing the efficacy assessments must be experienced 
in the use of the various scales and questionnaires. 
To ensure consistency of ratings on each efficacy measure for each participant during the study, 
the same rater should perform the assessments where possible. 
Wherever possible the NRS, part 1B and II of the MDS-UPDRS, the HADS and the PGI-C 
should be completed by the participant. However, in the case of the participant's incapacity, for 
example due to dyskinesia, tremor, etc., the participant's caregiver may complete the NRS, part 
1B and II of the MDS-UPDRS, the HADS and the PGI-C based on information reported by the 
participant. 
The following parameters are to be completed by the rater: 
• 
MDS-UPDRS (part IA, III and IV). 
• 
CGI-S. 
• 
CGI-C. 
8.1.1. 
Pain Assessments 
The primary efficacy endpoint for the study is the mean change in pain severity ("average pain 
experienced in the last 7 days"), as assessed by an 11-point NRS, from baseline to week 16. 
Pain severity data will be derived from the daily diary. 
Daily Diary 
An electronic diary will be completed daily by each participant as follows: 
• 
to record the PD pain score at screening (Visit 1 ), by completion of an 11-point NRS, to 
confirm eligibility 
• 
the NRS score is calculated over 7 consecutive days immediately prior to baseline (Visit 2/Day 
1) and Visits 3, 4 and 5-/EOT/ET (Weeks 4, 8 and 16), completion of an 11-point NRS, to 
allow for the assessment of the average pain experienced in the last 7 days during which patient 
records on a daily basis the most severe pain using an 11-point NRS. 
• 
on a daily basis from baseline onwards, an accurate record of the use of PRN pain medication 
for PD-associated pain (Section 10.1.6.2). 
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Daily Diary Training 
At the screening visit, the Investigator ( or other trained, qualified personnel) will reinforce 
recognition of PD-related chronic pain, as well as the use of the daily diary. 
On each visit, the Investigator will instruct the participant to complete the daily diary at home for 
the 7 consecutive days immediately prior to the next visit. 
Participants will record the intensity of their PD-associated pain, as the worst pain experienced 
over the past 24 hours, (from O [no pain] to 10 [worst possible pain]) using an 11-point NRS. Pain 
intensity should be recorded if possible, in the evening before going to sleep. If the subject suffered 
from more than 1 PD-associated pain, the more severe pain will be documented. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, assessments of the general 
appearance, head, ears, eyes, nose, throat, neck, skin, cardiovascular system, respiratory 
system, abdominal system and nervous system. 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. 
Vital Signs 
Blood pressure and heart rate will be assessed in the supine position with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
Measurement should be preceded by at least 5 minutes of rest for the participant in a quiet setting 
without distractions ( e.g., television, cell phones). 
8.2.3. 
Cognitive Impairment 
Participants will be evaluated for cognitive impairment using the MMSE. The MMSE (Folstein et 
al, 1975) is a brief practical screening test for cognitive dysfunction. The test consists of 5 sections 
( orientation, registration, attention and calculation, recall, and language) and has a total possible 
score of 30. It will be used as a quick method to assess the severity of cognitive dysfunction. The 
MMSE will be used for screening participants (a total score< 24 is exclusionary). 
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8.2.4. 
Clinical Safety Laboratory Assessments 
• 
See Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
• 
The investigator must review the laboratory repmi, document this review, and record any 
clinically relevant changes occurring during the study both in the appropriate section of 
eCRF study's visit and in the AE section of the eCRF. The laboratory reports must be filed 
with the source documents. Clinically significant abnormal laboratory findings are those 
which are not associated with the underlying disease, unless judged by the investigator to 
be more severe than expected for the subject's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 2 weeks after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
8.2.5. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
o All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA. 
o If laboratory values from non-protocol specified laboratory assessments performed 
at the institution's local laboratory require a change in participant management or 
are considered clinically significant by the investigator ( eg, SAE or AE or dose 
modification), then the results must be recorded in the CRF. 
Suicidal Risk Monitoring 
Not applicable. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
AE will be reported by the subject ( or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7) 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All (S)AEs will be collected from the signing of the informed consent form (ICF) until the follow-
up call at the time points specified in the SoA (Section 1.3). 
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All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 24hours of 
it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7 .3). Further 
information on follow-up procedures is given in Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent 
Ethics Committees (IEC), and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information ( e.g., summary or listing of SAEs) from the sponsor will review 
and then file it in the Investigator Study File and will notify the IRB/IEC, if appropriate 
according to local requirements. 
• 
The reference safety information for this study is the Summary of Product Characteristics 
of Safinamide 
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8.3.5. 
Pregnancy 
• 
Details of all pregnancies in female will be collected after the start of study intervention and 
until 1 month after the last dose of study drug 
• 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
• 
Abnormal pregnancy outcomes ( e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable 
8.4. 
Treatment of Overdose 
The anticipated pattern of events or symptoms following intentional or accidental overdose with 
safinamide is that related to its pharmacodynamic profile (MAO-B inhibition with activity 
dependent inhibition of sodium channels). The symptoms of excessive MAO-B inhibition 
(increase in dopamine level) could include hypertension, postural hypotension, hallucinations, 
agitation, nausea, vomiting and dyskinesia. 
There is no known antidote to safinamide or any specific treatment for a safinamide overdose. If a 
significant overdose should occur, safinamide treatment should be discontinued and supportive 
treatment should be administered as clinically indicated. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE or laboratory abnormalities 
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with_the Medical Monitor based on the clinical evaluation of the participant. 
8.5. 
Pharmacokinetics 
PK parameters are not evaluated in this study. 
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8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8. 7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Bio markers 
Biomarkers are not evaluated in this study. 
8.9. 
Health Economics 
Health Economics are not evaluated 
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9. 
9.1. 
Amendment: 2 -AUS GER ITA ESP 
Statistical Considerations 
Statistical Hypotheses 
Version: 3.0 
Date: 27th October 2020 
The null hypothesis is that safinamide is not able to reduce pain severity compared to placebo. 
9.2. 
Sample Size Determination 
On the basis of previous post-hoe analyses of pain (Cattaneo et al 2017) and of similar studies 
(Folstein et al, 1975), it is anticipated that a sample size of 144 participants would permit detection 
of a 1 point treatment difference in the NRS between safinamide and placebo assuming a standard 
deviation of 2, 5% significance and 80% power. A 1 point treatment difference is considered to be 
a clinically meaningful treatment effect (Rascal et al, 2016). 
Approximately 220 participants will be screened to achieve 177 randomly assigned to study 
intervention and of which approximately 144 participants complete the study (96 and 48 evaluable 
participants in the active and placebo group respectively). 
Since March 2020, the COVID-19 emergency has impacted the feasibility of the trial, which is 
being conducted in a vulnerable group of patients. Upon receipt of the guidance "Statistical 
Considerations for Clinical Trials During the COVID-19 Public Health Emergency" issued by 
FDA on June 2020, released with the aim of helping sponsors ensure that trials conducted during 
the Covid-19 emergency could continue, where appropriate, to provide interpretable findings with 
correct statistical quantification of uncertainty, the Sponsor performed a Blind Data Review 
Analysis of the primary endpoint data (pain severity) for the 26 patients who had completed the 
study as of June 2020. 
The results of the analysis show that the standard deviation used in the original sample size 
estimation (SD = 2. was a conservative overestimate of the observed SD from the actual trial data, 
which is 1.43. 
Based on this, the Standard Deviation, for the estimation of sample size has now been amended to 
1.50, and the power has been maintained as 80%. New sample size estimates have been performed 
considering different magnitudes of Treatment Difference, but keeping the same assumptions of 
screen failure rates and drop out rates. These are summarized below in Table below 
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SCENARIO 
SAMPLE SIZE 
Power= 80% 
Pts to screen= 132 
Standard deviation= 1.5 
Pts to randomize= 105 
Treatment Difference = 1 point 
Pts completing study= 84 
Power= 80% 
Pts to screen= 66 
Standard deviation= 1.5 
Pts to randomize= 51 
Treatment Difference = 1.5 points 
Pts completing study= 39 
Power= 80% 
Pts to screen= 39 
Standard deviation= 1.5 
Pts to randomize= 30 
Treatment Difference = 2 points 
Pts completing study= 24 
It is now planned to keep the initial conservative estimate of treatment difference as 1 and change 
the SD to 1.5 in line with what was observed with the Blind Data Review Analysis. Using these 
parameters, up to 132 participants will be screened to achieve up to 105 randomized, to have 
approximately 84 patients complete the study ( 56 in the active and 28 in the placebo group 
respectively). 
However, given the continuous and uncertain impact that COVID-19 outbreak is having in the 
countries participating in the trial, any of other scenarios might be adopted if at the end of 
December 2020 the above enrollment goal will not be achieved. From the table above it can be 
seen that if the treatment difference is greater than 1, statistical significance can be achieved with 
a substantially lower sample size. Thus, the study maintains its robustness. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Full analysis set 
The FAS is defined as all randomized subjects in the study, with 
at least one measurement of the primary efficacy variable 
following at least one dose of study medication. Summaries on the 
FAS will be performed for all efficacy endpoints. Subjects in this 
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analysis set will be summarized according to the treatment they 
were randomly assigned to. 
Per Protocol 
The PP Set will be a subset of subjects in the FAS who completed 
the study and for whom no relevant protocol deviations were 
documented. Identification of relevant protocol deviations will 
occur on a blinded review meeting preceding database lock. A 
second analysis of the primary efficacy endpoint will be based on 
the PP Set. All subjects in the PP Set will be summarized 
according to the treatment they were assigned to. 
Safety 
The Safety Set will include all randomized subjects assigned to 
study intervention and who take at least 1 dose of study 
medication. The Safety Set will be used for the analysis of all 
safety endpoints. All subjects in the Safety Set will be 
summarized according to the treatment they actually received 
( according to the Drug Accountability eCRF page). 
The decision whether a protocol deviation is relevant or not for the exclusion of participants from 
the per protocol (PP) set will be made case-by-case in a blind data review meeting. 
The primary analysis of the primary efficacy variable will be based on the FAS data set. A 
secondary analysis of the primary efficacy parameter will be based on the PP set. 
All other secondary efficacy analyses will be based on the FAS. 
Safety analyses will be based on the safety analysis (SA) set. 
9.4. 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
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9.4.1. 
Efficacy Analyses 
• 
Primary efficacy endpoint 
The primary endpoint evaluated in this study is the mean change in pain severity ("average 
worst pain experienced in the last 7 days", i.e. average of the worst pain score on each of the 
7 days preceding the site visit), as assessed by an 11-point NRS, from baseline to Week 16. 
The primary efficacy endpoint, change from baseline to Week 16 in pain severity score, will 
be analyzed using a mixed model repeated measures (MMRM) using visit on subject ID as the 
repeated factor with unstructured covariance term. 
The model will include fixed effects terms for treatment, country, visit and regular pain 
medication use at baseline (yes or no) and covariate term for pain severity score at baseline. 
• 
Secondary efficacy endpoint 
Percentage of pain responders defined as subjects with reduction in pain severity of ~2 
points ("average worst pain experienced in the last 7 days"), at weeks 4, 8 and 16 as 
assessed by an 11-point NRS, compared to baseline; 
The pain severity score (average worst pain score using 11 point NRS scale) at weeks 4 
and 8; 
The Clinical Global Impression of Severity (CGI-S) score at weeks 4, 8 and 16 (rated by 
Investigator); 
The change from baseline to Weeks 4, 8 and 16 in the Clinical Global Impression of 
Change (CGI-C) score rated by Investigator; 
The change from baseline to Weeks 4, 8 and 16 in the Patient Global Impression of Change 
(PGI-C) score rated by the subject; 
The percentage of subjects with a reduction in the number of days using concomitant pain 
drugs in the 7 days before each visit at Weeks 4, 8 and 16; 
The number of days with PRN pain medication in the 7 days before each visit at weeks 4, 
8 and 16; 
The change from baseline to week 16 in the Hospital Anxiety and Depression Scale 
(HADS) score; 
The change from baseline to weeks 4, 8 and 16 in the Movement Disorder Society - Unified 
Parkinson's Disease Rating Scale (MDS-UPDRS) (total score and subscores) during the 
"ON" phase; 
Percentage of pain responders defined as subjects with reduction in pain severity of ~2 
points ("average worst pain experienced in the last 7 days") as assessed by an 11-point 
NRS, compared to baseline), will be analysed at weeks 4, 8 and 16 using a Cochran-
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Mantel-Haenszel adjusted test of the difference in proportions between the two treatment 
groups. Country will be used as the stratification factor. 
The analysis of amount of concomitant PRN PD pain medication (as reported in the Patient 
Diary) and concomitant pain drugs (as reported on the "Concomitant Medication" eCRF 
page) will be done in the same way at weeks 4, 8 and 16 
PGI-C, CGI-C, CGI-S, and MDS-UPDRS will be analysed at weeks 4, 8 and 16 using 
the same statistical method as for the primary efficacy parameter. 
Change from baseline in HADS at Week 16 will be analysed using an ANCOV A. The 
model will include treatment, baseline HADS and country as fixed effects. 
9.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. 
Descriptive statistics analysis will be applied to safety variables and the summaries will be 
presented in descending order of frequency by SOC. Likewise, within each SOC, the PTs will be 
presented by descending order of frequency. 
9.4.3. 
Baseline Descriptive Analyses 
Data collected at screening visit (i.e. age, sex, ethnicity, smoking and alcohol use, MMSE score, 
Hoehn and Yahr stage, duration of PD, as well as the participant's Medical History, Prior and 
Concomitant medication) will be tabulated with descriptive statistics or counts/percentages 
depending on the variable and where appropriate. 
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9.5. 
Interim Analyses 
No interim analysis planned. 
9.5.1. 
Data Monitoring Committee (DMC) 
No Data Monitoring Committee planned. 
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10. 
10.1. 
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Supporting Documentation and Operational Considerations 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• 
The investigator will be responsible for the following: 
10.1.2. 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
• 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
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that meets the requirements of ICH E6 (R2) Good clinical practice, local regulations, 
Regulation (EU) 2016/679 (GDPR) requirements, where applicable, and the IRB/IEC or 
study center. 
• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant or the participant's legally 
authorized representative. 
10.1.4. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• 
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 
• 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
Internal approval process involves protocol reviewed by the Protocol Review Committee, 
Pharmacovigilance & Quality Assurance. 
10.1.6. 
Dissemination of Clinical Study Data 
A Clinical Trial Report of the study will be prepared and written by the CRO according to ICH 
topic E3 (CPMP/ICH/137/95). A summary of the report will be sent to Investigators / ECs / 
Regulatory Authorities, according to current regulations. 
10.1.7. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on electronic CRF unless 
transmitted to the sponsor or designee electronically ( eg, laboratory data). The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
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• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
10.1.8. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator's site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• 
As per ICH E6 document, section 1.52, source documents are defined as "Original 
documents, data and records ( e.g., hospital records, clinical and office charts, laboratory 
notes, memoranda, participants' diaries of evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical trial). 
10.1.9. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
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10.1.10. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 1 will be performed by the local laboratory. 
• 
If the local laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be entered into the eCRF. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
• 
Investigators must document their review of each laboratory safety report, by signing and 
dating it. 
Table 1 Protocol-Required Safety Laboratory Assessments 
Laboratory 
Parameters 
Assessments 
Hematology 
Platelet Count 
White blood cell (WBC) count 
with Differential: 
Red blood cell (RBC) 
Neutrophils 
Count 
Hemoglobin 
Lymphocytes 
Monocytes 
Hematocrit 
Eosinophils 
Basophils 
Clinical 
Blood 
Potassium 
Aspartate 
Total and direct bilirubin 
Chemistry 
urea 
Aminotransferase 
nitrogen 
(AST)/ Serum 
(BUN) 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Creatinine 
Sodium 
Alanine 
Total Protein 
Aminotransferase 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Calcium 
Alkaline 
Gamma-glutamyltranspeptidase 
phosphatase 
Pregnancy 
Dipstick - urine pregnancy test 
Tests: 
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NOTES: 
1 All events of ALT 23 x upper limit of normal (ULN) and bilirubin 22 x ULN (>35% direct 
bilirubin) or ALT 23 x ULN and international normalized ratio (INR) > 1.5, if INR measured 
which may indicate severe liver injury (possible Hy's Law), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). 
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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or 
SAE. 
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Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant's condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant's 
condition. 
• 
Medical or surgical procedure ( eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met ( eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician's office or 
outpatient setting. Complications 
that occur during hospitalization 
are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether "hospitalization" occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. 
Results in persistent disability/incapacity 
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• 
The term disability means a substantial disruption of a person's ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma ( eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
R . ecor mg an 
d' 
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an or 
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f AE 
di 
SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation ( eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF . 
• 
It is not acceptable for the investigator to send photocopies of the participant's medical 
records to CRO's Pharmacovigilance in lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested 
by the Medical Monitor or Pharmacovigilance. In this case, all participant identifiers, 
with the exception of the participant number, will be redacted on the copies of the 
medical records before submission to the requestor. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories: 
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• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as 'serious' when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the Summary of Product Characteristics of 
Safinamide in his/her assessment. 
• 
For each AE/SAE, the investigator mus! document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to Pharmacovigilance. However, it 
is very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to 
Pharmacovigilance. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
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Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide CRO's Pharmacovigilance with a copy of any 
post-mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to pharmacovigilance within 24 
hours of receipt of the information. 
Reportin2 of SAEs 
SAE Reporting to Pharmacovigilance via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to Pharmacovigilance will be the 
electronic data collection tool. 
• 
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section). 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor by telephone. 
• 
Contacts for SAE reporting can be found in the Investigator Study File. 
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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel's: review of the participant's 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient. 
• 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance: 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 2. 
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Table 2 Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly. 
Combined ( estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
• Oral 
• Intravaginal 
• Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral 
• Injectable 
Highly Effective Methods That Are User Independent a 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. l.J 
not, an additional hi~hlv effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies. 
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Pregnancy Testing: 
• 
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive urine pregnancy test. 
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy 
is otherwise suspected 
Collection of Pregnancy Information: 
Female Participants who become pregnant 
• 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the sponsor within 24 hours of learning of a participant's pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the participant and the neonate and the information will 
be forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion 
is always considered to be an SAE and will be reported as such. Any post-study pregnancy 
related SAE considered reasonably related to the study intervention by the investigator will 
be reported to the sponsor as described in Section 8.3.4. While the investigator is not obligated 
to actively seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting. 
• 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study. 
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10.5. 
Appendix 9: Abbreviations 
Abbreviation 
Definition 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ANCOV A 
Analysis of covariance 
CA 
Competent Authority 
CGI 
Clinical Global Impression 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
COMT 
Catechol-O-methyltransferase 
CR 
Controlled release 
CRF 
Case report form 
CRO 
Contract research organization 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EOT 
End of treatment 
ePRO 
Electronic patient reported outcomes 
ET 
Early termination 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
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HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonization (now International Council 
on Harmonization) 
IMP 
Investigational medicinal product 
IPD 
Idiopathic Parkinson's Disease 
IR 
Immediate release 
IWRS 
Interactive web response system 
L-Dopa 
Levodopa 
LOCF 
Last observation carried forward 
MAO-B 
Monoamine oxidase-B 
MAOI 
Monoamine oxidase inhibitor 
MDS-UPDRS 
Movement Disorder Society - Unified Parkinson's Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
mL 
Millilitres 
MMSE 
Mini-mental State Examination 
NRS 
Numerical Rating Scale 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
od 
Once daily 
PD 
Parkinson's Disease 
PGI 
Patient Global Impression 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PP 
Per protocol 
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PT 
Preferred term 
SA 
Safety analysis 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SETTLE 
SafinamidE Treatment as add-on To LEvodopa in idiopathic Parkinson's 
disease with motor fluctuations 
SOC 
System organ class 
SOP 
Standard operating procedures 
SSRI 
Selective serotonin reuptake inhibitor 
SUSAR 
Suspected unexpected serious adverse reaction 
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10.6. 
Appendix 10: Contingency Plan 
Zambon PAIN study Coronavirus (2019-nCoV) 
Contingency Plan - V7 - 07 April 2020 
Study Code: Z7219M01 
EUDRACT number: 2017-002426-20 
Background and Rationale 
CDC is closely monitoring an outbreak ofrespiratory illness caused by a novel (new) coronavirus 
(named "2019-nCoV") that was first detected in Wuhan City, Hubei Province, China and which 
continues to expand. On January 30, 2020, the International Health Regulations Emergency 
Committee of the World Health Organization declared the outbreak a "public health emergency of 
international concern" and subsequently on March 11, 2020 the pandemic status has been declared. 
Corona viruses are a large family of viruses that are common in many different species of animals, 
including camels, cattle, cats, and bats. Rarely, animal coronaviruses can infect people and then 
spread between people such as with MERS, SARS, and now with 2019-nCoV. 
In response to this outbreak, many restrictions have been implementing by government and health 
departments in the affected countries. These restrictions include but are not limited to the 
establishment of quarantine zones, recommended self-quarantine periods, and travel restrictions. 
To mitigate the impact of such restrictions on the conduct of these studies and ensure the safety 
and wellbeing of participating patients and investigator sites, as well support patient retention and 
maintain data integrity, the following plan has been created. 
1. 
Close monitoring of the contingency and monitoring activities 
In the agenda of the study regular calls between Zambon and CRO, a specific item for discussion 
should be added aimed at sharing for each of the countries involved in the study the current status 
of the coronavirus emergency (government recommendations, any specific restriction in the areas 
of the study sites) covering: 
• 
impacts on the study enrolment/patients' visit at site: for this topic please refers to 
sections 2 and 3) 
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• 
impacts on monitoring activities: for this topic, on top of what is reported in section 
2, please note that Zambon should be informed about any CRO's restrictions in 
performing visit activities at site; all the efforts should be spent to respect the 
monitoring visit frequency as per Monitoring Plan; deviations should be 
documented and approved by Sponsor. The Monitoring plan will be updated and 
will reflect the new conditions for the micro-management. The updated monitoring 
Plan will be approved by Zambon. 
2. 
Communication with site 
Ongoing communication with the PI/site should happen according to the study specific frequency 
agreed with Zambon until the concerned site continues activity under standard working conditions. 
The frequency of the communications should be increased after agreement with the Zambon if the 
status at site changes. 
Topics to be discussed during the calls (on top of the standard ones): 
a) 
Investigate any potential issue related to coronavirus outbreak 
b) 
Health status of patients (AE/SAE recording) 
c) 
Inform the PI/site of any delay to planned SIV or MV. 
d) 
Confirm with the PI/sites whether or not they plan to continue enrolling new 
patients. 
e) 
Perform remote motoring ( details will be in the MP) 
f) 
For sites with ongoing patients, please see next section. 
3. 
Sites with ongoing patients: 
Wherever possible, every effort should be made to have the patient attend the hospital for their on 
site study visits according to the schedule in the protocol. 
During the contact with sites please consider the following options that should be discussed case 
by case and approved by Zambon prior to implementation: 
a) 
If the patient does not want to go the hospital for the visit or they are not allowed 
by local authorities, the following can be explored with the site in order to maintain patient 
retention and then feedback to Sponsor for approval: 
© 2018 Zambon SpA 
• 
Recommend patients to use private car/driver or to pay a taxi for the on site 
visits. Costs will be reimbursed upon the evidence of receipts; 
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• 
Decide whether assessment might be performed via phone call like for 
example interviewing patients about general health conditions (Adverse 
Event, Concomitant Medication) and collection of vital signs using patient's 
domestic equipment (if feasible). The study's e-questionnaires MDS-
UPDRS, CGI-s and CGI-c to be completed by the site staff at specific study 
visits through the study device might be compiled during the phone call. In 
case of site inability in using the site-based device, the site staff might make 
use of the paper version of the e-questionnaires which will be provided by 
the Sponsor. 
The data collected through the paper form will then be transferred into the 
specific study database via data correction form. This will also be 
documented in medical charts and paper forms retained as source document. 
• 
Patient verbal consent to continuing in the study and to being contacted by 
site staff via phone call will be documented in medical charts as well as the 
details of which assessment have been done via phone call and with which 
equipment and method 
b) 
If the clinic location where study visits are routinely performed is not available due 
to the Coronavirus outbreak (e.g. closed, being utilized for non-study purposes, etc.), sites 
may conduct study visits at a suitable alternative location and lab samples can be taken and 
analysed from the local lab of the alternative site ( every effort should be spent to collect 
normal ranges). In such case, it should first be checked ifthere is any regulatory or ethical 
implication for involving an alternative location. 
c) 
Confirm with the site if it is permitted by the EC/GCP/local authorities to send 
study drug directly to the patient's home. If the study drug is to be sent to patient's home, 
the patient must also confirm their agreement for the courier to be provided with their name 
and address for shipping purposes. This confirmation will be documented in the patient's 
source notes. The patient's name and address will not be provided to any other parties ( e.g. 
Sponsor, CRO, vendor, etc.). Upon receipt of study drug, the patient should promptly 
inform the site staff if the drug has been received in good condition. Site staff need to 
document the entire process from site to home in the patient chart. 
Site can also explore if a patient's care-giver is willing to go at site to pick up the IMP. 
Details will be given at sites case by case according to the recommendation coming from 
regulatory/local authorities. 
d) 
Where required, patient visits may be changed beyond the maximum visit window 
permitted in the current approved protocol. The permissible duration of any delay will be 
assessed on a case by case basis and supported by a phone call between PI/study staff and 
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patient in order to assess any potential adverse events (AEs), whether the patient has 
sufficient study supplies and to confirm the patient's status and wellbeing. Patients will 
continue on study treatment at home during this extension and the site is authorised to allow 
subjects to administer the additional tablets present in the wallet that are in the 'grey 
colored slots' and that are marked as Do Not Take in the IP label. As confirmed by Almac 
(CMO responsible for IP secondary packaging) the tablets in those slots can be dispensed 
in the same manner as for the other tablets in the wallet and there are no blinding concerns 
• 
Patient verbal consent to continuing in the study and to being contacted by 
site staff via phone call will be documented in medical charts. 
• 
All decisions regarding patient re-scheduling and follow-up must be clearly 
documented in the patient's source notes. 
• 
The CRA will document all patient visits performed outside of the protocol 
defined visit window as protocol deviations, referencing this contingency 
plan. 
• 
In cases where approval is given to extend home-treatment for a patient, 
and they do not have sufficient IMP to enable continued treatment until 
the rescheduled visit date, the site will ship additional IMP to the patient 
(please refer to paragraph 3c ). If not feasible, Zambon may consider with 
ALMAC the IMP delivery at patient home. Details will be given at sites 
case by case according to the recommendation coming from 
regulatory/local authorities. For IMP shipping from site to patient home, a 
dedicated courier appointed by the Sponsor/CRO/site will be involved and 
a data privacy infographic for the subject will be included in the shipping 
packaging either by site pharmacist or directly by the appointed courier 
e) 
At the end of the 2019-nCo V emergency and when it will be possible to reach the 
site, the subject or caregiver/familiar will return the IP and eDiaries to site at the earliest 
opportunity. The site staff will ensure it and will document it in the patient's source 
document 
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11. 
References 
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Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt MH, Chirilineau D et al. Two-year, 
randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson's 
Disease. Mov Disord 2014; 29(10): 1273-1280. 
Cattaneo C, Barone P, Bonizzoni E, Sardina M. Effects of safinamide on pain in fluctuating 
Parkinson's Disease patients: a post-hoe analysis. J Parkinsons Dis 2017; 7(1): 95-101. 
Cattaneo C, Perla RL, Bonizzoni E, Sardina M. Long-term effects of safinamide on 
dyskinesia in mid- to late-stage Parkinson's Disease patients: a post-hoe analysis. J 
Parkinsons Dis 2015; 5(3): 475-481. 
Chaudhuri K, Schapira AH. Non-motor symptoms of Parkinson's Disease: dopaminergic 
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De Lau LM, Giesbergen PC, De Rijk MC, Hofman A, Koudstaal P J, Breteler MM. Incidence 
of parkinsonism and Parkinson's Disease in a general population: the Rotterdam Study. 
Neurology 2004; 63(7): 1240-1244. 
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading 
the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12(3): 189-98. 
Goetz CG, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stebbins GT et al. Movement 
Disorder Society-sponsored revision of Unified Parkinson's Disease Rating Scale (MDS-
UPDRS): Process, format, and clinimetric testing plan. Mov Disord 2007; 22(1): 41-47. 
Guy W. Clinical Global Impression. In ECDEU Assessment Manual for Psychopharmacology. 
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Hoehn M, Yahr M. Parkinsonism: onset, progression and mortality. Neurology 1967; 17(5): 
427-442. 
Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on 
subjective outcome measures. J Manipulative Physiol Ther 2004; 27(1): 26-35. 
National Collaborating Centre for Chronic Conditions. Parkinson's Disease: national clinical 
guideline for diagnosis and management in primary and secondary care. London: Royal 
College of Physicians, 2006. 
Rascol 0, Lozano A, Stem M, Poewe W. Milestones in Parkinson's disease therapeutics. 
Mov Disord 201 J; 26(6): 1072-1082. 
Rascol 0, Zesiewicz T, Chaudhuri KR, Asghamejad M, Surmann E, Dohin E et al. A 
randomized controlled exploratory pilot study to evaluate the effect of rotigotine transdermal 
patch on Parkinson's Disease-associated chronic pain. J Clin Pharmacol 2016; 56(7): 852-
861. 
© 2018 Zambon SpA 
65 


CONFIDENTIAL 
Protocol Z72 l 9M0 1 
Version: 3.0 
Amendment: 2 - AUS GER IT A ESP 
Date: 27th October 2020 
Schapira AH, Fox SH, Hauser RA, Jankovic J, Jost WH, Kenney C et al. Assessment of 
safety and efficacy of safinamide as a levodopa adjunct in patients with Parkinson's Disease 
and motor fluctuations: a randomized clinical trial. JAMA Neurol 2017; 74(2): 216-224. 
Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency 
- Guidance for Industry - June 2020Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, 
Mandel J. Epidemiology and etiology of Parkinson's Disease: a review of the evidence. Eur J 
Epidemiol 2011; 26 Suppl 1: Sl-S58. 
Zigmond AS, Snaith RP The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 
1983; 67(6): 361-370. 
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SAP_001.pdf: 
Zambon SpA 
 
Safinamide 
Protocol: Z7219M01 
Clinical study report 
 
12.1.9 
Documentation of Statistical Methods  
This section includes the following: 
Statistical Analysis Plan Version 1.0, dated 25 Jan 2021 
 
1


ZambonSpA 
Z7219M0J 
A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF SAFINAMIDE 100 MG 
ONCE DAILY, AS ADD-ON THERAPY, IN IDIOPATHIC PARKINSON'S 
DISEASE (PD) PATIENTS WITH MOTOR FLUCTUATIONS AND PD 
RELATED CHRONIC PAIN 
Issued by: 
25-JAN-2021 
Statistical Analysis Plan 
Version 1.0 
Prepared by: 
PPD 
9th Floor, Valence Building 
Prestige Tech Park, Bengaluru, India-560103 
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Sc11ior Aioslalis1idan 
Punj ita Baran\val i;~~~1;i;•:11~;:~~~~~s !,~~~~cnt 
Punjita Baranwal 
Lead Biostatistician, Biostatistics 
PPD 
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Reviewed by: -
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Stephane Lavigne 
Principal Biostatistician, Biostatistics 
PPD 
Date: 
/ 
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Date: 
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-- -
Upon review of this document, the undersigned approves the statistical analysis plan. The 
analysis methods and data presentation are acceptable. 
Approved by: ~~'<:) 
Elena Tiberio 
Zambon SpA 
Confidential 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 4 
1. 
INTRODUCTION ............................................................................................................ 6 
2. 
OBJECTIVES ................................................................................................................... 7 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 7 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 7 
3.2. STUDY ENDPOINTS ............................................................................................................. 8 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 9 
4.1. SAMPLE SIZE .................................................................................................................... 10 
4.2. RANDOMISATION, STRATIFICATION, AND BLINDING ........................................................ 11 
4.3. ANALYSIS SET .................................................................................................................. 12 
5. 
VISIT ATTENDANCE................................................................................................... 13 
6. 
SUBJECT DISPOSITION ............................................................................................. 13 
6.1. DISPOSITION ..................................................................................................................... 13 
6.2. PROTOCOL DEVIATIONS ................................................................................................... 14 
7. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 14 
7.1. DEMOGRAPHICS ................................................................................................................ 14 
7.2. BASELINE DISEASE CHARACTERISTICS ............................................................................. 14 
7.3. MEDICAL HISTORY ........................................................................................................... 15 
7.4. INCLUSION AND EXCLUSION CRITERIA ............................................................................. 15 
8. 
PRIOR AND CONCOMITANT MEDICATIONS ..................................................... 15 
8.1. PRIOR MEDICATIONS ........................................................................................................ 16 
8.2. PRN MEDICATIONS .......................................................................................................... 16 
9. 
EXPOSURE AND COMPLIANCE .............................................................................. 16 
9.1. EXPOSURE TO STUDY TREATMENT .................................................................................... 16 
9.2. STUDY COMPLIANCE ......................................................................................................... 17 
10. 
EFFICACY ANALYSIS................................................................................................. 17 
10.1. 
PRIMARY EFFICACY ENDPOINT ..................................................................................... 17 
10.2. 
SENSITIVITY OF PRIMARY ENDPOINT ............................................................................ 18 
10.3. 
SECONDARY EFFICACY ENDPOINTS............................................................................... 19 
11. 
SAFETY ANALYSIS ..................................................................................................... 20 
11.1. 
ADVERSE EVENTS ......................................................................................................... 20 
11.1.1. 
Incidence of Adverse Events .................................................................................. 21 
11.1.2. 
Severity of Adverse Event to Study Drug ............................................................... 21 
11.1.3. 
Relationship of Adverse Events to Study Drug ...................................................... 22 
11.1.4. 
Serious Adverse Events .......................................................................................... 22 
11.1.5. 
Adverse Events Leading to Treatment Discontinuation ........................................ 22 
11.1.6. 
Adverse Events Leading to Study Discontinuation ................................................ 23 
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11.1.7. 
Overdose ................................................................................................................ 23 
11.1.8. 
Death ..................................................................................................................... 24 
11.2. 
TELEPHONE CONTACT ................................................................................................... 24 
11.3. 
CLINICAL LABORATORY EVALUATIONS ........................................................................ 24 
11.3.1. 
Haematology .......................................................................................................... 24 
11.3.2. 
Clinical Chemistry ................................................................................................. 24 
11.3.3. 
Urinalysis............................................................................................................... 24 
11.4. 
VITAL SIGN MEASUREMENTS ........................................................................................ 24 
11.5. 
PHYSICAL EXAMINATION .............................................................................................. 25 
11.6. 
NEUROLOGICAL EXAMINATION ..................................................................................... 25 
12. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 25 
13. 
REFERENCES ................................................................................................................ 25 
14. 
APPENDICES ................................................................................................................. 27 
14.1. 
SCHEDULE OF ACTIVITIES (SOA) .................................................................................. 27 
14.2. 
HADS SCORES AND MDS-UPDRS SCORES .................................................................. 30 
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List of Abbreviations 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BUN 
Blood Urea Nitrogen 
CGI 
Clinical Global Impression 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
CMH 
Cochran-Mantel-Haenszel 
eCRF 
Electronic Case Report Form 
EoT 
End of Treatment 
EMA 
European Medicines Agency 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GGT 
Gamma Glutamyl transpeptidase 
HADS 
Hospital Anxiety and Depression Scale 
ICF 
Informed Consent Form 
IPD 
Idiopathic Parkinson’s Disease 
IWRS 
Interactive Web Response System 
L-Dopa 
Levodopa 
LLT 
Lower Level Term   
LOCF 
Last Observation Carried Forward 
MAO-B 
Monoamine Oxidase-B 
MAR 
Missing at Random 
MDS-UPDRS 
Movement Disorder Society - Unified Parkinson’s Disease 
Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MMRM 
Mixed Model Repeated Measures 
MMSE 
Mini-mental State Examination 
NRS 
Numerical Rating Scale  
od 
Once Daily 
PD 
Parkinson’s Disease 
PGI 
Patient Global Impression 
PGI-C 
Patient Global Impression of Change 
PP 
Per Protocol 
PRN 
Pro Re Nata (When Necessary) 
PT 
Preferred Term 
RBC 
Red Blood Cell 
REML 
Restricted Maximum Likelihood 
SAE 
Serious Adverse Event 
SE  
 
   Standard Error 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase  
SGPT 
Serum Glutamic-Pyruvic Transaminase 
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SoA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
TEAE 
Treatment-Emergent Adverse Events 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
WBC 
White Blood Cell 
 
 
 
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1. Introduction 
Safinamide is an alpha-aminoamide derivative, structurally unrelated to any other drug for 
the treatment of Parkinson’s Disease (PD).  
Safinamide has both dopaminergic and non-dopaminergic activities. It is a potent, selective 
and reversible Monoamine oxidase-B (MAO-B) inhibitor, a mechanism associated with 
enhancement of dopaminergic transmission in the brain. Safinamide is also a state-dependent 
inhibitor of voltage-gated sodium channels and, at higher concentrations, inhibits calcium 
channels. These molecular mechanisms act in animal models of PD to increase brain 
dopamine, extend levodopa (L-Dopa) induced ON-time (dopaminergic actions) and reduce 
the severity of L-Dopa induced dyskinesia (non-dopaminergic action).  
It is suggested that dopaminergic effects through selective and reversible inhibition of MAO-
B, and non-dopaminergic effects through state dependent inhibition of voltage-gated sodium 
channels, are likely to be the principal relevant mechanisms for therapeutic activity in PD. 
Safinamide (50mg and 100mg) has been approved by the European Medicines Agency 
(EMA) and Food and Drug Administration (FDA) for the treatment of mid- to late-stage 
fluctuating PD subjects as add-on therapy to L-Dopa (alone or in combination with other 
anti-Parkinson drugs). 
Pain is a frequent non-motor symptom of PD, often underestimated and inadequately treated, 
with a significant impact on patients’ quality of life. 
There is growing evidence that motor complications and pain may share common 
pathophysiologic mechanisms that include not only dopaminergic but also non-
dopaminergic systems dysfunction, such as glutamatergic hyperactivity. 
Results from a post-hoc analysis of the pooled data of two Phase III studies (016 and 
SETTLE) indicate that safinamide 100 mg/day significantly reduced in fluctuating PD 
patients the individual use of pain treatments by about 24% and improved two out of three 
items of the Parkinson’s Disease Quality of Life Questionnaire (PDQ-39) related to pain 
(Cattaneo et al. 2017).  
Therefore, drugs that modulate glutamate release, such safinamide, may be a further option 
for the treatment of PD chronic pain. 
This statistical analysis plan (SAP) defines the statistical methods and data presentations to 
be used by the PPD Biostatistics department in the analysis and presentation of data for 
Zambon protocol number Z7219M01 entitled ‘A randomised, double-blind, placebo-
controlled study to evaluate the efficacy and safety of safinamide 100 mg once daily, as add-
on therapy, in idiopathic Parkinson’s Disease (IPD) subjects with motor fluctuations and PD 
related chronic pain’. 
 
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This SAP has been written in accordance with International Conference on Harmonisation 
(ICH E9) and PPD Global Biostatistics and Programming standard operating procedures 
(SOPs) and using the final study protocol Version 3.0 (27 October 2020), electronic case 
report form (eCRF) Version 2.0 (10 January 2020). 
2. Objectives 
The primary objective is to evaluate the efficacy of safinamide 100 mg once daily (od), 
compared to placebo, as add-on therapy, for PD related chronic pain. 
The secondary objectives include the following: 
1) 
To assess the percentage of pain responders. 
2) 
To assess the Clinical Global Impression. 
3) 
To assess the Patient Global Impression. 
4) 
To assess the reduction in use of pain drugs. 
5) 
To assess the mood. 
6) 
To assess motor and non-motor symptoms. 
7) 
To evaluate of the safety and tolerability of safinamide 100mg compared to placebo 
in fluctuating PD patients with PD related pain.  
3. Investigational Plan 
3.1. Overall Study Design and Plan 
 
This is a Phase IV, international, multicentre, randomised, double-blind, placebo-controlled 
study in IPD male and female subjects 30 years of age or older, experiencing motor 
fluctuations and PD related chronic pain while on stable doses of L-Dopa. The duration of 
the study for each subject is 19 weeks (including the Screening period). Subjects will be 
randomised to receive either active or placebo in a 2:1 ratio, respectively. A telephone 
follow-up call will be performed 1 week after the end of treatment. 
Study consists of two periods, screening (1-2 weeks) and a treatment period (16 weeks), with 
a follow-up call at 1 week after treatment, so total duration of 19 weeks. 
The Screening visit (Visit 1) should occur up to 14 days before Day 1. At baseline (Visit 2, 
Day 1), eligible subjects will enter the treatment period and will receive study medication 
50 mg (from Day 1 to Day 7) and then 100 mg (from Day 8 onwards), to be taken orally 
once daily (od). Following completion of all baseline assessments, they will receive the first 
dose of study medication at the study centre. Thereafter, study drug will be taken, at home, 
each morning along with their first morning dose of L-Dopa and other (if any) PD 
medications. On Day 8 the dose of study drug will be increased, at home, to 100 mg od. 
Each subject will receive treatment for 16 weeks, with visits at Week 0/Day 1 (baseline) and 
at Weeks 4, 8 and 16 (or early termination). 
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From day 1 onwards, participant will record the use of PRN medications along with 
indicating the worst pain experienced on a daily basis. 
Diagram of Study Schedule: 
 
Figure 1: Diagram of Study Schedule 
 
 
 
 
Randomisation is in a 2:1 ratio of active:placebo; up to 132 participants will be screened to 
achieve up to 105 randomized, to have approximately 84 patients complete the study (56 in 
the active and 28 in the placebo group respectively).  The detailed description is present in 
Section 4.1. 
 
Subjects will take their allocated study drug in accordance with the assigned regimen: 
 
Safinamide: 50 mg (from Day 1 to Day 7) and then 100 mg (from Day 8 onwards) 
or 
Placebo: 50 mg (from Day 1 to Day 7) and then 100 mg (from Day 8 onwards) 
3.2. Study Endpoints 
The primary endpoint measured in this study will be:   
x The change from baseline to Week 16 in pain severity (“average worst pain 
experienced in the last 7 days”), as assessed by an 11-point Numerical Rating Scale 
(NRS). 
The secondary endpoints measured in this study will be: 
x The percentage of pain responders defined as  the subjects with reduction in pain 
severity of ≥2 points (“average worst pain experienced in the last 7 days”), at weeks 
4, 8 and 16 as assessed by an 11-point NRS, compared to baseline  
x The pain severity score (average worst pain score using 11-point NRS Scale) at week 
4, 8. 
Screening 
1 to 2 weeks 
before Day 1 
Active 
Placebo 
Day 1 
Baseline, 
Randomisation to 
Active or Placebo 
(2:1) 
16 week treatment period 
Day 8 
Uptitration 
from 50 to 100 mg 
Follow up 
Phone Call 
1 week 
after EoT 
Day 112 
End of Treatment 
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x The Clinical Global Impression of Severity (CGI-S) score at weeks 4, 8 and 16 (rated 
by Investigator),  
x The change from baseline to Weeks 4 8 and 16 in the Clinical Global Impression of 
Change (CGI-C) score rated by Investigator,  
x The change from baseline to Weeks 4, 8 and 16 in the Patient Global Impression of 
Change (PGI-C) score rated by the subject  
x The percentage of subjects with a reduction in number of days using concomitant 
pain drugs in the 7 days before each visit at Weeks 4 8 and 16. 
x The number of days with PRN pain medication in the 7 days before each visit at 
Week 4, 8 and 16 (by analysing 7-day intervals before each visit). 
x The change from baseline to week 16 in the Hospital Anxiety and Depression Scale 
(HADS) score. 
x The change from baseline to weeks 4, 8 and 16 in the Movement Disorder Society - 
Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) (total score and sub 
scores) during the “ON” phase. 
Tolerability will be assessed by means of incidence of treatment emergent adverse events. 
Safety variables include physical and neurological examinations, vital signs (blood pressure 
and heart rate) and clinical safety laboratory values (haematology, clinical chemistry). 
4. General Statistical Considerations 
Continuous data will be summarised using summary statistics (i.e. n, mean, standard 
deviation, median, minimum, and maximum). For the summary statistics of all continuous 
data, minimum and maximum values will be displayed to the same level of precision as 
reported, unless otherwise specified. Mean and median will be displayed to one level of 
precision greater than the data collected. Standard deviation will be displayed to two levels 
of precision greater than the data collected.  
Categorical data will be described using the subject count and percentage in each category. 
When counts are presented, in cases where the count is zero, the percentage will not be 
displayed in order to draw attention to the non-zero counts. A row denoted ‘Missing’ will be 
included in count tabulations where specified on the shells to account for missing values. 
The denominator for all percentages will be the number of populated subjects in that 
treatment within the analysis set of interest, unless otherwise specified. Frequency statistics 
will be displayed using one decimal place except for the display of 100% frequency which 
will be displayed as ‘XX (100)’. 
 P-values will be rounded to three decimal places. If a p-value is less than 0.001 it will be 
reported as ‘<0.001’. If a p-value is greater than 0.999 it will be reported as ‘>0.999’. 
Confidence intervals will be displayed to one level of precision greater than the data 
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collected. Data will be displayed in all listings sorted by treatment group, country, centre, 
and subject ID. 
Unless otherwise specified, baseline will be defined as the last non-missing evaluation prior 
to or on the date that the first dose of treatment is taken. Study day is defined in relation to 
the date of first dose of study drug. Therefore, when an assessment date is before the first 
dose: 
         Study day = assessment date - first dose date of study drug 
and when an assessment is on or after the first dose: 
         Study day = assessment date - first dose date of study drug + 1 
All analyses will be conducted using SAS Version 9.4 or higher and all data will be 
summarised based on the visit name collected on the eCRF page.  
4.1. Sample Size 
On the basis of previous post-hoc analyses of pain (Cattaneo et al 2017) and of similar 
studies (Folstein et al, 1975), assuming a standard deviation of 2 it is anticipated that a 
sample size of 144 subjects would permit detection of a 1 point treatment difference in the 
NRS between safinamide and placebo at the 5% significance level with 80% power. A 1-
point treatment difference is considered to be a clinically meaningful treatment effect 
(Rascol et al, 2016). 
Approximately 220 subjects will be screened to achieve approximately 177 randomly 
assigned to study treatment and of which approximately 144 subjects completing the study 
(n= 96 and n= 48 evaluable subjects in the active and placebo group respectively). 
Since March 2020, the COVID-19 emergency has impacted the feasibility of the trial, which 
is being conducted in a vulnerable group of patients. Upon receipt of the guidance “Statistical 
Considerations for Clinical Trials During the COVID-19 Public Health Emergency” issued 
by FDA on June 2020, released  with the aim of helping sponsors ensure that trials conducted 
during the Covid-19 emergency could continue, where appropriate, to provide interpretable 
findings with correct statistical quantification of uncertainty, the Sponsor performed a Blind 
Data Review Analysis of the primary endpoint data (pain severity) for the 26 patients who 
had completed the study as of June 2020. 
The results of the analysis show that the standard deviation used in the original sample size 
estimation (SD = 2) was a conservative overestimate of the observed SD from the actual trial 
data, which was 1.43 at the time of the blinded data review.  
Based on this, the Standard Deviation, for the estimation of sample size has now been 
amended to 1.50, and the power has been maintained as 80%. New sample size estimates 
have been performed considering different magnitudes of Treatment Difference but keeping 
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the same assumptions of screen failure rates and dropout rates. These are summarized below 
in Table 4.1. 
Table 4.1 Sample Size Estimations  
SCENARIO  
SAMPLE SIZE 
Power = 80% 
Pts to screen= 132 
Standard deviation = 1.5  
Pts to randomize= 105 
Treatment Difference = 1 point 
Pts completing study= 84 
  
  
  
  
Power = 80% 
Pts to screen= 66 
Standard deviation = 1.5  
Pts to randomize= 51 
Treatment Difference = 1.5 points  
Pts completing study= 39 
  
  
  
  
Power =  80% 
Pts to screen= 39 
Standard deviation = 1.5  
Pts to randomize= 30 
Treatment Difference = 2 points  
Pts completing study= 24 
  
  
Currently, it is planned to keep the initial conservative estimate of treatment difference as 1 
and change the SD to 1.5 in line with what was observed with the Blind Data Review 
Analysis. Using these parameters, up to 132 participants will be screened to achieve up to 
105 randomized, to have approximately 84 patients complete the study (56 in the active and 
28 in the placebo group respectively). 
However, given the continuous and uncertain impact that COVID-19 outbreak is having in 
the countries participating in the trial, any of other scenarios might be adopted if at the end 
of December 2020, the above enrollment goal will not be achieved. From the table above it 
can be seen that if the treatment difference is greater than 1, statistical significance can be 
achieved with a substantially lower sample size. Thus, the study maintains its robustness. 
4.2. Randomisation, Stratification, and Blinding 
Subjects will be randomised to double-blinded treatment in a 2:1 ratio to receive either 
safinamide or placebo at Visit 2 (day 1). An interactive web response system (IWRS) will 
be used for the randomisation. PPD Biostatistics will generate the randomisation schedule 
for IWRS, which links sequential subject randomisation numbers to treatment codes.  
In case of an emergency, the investigator has the sole responsibility for determining if 
unblinding of a subject’s treatment assignment is warranted and should make every effort to 
contact the sponsor prior to unblinding a subject’s treatment assignment unless this could 
delay emergency treatment of the subject. If a subject’s treatment assignment is unblinded, 
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the sponsor must be notified within 24 hours after breaking the blind. The date and reason 
that the blind was broken must be recorded in the source documentation and case report 
form, as applicable. 
4.3. Analysis Set 
The analysis sets that will be used in this study are detailed below in Table 4.2. Membership 
to each analysis set will be reviewed and confirmed prior to database lock. 
The number and percentage of subjects in each analysis population will be summarised by 
the treatment they were randomised to as well as for the total number of subjects. A listing 
will also be produced displaying subjects excluded from each population. 
Table 4.2 Analysis Populations Definition 
 
Population 
Description 
Full analysis set 
The FAS is defined as all randomized subjects in the study, 
with at least one measurement of the primary efficacy variable 
following at least one dose of study medication. Summaries 
on the FAS will be performed for all efficacy endpoints. 
Subjects in this analysis set will be summarized according to 
the treatment they were randomly assigned to. 
Per Protocol 
The PP Set will be a subset of subjects in the FAS who 
completed the study and for whom no relevant protocol 
deviations were documented. Identification of relevant 
protocol deviations will occur on a blinded review meeting 
preceding database lock. A second analysis of the primary 
efficacy endpoint will be based on the PP Set. All subjects in 
the PP Set will be summarized according to the treatment they 
were assigned to. 
Safety 
The Safety Set will include all randomized subjects assigned 
to study intervention and who take at least 1 dose of study 
medication. The Safety Set will be used for the analysis of all 
safety endpoints. All subjects in the Safety Set will be 
summarized according to the treatment they actually 
received (according to the Drug Accountability eCRF page). 
 
The Screened Population will include all subjects who sign the informed consent form (ICF). 
This population will be listed but not used for statistical analyses. The data from this 
population will be summarized and used for presenting subject study disposition 
 
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All Enrolled population includes all subjects who signed the informed consent form (ICF) 
and enrolled into the study. The data from this population will be summarized and used for 
presenting subject study disposition. 
The decision whether a protocol deviation is relevant or not for the exclusion of subjects 
from the per protocol (PP) set will be made case-by-case in a blind data review meeting.  
The primary analysis of the primary efficacy variable will be based on the FAS data set. A 
secondary analysis of the primary efficacy parameter will be based on the PP set.  
All other secondary efficacy analyses will be based on the FAS. 
Safety analyses will be based on the safety analysis (SA) set. 
5. Visit Attendance 
The number and percentage of subjects who attended a visit or received a safety call will be 
presented for the following visits: 
x Visit 2 (Baseline or Day 1) 
x Visit 3 (Day 28) 
x Visit 4 (Day 56) 
x Visit 5 (EoT or Day 112) 
x Follow-up Call 
For Subjects with on-going site visits, wherever possible all efforts will be made to have the 
patient attend the hospital for their on-site study visits accordingly to schedule in the 
protocol. Assessment will be performed via phone call for Adverse event, Concomitant 
medication and e-questionnaires MDS-UPDRS, CGI-s and CGI-c if site visit is not possible. 
Anticipated data which will be missing due to COVID-19 outbreak is mostly LAB and ECG 
which requires on-site attendance. 
6. Subject Disposition 
6.1. Disposition 
A listing of randomisation information (including randomisation and kit number) for all 
randomised subjects will be produced. 
Subject disposition will be summarised for the following categories: subjects in the All 
Enrolled, FAS, PP Set and Safety Set. A disposition of subjects includes the number and 
percentage of subjects who were enrolled, subjects that were screening failures, subjects 
randomised and subjects who completed the study, subjects who discontinued from the 
study, and subjects that were unblinded during the study. The number of subjects will be 
displayed by treatment group and overall, except screening failures where counts will only 
be displayed in the overall group. The reasons for study discontinuation may include any of 
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the following: Lost to Follow-up, Subject withdraws consent, Death, Adverse event, 
Physician decision, Pregnancy, Protocol violation, Study terminated by the Sponsor, and 
Other. The reasons for study discontinuation will also be summarised in this table. The 
percentages will be based on the number of subjects randomised. 
Disposition data, displaying both randomised and actual treatment in case of 
randomised/treated subjects, will be listed, for all enrolled set.  
6.2. Protocol Deviations 
Major (relevant) protocol deviations will be identified and confirmed prior to database lock 
and summarised by the deviation categories shown in study deviation rules document. 
The major protocol deviations will be summarised for the FAS and includes the number and 
percentage of subjects who had each major deviation. Subjects can have more than one type 
of major deviation. Percentages will be based on the total number of subjects in the FAS. 
Protocol deviations (including minor deviations) will also be presented in a listing. A flag 
(Y/N) will be added to the listing to denote whether a subject is included or excluded from 
the PP Set.  
7. Demographics and Baseline Characteristics 
7.1. Demographics 
A summary of demographics and baseline information will be presented for the Safety and 
Full Analysis Sets. The demographic characteristics consist of age (years), sex (Female, or 
male), race (Caucasian, Asian, African, Indian, or Mixed/Other), smoking and alcohol use.  
Age (years) will be summarised using descriptive statistics. The number and percentage of 
subjects by sex, race, smoking and alcohol consumption will also be reported. Percentages 
will be based on the total number of subjects in the specific analysis set being summarised 
(Safety Set or Full Analysis Set as applicable).  
7.2. Baseline Disease Characteristics 
The following baseline disease characteristics of PD history, Mini-mental State Examination 
(MMSE), and duration of PD, will be summarised for the Safety and Full Analysis Sets 
(FAS), as recorded on the “Demography” and “Mini-mental State Examination (MMSE)” 
eCRF pages. MMSE score and duration of PD will be summarised using descriptive 
statistics. The number and percentage of subjects by PD history by Hoehn and Yahr stage 
and MMSE score category: abnormal (severe (≤9 points), moderate (10-18 points), mild (19-
23 points)) and normal (≥24 points), and the number and percentage of duration of PD 
category (<5 years, 5-10 years, and >10 years), will also be reported. Percentages will be 
based on the total number of subjects in the specific analysis set being summarised).  
 
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Subject demographic and baseline characteristics will be listed for all patients enrolled in 
the study, including screen failures  
7.3. Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 21.0. The primary system organ class (SOC) and preferred term (PT) 
will be coded according to the Lower Level Term (LLT).  The number and percentage of 
subjects with any medical history will be summarised overall and for each SOC and PT. 
Percentages will be calculated based on number of subjects in the Safety Set. 
This summary will be presented in alphabetical order for the SOC. Within each SOC, the 
PTs will be presented by descending order of frequency.  
Subject medical history data will be presented for the Safety Set in a listing.  
7.4. Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria for eligibility for participation in the study are listed in 
sections 5.1 and 5.2 of the study Protocol. Subjects including screen failure subjects along 
with the inclusion/exclusion criteria will be listed for all subjects enrolled.  
8. Prior and Concomitant Medications 
All medications or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of enrollment or receives 
during the study, will be will be collected on the eCRF. All medications will be coded 
according to the World Health Organization Drug Dictionary Enhanced (WHODDE, March 
2018). In addition, the Anatomical Therapeutic Chemical (ATC) classes are assigned to the 
drug code for Anti-Parkinson Treatment Prior and Concomitant Medication, and Level 4 of 
the ATC coding and PT is required.  
For summary purposes, medications will be considered prior medications if they stopped 
prior to the first dose of study drug and concomitant medications if they were taken at any 
time on and after the first dose of study drug (i.e. started prior to the first dose of study drug 
and were ongoing or started on and after the first dose of study drug). 
For the purpose of inclusion in prior and/or concomitant medication tables, incomplete 
medication start dates and end dates will be imputed as follows: 
x 
If year and month are present and day is missing, then set day to first day of month 
for start date, and set day to last day of month for end date  
x 
If year and day are present and month is missing, then set month to January for start 
date, and set month to December for end date  
x 
If year is present and month and day are missing, then set month and day to January 
1 for start date, and set month and day to December 31 for end date  
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x 
Completely missing dates will not be imputed 
If start date is completely missing and end date is not prior to the first dose, then the 
medication will be classified as concomitant. If the start date is completely missing and end 
date is prior to the first dose of study drug, then the medication will be classified as prior. If 
the end date is missing, then the medication will be classified as ongoing. 
8.1. Prior Medications 
The total number of prior and concomitant medications, as reported on the “Concomitant 
Medications” eCRF page (identified based on start date in relation to first dose date), the 
number and percentages of subjects using each type of  prior and concomitant medication, 
and the number and percentages of subjects with at least one prior  and concomitant 
medication,), will be summarised by treatment group and listed by ATC level 4 category, 
and PTs.  
Anti-Parkisonian Prior and Concomitant medication as reported on “Anti-Parkinsonian Prior 
and Concomitant” eCRF page will be defined in a similar way as for Prior and Concomitant 
Medication. 
These will be presented in a single summary table. 
These summaries will be presented in descending order of frequency, by ATC level 4 
category. Likewise, within each ATC level 4 category, preferred terms will be presented by 
descending order of frequency. 
All summaries and listings will be performed using the Safety Set. 
8.2. PRN Medications 
The total number of PRN PD pain medications, the number and percentages of subjects using 
each type of PRN PD pain medication, and the number and percentages of subjects with at 
least one intake of PRN PD pain medication as reported on the “PRN Parkinson’s Disease 
Pain Medication” eCRF page, will be summarised by treatment group and listed by ATC4 
category, and PT. All summaries and listings will be performed using the Safety Set. 
9. Exposure and Compliance 
9.1. Exposure to study treatment 
In case an additional kit is obtained to replace the Randomization Kit that might have been lost 
or damaged, Investigator shall initiate an unscheduled dispensation. A listing of subjects’ 
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unscheduled dispensing, as recorded in “Unscheduled Dispensation” eCRF page will be 
produced for the Safety Set.  
9.2. Study compliance 
Study medication accountability and subject compliance will be documented throughout the 
treatment period, using study-specific study medication dispensing and return record forms, 
and will be reported in ‘Drug Accountability’ eCRF page. The eCRF does not collect 
exposure data in a fashion that enables to calculate compliance, only investigator’s 
assessment result for compliance is collected by visit as Yes or No. Compliance categories 
of “Yes” or “No” indicate that the patients took at least 80% of the study medication during 
any visit- to- visit evaluation Period “Yes” and non-compliance is defined as taking less than 
80 % of study medication “No”.  
Complete data about study medication accountability and subject compliance will be 
presented in a listing. 
10. Efficacy Analysis 
The primary analysis of the efficacy endpoint will be performed for the FAS and in case 
there is a difference of more than 10% between FAS & PP, will be repeated on the PP Set 
as a sensitivity analysis.  
Secondary efficacy endpoints will be analysed for the FAS population at Week 4,8 and 16. 
Data listings will be provided for all endpoints. An additional listing of diary collection status 
by visit, as reported in “Questionnaire Collection Status -Baseline”, “Questionnaire 
Collection Status”, and “Questionnaire Collection Status – V5 EoT WK16” eCRF pages, 
will be presented. 
10.1. 
Primary Efficacy Endpoint 
Pain severity data will be derived from the daily diary. 
The primary endpoint evaluated in this study is the mean change in pain severity (“average 
worst pain experienced in the last 7 days”, i.e. average of the worst pain score on each of the 
7 days preceding the site visit), as assessed by an 11-point NRS, from baseline to Week 16. 
For efficacy analysis, at least 4 out of 7 daily pain scores are needed to calculate a valid 
average over 7 days. 
The null hypothesis for the primary endpoint is that safinamide is no better than placebo in 
managing pain; thus μ(Safinamide) > μ(Placebo), where μ represents the population mean 
change in pain severity score from baseline at Week 16 and a negative change would indicate 
improvement.  
The primary efficacy endpoint, change from baseline to Week 16 in pain severity score, will 
be analysed using a mixed model repeated measures (MMRM) using visit on subject ID as 
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the 
repeated 
factor 
with 
unstructured 
covariance 
term 
(REPEATED 
VISIT/SUBJECT=SUBJID TYPE=UN). If convergence is not achieved, then other 
covariance structures will be investigated such as compound symmetric (TYPE=CS). The 
model will include fixed effects terms for treatment, country, visit and regular pain 
medication use at baseline (yes or no) and covariate term for pain severity score at baseline. 
The method above (e.g. MMRM) is unbiased under the MAR assumption and can be thought 
of as aiming to estimate the treatment effect assuming that after withdrawal, subjects would 
have continued on a similar trajectory to their peers in the same arm who have the same 
covariates.  
The likelihood-based mixed-effect model repeated measure will be performed using a SAS 
PROC MIXED procedure, and the Kenward-Roger method for degrees of freedom will be 
applied. The restricted maximum likelihood (REML) method will be used for estimation. 
The least square (LS) means of change from baseline in pain severity along with the 
associated SE and 95% CIs will be calculated from the model at each time point. The LS 
mean difference between the treatment groups at Week 16 will also be reported, along with 
the corresponding SE, 95% CIs, and the p-value derived for the difference between treatment 
arms (safinamide – placebo). No adjustment is being made for multiple comparisons.  
Results for time points other than Week 16 (Weeks 4 and 8) will be presented in both the 
above discussed model-adjusted and descriptive forms. 
10.2. 
Sensitivity of Primary Endpoint 
The following two sensitivity analyses will be performed: 
a) This sensitivity analysis will be based on the PP Set, and the primary endpoint (mean 
change pain severity as assessed by an 11-point NRS, from baseline to Week 16), 
will be analysed using similar MMRM approach as specified in Section 10.1. No 
imputation will be performed in this analysis. 
 
b) This sensitivity analysis will be based on the FAS population. Missing records of 
subjects who prematurely discontinued the randomly assigned study drug, will be 
imputed with the worst value from baseline before drop out within each subject. 
Intermittent missing data will not be imputed and all missing values after 
discontinuation will be imputed. The worst value is the highest pain score from 
baseline to before drop out.  Change from baseline for the imputed Week 16 value 
will then be calculated as imputed Week 16 - baseline.  For example in the following 
case: 
3 1 x 2 3 y y 
where x and y are missing data, the imputation will complete y values but not x as it 
is the intermittent missing data. 
The primary endpoint (mean change in pain severity as assessed by an 11-point NRS, 
from baseline to Week 16), will be  analysed by using a repeated measures analysis 
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of covariance (ANCOVA) for the imputed population, using visit on subject ID as 
the 
repeated 
factor 
with 
unstructured 
covariance 
term 
(REPEATED 
VISIT/SUBJECT=SUBJID TYPE=UN). If convergence is not achieved then other 
covariance structures will be investigated such as compound symmetric (TYPE=CS). 
The model will include fixed effects terms for treatment, country, and visit, and 
covariate term for pain severity score at baseline. 
10.3. 
Secondary Efficacy Endpoints 
The PGI-C, CGI-C, CGI-S, and MDS-UPDRS will be analysed at weeks 4, 8 and 16 using 
the same statistical methods i.e. MMRM as for the primary efficacy parameter defined in 
Section 10.1 by replacing covariate of  pain severity at baseline with respective efficacy 
parameter 
Pain severity score at Weeks 4 and 8 will also be analysed by the same MMRM method used 
for Pain severity score at Week 16 as defined in Section 10.1 
Change from baseline in HADS at Week 16 will be analysed using an ANCOVA. The model 
will include treatment, baseline HADS and country as fixed effects. The Least Square (LS) 
means of the change from baseline in HADS score along with the associated SE and 95% 
CIs will be calculated, and the p-value derived for the difference between treatment groups 
at Week 16 will be presented. 
Percentage of pain responders  defined as subjects with reduction in pain severity of ≥2 
points (“average worst pain experienced in the last 7 days”)  as assessed by an 11-point NRS, 
compared to baseline), will be analysed at weeks  4, 8 and 16 using a Cochran-Mantel-
Haenszel adjusted test of the difference in proportions between the two treatment groups. 
Country will be used as the stratification factor. A 95% confidence interval of the difference 
in proportions and p-value will be reported.   For percentage of pain responders, a missing 
value at each visit will be imputed to indicate that a subject was a non-responder i.e. a Worst-
Case imputation. It will be summarized for both Observed data and Imputed data. 
The analysis of amount of concomitant PRN PD pain medications (as reported in the Patient 
Diary) and concomitant pain drugs (as reported on the ‘Concomitant Medications’ eCRF 
page) will be summarized in two ways i.e. the number of days on which pain medication 
was taken in the 7 days preceding Visits at Weeks 4, 8 and 16 and the number of patients 
taking pain medication in the 7 days preceding Visits at Weeks 4, 8 and 16.  
The number of days that pain medication was taken will be analysed using a two-sided Mann 
Whitney test at the 5% level of significance level to test the null hypothesis of no difference 
between the two treatments. In case if the patient has not taken any pain medication in the 7 
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days preceding Visits at Weeks 4, 8 and 16, then the number of days will be considered as 
zero for that particular patient for that particular visit.  
The percentage of patients using pain medication will be analysed using a Cochran-Mantel-
Haenszel (CMH) adjusted test of the difference in proportions between the two treatment 
groups.  Country will be used as the stratification factor. A 95% confidence interval of the 
difference in proportions and p-value will be reported. 
11. Safety Analysis 
All analyses of safety will be conducted using the Safety Set. 
11.1. 
Adverse Events 
An AE is any untoward medical occurrence in a subject or clinical study subject, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
A treatment-emergent AE (TEAE) is defined as an AE that meets any of the following 
conditions: 
x begins on or after the first dose of study drug and before the end of study drug + 30 days; 
x begins before the first dose of study drug and worsens in severity on or after the first 
dose of study drug and before the end of study drug + 30 days; 
x is completely missing an onset date and end date; 
x is completely missing an onset date and the end date is on or after the first dose of study 
drug. 
For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be 
imputed as follows: 
Missing onset dates (where UN and UNK indicate unknown or missing day and month 
respectively):  
x 
UN-MMM-YYYY: If the month and year are different from the month and year of 
the first dose of study drug, assume 01-MMM-YYYY. If the month and year are the 
same as the first dose of study drug month and year, and the end date (after any 
imputation) is on or after the first dose of study drug, then assume the date of the first 
dose of study drug. If the month and year are the same as the first dose of study drug 
month and year, and the end date (after any imputation) is prior to the first dose of 
study drug, then assume the end date for the onset date.  
x 
DD-UKN-YYYY/UN-UNK-YYYY: If the year is different from the year of first 
dose of study drug, assume 01-JAN-YYYY of the year the data was collected. If the 
year is the same as the first dose of study drug year, and the end date (after any 
imputation) is on or after the first dose of study drug, then assume the date of the first 
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dose of study drug. If the year is the same as the first dose of study drug, and the end 
date (after any imputation) is prior to the first dose of study drug, then assume the 
end date for the onset date.  
 
Missing end dates (where UK and UNK indicate unknown or missing day and month 
respectively):  
x UN-MMM-YYYY: Assume the last day of the month; 
x DD-UNK-YYYY/UK-UNK-YYYY: Assume DD-DEC-YYYY or 31-DEC-YYYY 
respectively. 
 
All adverse events will be classified by SOC and PT according to MedDRA (Version 21.0). 
Percentages will be calculated based on the number of subjects in the Safety Set, unless 
otherwise specified. 
An overview summary of the number and percentage of subjects with any TEAE, serious 
TEAE, study drug-related TEAE, study drug-related serious TEAE, TEAE leading to study 
discontinuation/ early withdrawal, TEAE leading to treatment discontinuation, and AE 
leading to death will be provided by treatment group.  
Summaries of the total number of TEAEs and the number and percentage of subjects with 
at least one TEAE will be provided by treatment group and overall. TEAEs will be presented 
in   descending order of frequency by SOC. Likewise, within each SOC, the PTs will be 
presented by descending order of frequency. 
11.1.1. Incidence of Adverse Events 
Summaries of the number and percentage of subjects with at least one TEAE will be 
provided for each treatment group by SOC and PT. Subjects that report more than one event 
will only be counted once for each level of SOC and PT summary. 
This summary will be presented in descending order of frequency by SOC. Likewise, within 
each SOC, the PTs will be presented by descending order of frequency.  
All AEs will be presented in a listing on the Safety Set. 
11.1.2. Severity of Adverse Event to Study Drug 
A summary of TEAEs by severity will be presented in a table. The possible severities are 
‘Mild,’ ‘Moderate,’ and ‘Severe.’ In this table, if a subject reported multiple occurrence of 
the same TEAE, only the most severe will be presented. Treatment-emergent AEs that are 
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missing severity will be presented in tables as ‘Severe’ but will be presented in the data 
listing with a missing severity. 
This summary will be presented in descending order of frequency by SOC. Likewise, within 
each SOC, the PTs will be presented by descending order of frequency.  
11.1.3. Relationship of Adverse Events to Study Drug 
The investigator will provide an assessment of the relationship of the event to the study drug. 
The possible relationships are ‘Not Related’, and ‘Related’. If a subject reports multiple 
occurrence of the same TEAE and any of those are ‘Related’, the subject will be counted as 
‘Related’ for that TEAE. Treatment-emergent AEs that are missing a relationship will be 
presented in the summary table as ‘Related’ but will be presented in the data listing with a 
missing relationship.  
This summary will be presented in descending order of frequency by SOC. Likewise, within 
each SOC, the PTs will be presented by descending order of frequency.  
The TEAE data will be categorized and presented by SOC, PT, and severity, for ‘Related’ 
and ‘Not Related’ separately. 
11.1.4. Serious Adverse Events 
The seriousness of an AE should be assessed by the Investigator independently from the 
severity of the AE. A serious AE (SAE) is defined as any untoward medical occurrence that 
at any dose results in death, is considered life-threatening, is a congenital anomaly/birth 
defect, requires in-subject hospitalization or prolongation of existing hospitalization, or 
results in significant disability. 
A summary of the total number of treatment-emergent SAEs and the number and percentage 
of subjects with at least one treatment-emergent SAE will be provided for each treatment 
group and presented by SOC and PT in a manner similar to that described in Section 11.1.1. 
A summary of treatment-emergent SAEs by relationship to study drug will be presented in 
a table in a manner similar to that described in Section 11.1.1. 
All SAEs will be presented in a listing on the Safety Set. 
11.1.5. Adverse Events Leading to Treatment Discontinuation 
A summary of TEAEs which leading tostudy drug discontinuation, as reported in Adverse 
Events CRF page (where action taken with study treatment will be “Drug Permanently 
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Withdrawn”) will be presented in a table. Subjects that report more than one event will only 
be counted once for each level of SOC and PT summary. 
This summary will be presented by SOC, PT in a manner similar to that described in Section 
11.1.1. 
All AEs leading to treatment discontinuation will be presented in a listing on the Safety Set. 
11.1.6. Adverse Events Leading to Study Discontinuation 
A summary of TEAEs leading to study discontinuation, as reported in ‘Study 
Completion/Termination’ CRF page (early withdrawals where primary reason for 
termination is ‘Adverse Event’), will be presented in a table. Subjects that report more than 
one event will only be counted once for each level of SOC and PT summarisation.  
This summary will be presented by SOC, PT in a manner similar to that described in Section 
11.1.1. 
All AEs leading to study discontinuation will be presented in a listing on the Safety Set. 
11.1.7. Overdose 
The anticipated pattern of events or symptoms following intentional or accidental overdose 
with safinamide is that related to its pharmacodynamic profile (MAO-B inhibition with 
activity dependent inhibition of sodium channels). The symptoms of excessive MAO-B 
inhibition (increase in dopamine level) could include hypertension, postural hypotension, 
hallucinations, agitation, nausea, vomiting and dyskinesia. 
If the investigator identifies a subject has taken an accidental overdose but none of the 
symptoms of overdose were reported, then the accidental overdose will not be recorded as 
an AE. If the investigator identifies an intentional overdose with suicidal intent, then this 
will be recorded as an SAE. 
The number and percentage of subjects with any overdose will be displayed, as reported on 
the “Drug Accountability” eCRF page. 
A listing will be provided for intentional overdose events. Intentional overdose will be 
reported as AE/SAE and will be identified based on MedDRA codes. 
The listing will be based on the Safety Set. 
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11.1.8. Death 
All subjects who have an AE with an outcome of ‘Death’ will be presented in a listing using 
the Safety Set.  
11.2. 
Telephone Contact 
All data will be presented in a listing on the Safety Set. 
11.3. 
Clinical Laboratory Evaluations 
Summary tables presenting numbers and percentages at Screening and Week 16 visits will 
be presented for clinical laboratory tests, by treatment group for subjects in the Safety Set. 
The following laboratory test results will be included: Normal; Abnormal (Clinically 
Significant), Abnormal (Not Clinically Significant).  
All data will be presented in a listing on the Safety Set. 
11.3.1. Haematology 
The following laboratory tests will be included: Platelet Count, Red Blood Cell (RBC) 
Count, Hemoglobin, Hematocrit, White Blood Cell (WBC) Count, Absolute Neutrophils, 
Neutrophils %, Absolute Lymphocytes, Lymphocytes %, Absolute Monocytes, Monocytes 
%, Absolute Eosinophils, Eosinophils %, Absolute Basophils, and Basophils %. 
11.3.2. Clinical Chemistry 
The following laboratory tests will be included: Blood Urea Nitrogen (BUN), Potassium, 
Sodium, Creatinine, Calcium, Aspartate Aminotransferase (AST)/ Serum Glutamic-
Oxaloacetic Transaminase (SGOT), Alanine Aminotransferase (ALT)/ Serum Glutamic-
Pyruvic Transaminase (SGPT), Alkaline phosphatase, Total bilirubin, Direct bilirubin, Urea, 
Total Protein, and Gamma Glutamyl transpeptidase (GGT).  
11.3.3. Urinalysis 
Urine pregnancy test results will be listed (where applicable). 
11.4. 
Vital Sign Measurements 
A summary table presenting observed values of vital signs data at Screening, Baseline and 
Week 16 visits, and changes from baseline for Week 16 visit assessed in the supine position, 
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including systolic blood pressure (mmHg), diastolic blood pressure (mmHg), and heart rate 
(bpm), by treatment group for subjects in the Safety Set.   
All vital sign data will be presented in a listing on the Safety Set. 
11.5. 
Physical Examination 
A table will summarise physical examination results at Screening and Week 16 visits by 
treatment group for the Safety Set. Each visit captures the status of multiple body systems 
and any finding associated with the body system as not assessed, normal, abnormal 
(clinically significant), abnormal (not clinically significant), or not done. The summary will 
include the number and percentage of subjects with each physical examination outcome for 
the following: general appearance; head, ears, eyes, nose, throat; neck; skin; cardiovascular 
system; respiratory system; abdominal system; nervous system; other.  
Physical examination results for all subjects will be presented in a listing on the Safety Set. 
11.6. 
Neurological Examination 
A table will summarise neurological examination results at Screening and Week 16 visits, 
by treatment group for the Safety Set. Each visit captures the status of the neurological 
system and any finding associated with the body system as normal, abnormal (clinically 
significant), abnormal (not clinically significant), or not done. The summary will include the 
number and percentage of subjects by neurological examination outcome for the following: 
Gait, Balance, Coordination, Cranial nerves, Motor examination, Sensory examination, and 
Other. 
Neurological examination results for all subjects will be presented in a listing on the Safety 
Set. 
12. Changes in the Planned Analysis 
Section 3 of the protocol states about the objective and endpoint of the study. The secondary 
objective and endpoint i.e. “Clinical Global Impression for pain” and “Patient Global 
Impression for pain” signifies “Clinical Global Impression” and “Patient Global 
Impression”. 
13. References 
1. ICH Harmonized Tripartite Guideline – Statistical Principals for Clinical Trials, E9. 
2. ICH Harmonized Tripartite Guideline – Clinical Trial Reports: Structure and Content, 
E3. 
3. Cattaneo C, Barone P, Bonizzoni E, Sardina M. Effects of safinamide on pain in 
fluctuating Parkinson’s Disease patients: a post-hoc analysis. J Parkinsons Dis 2017; 
7(1): 95-101. 
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4. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for 
grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12(3): 
189 98. 
5. Handling missing items in the Hospital Anxiety and Depression Scale (HADS): a 
simulation study (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075158/) 
6. Handling Missing Values in the MDS-UPDRS 
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072275/) 
7. Rascol O, Zesiewicz T, Chaudhuri KR, Asgharnejad M, Surmann E, Dohin E et al. A 
randomised controlled exploratory pilot study to evaluate the effect of rotigotine 
transdermal patch on Parkinson’s Disease-associated chronic pain. J Clin Pharmacol 
2016; 56(7): 852-861 
 
 
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14. Appendices 
14.1. 
Schedule of Activities (SoA) 
Visit 
 
1  
Screening 
2  
Baseline 
3 
Interim
Week 4 
4 
Interim
Week 8 
5  
EoT 
Week 16 
6  
Call 
 
Day / 
Procedure 
(up to 14 
days before 
Day 1) 
 
1 
 
28 ± 3 
 
56 ± 3 
 
112 ± 3 
 
119 ± 3 
 
Notes 
 
Informed 
consent 
 
X 
 
 
 
 
 
After informed 
consent 
signing, enter 
details in 
IWRS to obtain 
screening 
number. 
 
Eligibility 
criteria 
 
X 
 
X 
 
 
 
 
Check prior to 
randomisation/
1st dose of 
study 
medication 
Randomisation  
 
X 
 
 
 
 
Use IWRS to 
randomise 
Demographics 
X 
 
 
 
 
 
Age, sex, race, 
smoking and 
alcohol use 
Medical history 
X 
 
 
 
 
 
PD diagnosis,  
Hoehn & Yahr 
staging, etc. 
Vital signs 
X 
X 
 
 
X 
 
Heart rate, 
systolic and 
diastolic blood 
pressure 
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Visit 
 
1  
Screening 
2  
Baseline 
3 
Interim
Week 4 
4 
Interim
Week 8 
5  
EoT 
Week 16 
6  
Call 
 
Day / 
Procedure 
(up to 14 
days before 
Day 1) 
 
1 
 
28 ± 3 
 
56 ± 3 
 
112 ± 3 
 
119 ± 3 
 
Notes 
Physical 
examination and 
neurological 
examination 
 
X 
 
 
 
 
 
X 
 
 
 
MMSE 
 
X 
 
 
 
 
 
 
eDiary Issue, 
Training and 
return 
 
X 
 
X 
 
 
 
X 
 
 
 
eDiary Review 
 
 
X 
 
X 
 
X 
 
X 
 
Participant to 
complete diary 
for 7 days prior 
to each visit. 
 
NRS Review  
 
 
X 
 
 
 
 
For eligibility:  
PI checks NRS 
score to confim 
eligibility  
MDS-UPDRS  
 
X 
X 
X 
X 
 
 
CGI-S 
 
X 
X 
X 
X 
 
 
CGI-C 
 
 
X 
X 
X 
 
 
PGI-C 
 
 
X 
X 
X 
 
 
HADS 
 
X 
 
 
X 
 
 
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Visit 
 
1  
Screening 
2  
Baseline 
3 
Interim
Week 4 
4 
Interim
Week 8 
5  
EoT 
Week 16 
6  
Call 
 
Day / 
Procedure 
(up to 14 
days before 
Day 1) 
 
1 
 
28 ± 3 
 
56 ± 3 
 
112 ± 3 
 
119 ± 3 
 
Notes 
Blood draw  
X 
 
 
 
X 
 
For 
Haematology 
& Clinical 
chemistry 
Pregnancy test  
 
X 
 
 
X 
 
Urine dipstick 
test for 
WOCBP only 
Prior and 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
 
Drug Dispense 
 
X 
X 
X 
 
 
 
Drug 
accountability 
 
 
X 
X 
X 
 
 
 
 
 
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Zambon SpA 
 
Statistical Analysis Plan, Version 1.0 
Z7219M01 
 
Date Issued: 25Jan2021 
 
  
 
 
 
30 
14.2. 
HADS scores and MDS-UPDRS scores 
 
The method for HADS questionnaires for missing items is to replace the missing items 
with the mean of the answered items in the subscale, if at least half of that subscale has 
been answered. The rationale behind this rule is that an individual’s score would not have 
enough information to be valid if fewer items than half were answered (see Handling 
missing items in the Hospital Anxiety and Depression Scale (HADS): a simulation study, 
for reference).  
 
The MDS-UPDRS is designed as four separate parts, with summary scores for each to 
provide an overall severity measure of a given aspect of Parkinson’s disease (part I, non-
motor experiences of daily living; part II, motor experiences of daily living; part III, motor 
examination; part IV, motor complications). The Hoehn and Yahr Scale is used to measure 
how Parkinson’s symptoms progress and the level of disability, including stages 1 to 5. 
x Stage 1 - Unilateral involvement only 
x Stage 2 - Bilateral involvement without impairment of balance 
x Stage 3 - Mild to moderate involvement; some postural instability but physically 
independent; needs assistance to recover from pull test 
x Stage 4 - Severe disability; still able to walk or stand unassisted 
x Stage 5 - Wheelchair bound or bedridden unless aided 
 
To provide valid part scores applicable across all Hoehn and Yahr (H&Y) stages when the 
same items are consistently missing, one missing item from Part I, one from Part II, three 
from Part III, but none from Part IV can be allowed (Table 1) (see Handling Missing 
Values in the MDS-UPDRS for reference).  To provide valid part scores applicable across 
all H&Y stages when random item entries are missing, one missing item from Part I, two 
from Part II, seven from Part III, but none from Part IV can be allowed (Table 1). These 
analyses are useful for constructing valid surrogate part scores for MDS-UPDRS when 
missing items fall within the identified threshold and give scientific justification for 
rejecting partially completed ratings that fall below the threshold. 
 
 
 
 
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Zambon SpA 
 
Statistical Analysis Plan, Version 1.0 
Z7219M01 
 
Date Issued: 25Jan2021 
 
  
 
 
 
31 
Table 1 
Maximal number of allowable missing items to calculate MDS-UPDRS total part scores 
 
 
Same Item(s) 
Consistently 
Missing 
Across All 
Patients 
Different Item(s) 
Randomly 
Missing Across 
Patients 
Part I: Across all 
HY 
1 
 
1 
 
  HY 1–2 only 
 
1 
 
2 
  HY 3 only 
 
1 
 
2 
  HY 4–5 only 
 
1 
 
1 
 
 
 
 
 
Part II: Across 
all HY 
1 
 
2 
 
  HY 1–2 only 
 
1 
 
3 
  HY 3 only 
 
1 
 
2 
  HY 4–5 only 
 
1 
 
2 
 
 
 
 
 
Part III: Across 
all HY 
3 
 
7 
 
  HY 1–2 only 
 
4 
 
 
  HY 3 only 
 
3 
 
9 
  HY 4–5 only 
 
3 
 
9 
 
 
 
 
7 
Part IV: Across 
all HY 
0 
 
0 
 
  HY 1–2 only 
 
0 
 
1 
  HY 3 only 
 
0 
 
0 
  HY 4–5 only 
 
0 
 
0 
 
 
 
 
 
The standard score for each patient’s MDS-UPDRS (Part I, II, III, IV) score is used as the gold standard, 
and standard scores are calculated for each permutation with missing values. The threshold of a minimum 
CCC >0.95 is used to indicate the number of missing values allowable to provide a valid standard score 
even with missing data. HY, Hoehn and Yahr stages. 
 
 
 
 
32