Clinical trial NCT04986982
Conditions: Parkinson Disease
Sponsor: Bial - Portela C S.A.
Start date: 2021-02-25; Completion date: 2024-02-16
Enrollment: 144 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this study is to investigate the efficacy of 50 mg opicapone when administered with the existing treatment of levodopa (L-dopa) plus a dopa decarboxylase inhibitor (DDCI), in Parkinson's disease (PD) patients with end-of-dose motor fluctuations and associated pain

Detailed description:
This is a randomised, double-blind, placebo-controlled, multi-centre, parallel group, interventional clinical study in PD patients with end-of-dose motor fluctuations and associated pain. The study consists of a 1-week screening period, a 24-week double-blind treatment period and 2 weeks of follow-up period. The duration of treatment for the individual patient is expected to be up to 24 weeks.

Arms: arm 1: Opicapone (BIA 9-1067) arm 2: Placebo
Interventions: intervention 1: Opicapone 50 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Opicapone (BIA 9-1067) 50 mg hard capsules. Oral administration, once daily, at least 1 hour before or after the last daily dose of L-dopa/DDCI intervention 2: Matching placebo hard capsules. Oral administration, once daily, at least 1 hour before or after the last daily dose of L-dopa/DDCI

Protocol documents:
Prot_000.pdf: 
Bial - Portela & Ca, S.A.
CLINICAL STUDY PROTOCOL
Synopsis
Randomised, double-blind, placebo-controlled, clinical study to evaluate the effect of 
opicapone 50 mg on Parkinson’s disease patients with end-of-dose motor fluctuations 
and associated pain.
Protocol Short Title
OpiCapone Effect on motor fluctuations 
and pAiN (OCEAN)
Protocol Number
BIA-91067-404
EudraCT Number
2020-001175-32
Phase
IV
Version
Final Version 1.0
Date
04-JUN-2020
Product Name
Opicapone
Indication
Parkinson´s Disease
Sponsor
Bial - Portela & Ca, S.A.
À Av. da Siderurgia Nacional
4745-457 Coronado (S. Romão e S. 
Mamede), Portugal
Phone: +351 229866100
Fax:     +351 229866192
http://www.bial.com 
24/7 Medical Contact
Scope International Medical Monitoring
Phone: +370 52 360 336 
The information contained in this document is the property of Bial - Portela & Ca, S.A. and 
may not be disclosed to parties not associated with the clinical investigation or used for any 
purpose without prior written consent of Bial - Portela & Ca, S.A.
Throughout this document, symbols indicating proprietary names (®, ™) are not 
displayed. Hence the appearance of product names without these symbols does not imply 
that these names are not protected.
This study will be performed in compliance with the protocol, Good Clinical Practice 
(GCP) and applicable regulatory requirements, including the archiving of essential 
documents.


Clinical Study Protocol, Synopsis
Study BIA-91067-404
Bial - Portela & Ca, S.A.
Final Version 1.0, 04-JUN-2020
CONFIDENTIAL 
Page 2 of 9
PROTOCOL SYNOPSIS
Name and address of sponsor/company: Bial - Portela & Ca, S.A., 
À Av. da Siderurgia Nacional, 4745-457 Coronado (S. Romão e S. Mamede), Portugal.
Name of active ingredient: Opicapone (BIA 9-1067)
Title of study: Randomised, double-blind, placebo-controlled, clinical study to evaluate the 
effect of opicapone 50 mg on Parkinson’s disease patients with end-of-dose motor fluctuations 
and associated pain.
Study number: BIA-91067-404
EudraCT number: 2020-001175-32 
Coordinating investigator: Prof. Kallol Ray Chaudhuri (King’s College Hospital, London, 
United Kingdom).
Clinical study site(s): Approximately 50 sites in Germany, Italy, Portugal, Spain and the 
United Kingdom. (Other countries and additional sites may be added as needed.)
Planned duration of the study: 
First patient first visit: August 2020
Last patient last visit: July 2022
Phase of development: Phase IV
Objectives and Endpoints: 
Objectives
Endpoints
Primary
To investigate the efficacy of 50 mg opicapone 
when administered with the existing treatment of 
levodopa (L-dopa) plus a dopa decarboxylase 
inhibitor (DDCI), in Parkinson’s disease (PD) 
patients with end-of-dose motor fluctuations and 
associated pain
Change from baseline in Domain 3 (fluctuation-
related pain) of King’s Parkinson’s Disease Pain 
Scale (KPPS)
Secondary

To investigate the efficacy of opicapone 
50 mg in reducing further symptoms 
1.
Change from baseline in Domain B (anxiety) 
of Movement Disorder Society-sponsored 
Non-motor Rating Scale (MDS-NMS) (Key 
secondary endpoint)
2.
Change 
from 
baseline 
in 
Domain A 
(depression) of MDS-NMS
3.
Change from baseline in Domain K (sleep 
and wakefulness) of MDS-NMS
4.
Change from baseline in total score of MDS-
NMS
5.
Change from baseline in Domain 4 (nocturnal 
pain) of KPPS


Clinical Study Protocol, Synopsis
Study BIA-91067-404
Bial - Portela & Ca, S.A.
Final Version 1.0, 04-JUN-2020
CONFIDENTIAL 
Page 3 of 9
6.
Change from baseline in total score of KPPS
7.
Change from baseline in Movement Disorder 
Society-sponsored 
Unified 
Parkinson’s 
Disease Rating Scale (MDS-UPDRS) Part III 
and IV
8.
Change from baseline in Parkinson’s Disease 
Questionnaire (PDQ-8) 
9.
Clinical Global Impression of Change 
(CGIC)
10. Patient’s Global Impression of Change 
(PGIC) 
11. Change from baseline in functional status via 
Hauser’s PD diary
12. Changes from baseline in morning dystonia 
13. Frequency of use of rescue medication

To investigate the safety and tolerability of 
opicapone 50 mg once daily
14. Incidence of adverse events (AEs) including 
serious adverse events (SAEs)
15. Changes from baseline in vital signs
16. Changes from baseline in physical and 
neurological examinations
17. Changes from baseline in routine laboratory 
parameters
Methods / study design: This is a randomised, double-blind, placebo-controlled, multi-centre, 
parallel group, interventional clinical study in PD patients with end-of-dose motor fluctuations 
and associated pain. The study consists of a 1-week screening period, a 24-week double-blind 
treatment period and 2 weeks of follow-up period.
At visit V1 (7 ± 2 days before V2b), the patient will complete specific questionnaires. The 
patient will be provided with a paper-based self-rating diary (Hauser’s PD diary) and will be 
instructed how to complete it. 
Completion of diary entries will be reviewed at V2a (5 to 6 days after V1). In case the patient 
completed the diary satisfactorily the investigator will immediately continue with V2b at the 
same day. If diary entries are non-compliant (i.e. more than 3 missing entries per day in the 
3 days prior to V2a), the patient will be re-trained on correct use of the diary and V2b will be 
postponed for 3 to 4 days. 
At V2b (Day 1) and if eligibility is confirmed, the patient will be randomised to 50 mg 
opicapone or placebo once daily (1:1) and start treatment in addition to current treatment with 
L-dopa/DDCI. 
Opicapone enhances the effects of L-dopa. Hence, it may be necessary to reduce the patient’s 
L-dopa/DDCI dose within the first days or weeks of opicapone treatment. Therefore, the 
investigator will call the patient on Day 8 ± 2 (V3) to ask for any changes in the medical 
condition. If dose decrease of L-dopa/DDCI is deemed necessary, it may be adjusted by phone 
at V3 or an unscheduled on-site visit may be performed at the investigator’s discretion. In case 
of L-dopa/DDCI adjustment an unscheduled phone call should be repeated up to 7 days after 
dose adjustment or V4 (Day 29 ± 2) should be performed, whatever applies first. The 
investigator can decrease the daily dose of L-dopa/DDCI (but keeping the number of daily 
intakes unchanged) as required until V4. If the investigator finds that the dose reduction was 


Clinical Study Protocol, Synopsis
Study BIA-91067-404
Bial - Portela & Ca, S.A.
Final Version 1.0, 04-JUN-2020
CONFIDENTIAL 
Page 4 of 9
too much, it can be increased again up to the baseline dose level. The dosage of L-dopa/DDCI 
should not be changed from V4 through the end of the study. No new anti-PD drugs should be 
started during the study and any that are ongoing at the start of the study must be kept at a 
stable dose throughout the study. No new pain medication should be started during the study 
except the allowed rescue medication. Baseline dose of pain medication may be reduced 
throughout the study if required due to pain medication-related AEs. If the investigator finds 
that the dose reduction was too much, it can be increased again up to the baseline dose level.
Further visits will be performed on Day 85 ± 4 (V5, after 12 weeks) and Day 169 ± 4 (V6, after 
24 weeks). The primary analysis will be performed on the data collected at V6. A follow-up 
Visit (FU) will be performed on Day 183 ± 4, approximately 2 weeks after last intake of the 
investigational product (IP; 50 mg opicapone or placebo).
Patients who discontinue study participation prematurely will be asked to come to the site for 
an early discontinuation visit (EDV).
At V6 (or EDV, if applicable) the investigator will arrange for the patient’s subsequent 
treatment, i.e. either prescribe further opicapone or switch to another treatment.
Number of patients (planned): 
Screened: 
176
Randomised:
140
Evaluable:
120
Diagnosis: Parkinson's disease patients with wearing-off motor fluctuations and associated 
pain.
Inclusion criteria at Visit 1 (Screening):
1. Able to comprehend and willing to sign an informed consent form and to comply with all 
aspects of the study. 
2. Male or female patients aged 30 years or older.
3. Experiencing PD associated pain for at least 4 weeks prior to V1.
4. Diagnosed with idiopathic PD according to the UK Parkinson’s Disease Society Brain 
Bank Clinical Diagnostic Criteria (2006) or according to MDS Clinical Diagnostic Criteria 
(2015).
5. Disease severity Stages I-III (modified Hoehn & Yahr staging) at ON.
6. Treated with 3 to 8 intakes per day of L-dopa/DDCI (which may include a slow-release 
formulation), on a stable regimen for at least 4 weeks before V1.
7. In case of any other anti-PD-treatment, it should be on a stable regimen for at least 4 weeks 
before V1, and not likely to need any adjustment until V6.
8. No changes in chronic treatment regimen for pain within the last 4 weeks before V1. This 
includes medication (including but not limited to paracetamol, opioids, nonsteroidal anti-
inflammatory drugs [NSAIDS], antidepressants, anticonvulsants and corticosteroids) and 
non-medication therapies (including but not limited to transcutaneous electrical nerve 
stimulation and bioelectrical therapy).
9. Signs of “wearing-off” phenomenon (end-of-dose motor fluctuations) with average total 
daily OFF time while awake of at least 1.5 hours, excluding the early morning pre-first 
dose OFF, despite optimal anti-PD therapy (based on investigator’s assessment).


Clinical Study Protocol, Synopsis
Study BIA-91067-404
Bial - Portela & Ca, S.A.
Final Version 1.0, 04-JUN-2020
CONFIDENTIAL 
Page 5 of 9
10. Domain 3 of KPPS ≥ 12. 
11. For females: Postmenopausal for at least 2 years before V1, surgically sterile for at least 
6 months before V1, or practicing effective contraception until V6. Female patients who 
request to continue with oral contraceptives must be willing to use non-hormonal methods 
of contraception in addition during the course of this study.
For males: Male patients who are sexually active with a partner of childbearing potential 
must use, with their partner, a condom plus an approved method of highly effective 
contraception during the treatment period until V6. 
Inclusion Criteria at V2b (Baseline):
12. Have filled-in self-rating diary in accordance with the diary instructions and with ≤ 3 
missing entries per day, in the 3 days preceding V2a/V2b.
13. With at least 1.5 OFF hours per day, excluding the early morning pre-first dose OFF period 
(i.e. the time between wake-up and response to the first L-dopa/DDCI dosage), as recorded 
in at least 2 of the 3 days in the self-rating diary for the 3 days preceding V2a/V2b.
14. Results of the screening laboratory tests are considered acceptable by the investigator (i.e. 
not clinically relevant for the well-being of the patient or for the purpose of the study).
15. Domain 3 of KPPS ≥ 12.
16. Adequate compliance to relevant (PD and pain related) concomitant medication during the 
screening period (based on the investigator’s judgment).
Exclusion criteria:
1. Non-idiopathic PD (atypical parkinsonism, secondary [acquired or symptomatic] 
parkinsonism, Parkinson-plus syndrome).
2. Severe and/or unpredictable OFF periods, according to investigator judgement.
3. Major/prominent non-PD-related pain (e.g. due to malignant disease).
4. Treatment with prohibited medication: entacapone, tolcapone, monoamine oxidase (MAO) 
inhibitors (except selegiline up to 10 mg/day in oral formulation or 1.25 mg/day in buccal 
absorption formulation, rasagiline up to 1 mg/day or safinamide up to 100 mg/day), or 
antiemetics with antidopaminergic action (except domperidone) within the last 4 weeks 
before V1.
5. Previous or planned (during the entire study duration) L-dopa/carbidopa intestinal gel 
infusion, deep brain stimulation or stereotactic surgery (e.g. pallidotomy, thalamotomy).
6. Treatment with apomorphine within the last 4 weeks before V1 or likely to be needed at 
any time until V6.
7. Previous or current use of opicapone. 
8. Use of any other IP, currently or within the 3 months (or within 5 half-lives of the IP, 
whichever is longer) before V1. 
9. Past (within the past year) or present history of suicidal ideation or suicide attempts.
10. Current or previous (within the past year) alcohol or substance abuse excluding caffeine or 
nicotine.
11. Phaeochromocytoma, paraganglioma, or other catecholamine secreting neoplasms. 
12. Known hypersensitivity to the excipients of IP (including lactose intolerance, galactose 
intolerance, Lapp lactase deficiency or glucose-galactose malabsorption) or of rescue 
medication. 
13. History of neuroleptic malignant syndrome or non-traumatic rhabdomyolysis. 


Clinical Study Protocol, Synopsis
Study BIA-91067-404
Bial - Portela & Ca, S.A.
Final Version 1.0, 04-JUN-2020
CONFIDENTIAL 
Page 6 of 9
14. History of severe hepatic impairment (Child-Pugh Class C). 
15. Previous history of psychosis or psychiatric disorders, including severe major depression.
16. Any medical condition that might place the patient at increased risk or interfere with 
assessments.
17. For females: Pregnant or breastfeeding.
18. Employees of the investigator, study centre, sponsor, clinical research organisation and 
study consultants, when employees are directly involved in this study or other studies under 
the direction of this investigator or study centre, and their family members.
19. Persons committed to an institution by virtue of an order issued either by the judicial or 
other authorities.
Duration of treatment for the individual patient: 
Twenty-four weeks
Test product, dose and mode of administration: 
Opicapone (BIA 9-1067) 50 mg hard capsules. Oral administration, once daily, at least 1 hour 
before or after the last daily dose of L-dopa/DDCI.
Reference therapy, dose and mode of administration: 
Matching placebo hard capsules. Oral administration, once daily, at least 1 hour before or after 
the last daily dose of L-dopa/DDCI.
Rescue medication, dose and mode of administration: 
Paracetamol 500 mg tablets. Oral administration, upon request with maximum daily dose of 
8 tablets (4 g).
Tramadol 50 mg hard capsules. Oral administration, upon request with maximum daily dose 
of 8 capsules (400 mg).
Paracetamol and tramadol are not allowed to be taken concomitantly.
Statistical methods: 
The analyses of all efficacy endpoints will be based on the full analysis set (primary analysis 
population) and per-protocol set for sensitivity purpose.
The primary efficacy endpoint (change from baseline to V6 in the Domain 3 of KPPS) will be 
analysed using Analysis of Covariance (ANCOVA) with treatment as fixed factor and baseline 
KPPS as a covariate to demonstrate superiority of opicapone against placebo.  
The key secondary endpoint (change from baseline in Domain B [anxiety] of MDS-NMS) as 
well as all other secondary efficacy endpoints will be analysed in an exploratory manner by 
treatment arm using appropriate parametric or non-parametric statistical methods. Descriptive 
statistics including 95%-confidence intervals will be presented per treatment arm. Potential 
sensitivity analyses will be specified in the statistical analysis plan (SAP).
The analyses of all safety endpoints will be based on the safety set.
All AEs will be summarised by number and percent of patients with AEs. Treatment-emergent 
AEs (TEAEs) will be summarised by calculating the number and percent of patients with AEs 
by preferred term (PT) and system organ class (SOC). TEAEs will also be summarised by 
severity and relationship to treatment. Number and percent of patients with serious TEAEs, 


Clinical Study Protocol, Synopsis
Study BIA-91067-404
Bial - Portela & Ca, S.A.
Final Version 1.0, 04-JUN-2020
CONFIDENTIAL 
Page 7 of 9
related serious TEAEs and TEAEs leading to discontinuation from study will be provided by 
SOC and PT. All AEs, SAEs and TEAEs leading to study termination will be listed.
Vital signs and laboratory parameters will be summarised by calculating summary statistics on 
the absolute values and on the change from baseline. Abnormal values will be assessed as 
clinically significant or not clinically significant. 
Summary statistics and shift tables will be performed for physical examinations and, 
neurological examinations. Abnormal values will be assessed as clinically significant or not 
clinically significant.
Sample size:
For the primary endpoint (change from baseline in Domain 3 of KPPS), a difference to placebo 
of 3.0 is regarded as clinically meaningful and from a former study (Rascol O et al 2016; DOI: 
10.1002/jcph.678) a standard deviation (SD) of 5.8 can be assumed. With a two-sided 
significance level  of 0.05, a power of 80%, a 1:1 treatment allocation ratio and with the 
abovementioned assumptions, 2 x 60 = 120 evaluable patients are required. A drop-out rate of 
15% is assumed, therefore 140 patients need to be randomised.


Clinical Study Protocol, Synopsis
Study BIA-91067-404
Bial - Portela & Ca, S.A.
Final Version 1.0, 04-JUN-2020
CONFIDENTIAL 
Page 8 of 9
Schedule of study procedures
Visit no./name
V1
V2a1
V2b
V32
V4
V5
V6/
EDV3
FU
Double-blind treatment period
Screening
Baseline
End of 
Study
Follow-up
Day
-7 (±2)
5-6 days 
after V1
1
8 (±2)
29 (±2) 85 (±4) 169 (±4)
183 
(±4)
On-site visit  / telephone contact 







Initiation procedures
Informed consent

Demographics

Height and weight

Medical/neurological history

Previous medications/therapies

In-/exclusion criteria


Modified Hoehn & Yahr staging at ON

Review of Hauser’s PD diary

4



Instructions on use and delivery of 
Hauser’s PD diary

4



Urine pregnancy test6




Medication
Concomitant medications/therapies







Record L-dopa/DDCI dose







Adjust L-dopa/DDCI dose, if necessary



Randomisation (1:1)

IP dispensing 



Dispensing rescue medication



Instructions on use and dispensing of 
rescue medication diary.

Review of rescue medication diary



Drug accountability (IP and rescue 
medication)



First IP administration5

Efficacy
KPPS





MDS-NMS




MDS-UPDRS Part I and II

MDS-UPDRS Part III and IV




PDQ-8 




Early morning dystonia 




CGIC



PGIC



Safety
Record adverse events

4






Vital signs (blood pressure, heart rate)





Physical and neurological examinations



Blood samples for routine laboratory




Clinical Study Protocol, Synopsis
Study BIA-91067-404
Bial - Portela & Ca, S.A.
Final Version 1.0, 04-JUN-2020
CONFIDENTIAL 
Page 9 of 9
CGIC: Clinical Global Impression of Change; DDCI: Dopa decarboxylase inhibitor; EDV: early discontinuation 
visit; FU: Follow-up; KPPS: King’s Parkinson’s Disease Pain Scale; L-dopa: levodopa; IP: investigational 
product; MDS-NMS: Movement Disorder Society-sponsored Non-motor Rating Scale; MDS-UPDRS: Movement 
Disorder 
Society-sponsored 
Unified 
Parkinson’s 
Disease 
Rating 
Scale; PD: 
Parkinson’s 
disease; 
PDQ-8: Parkinson’s Disease Questionnaire; PGIC: Patient’s Global Impression of Change.
1)
If self-rating diary (Hauser’s PD diary) entries are non-compliant, the patient will be re-trained on correct use 
of the diary and V2b will be postponed for 3 to 4 days. If the patient completed the diary  satisfactorily, V2b 
is to be performed immediately, at the same day.
2)
If L-dopa/DDCI adjustment is deemed necessary, an unscheduled on-site visit for dose adjustment may be 
performed at the investigator’s discretion. After L-dopa/DDCI adjustment, either the phone call should be 
repeated up to 7 days after dose adjustment or V4 should be performed, whatever applies first.
3)
An EDV should be performed as soon as possible (not exceeding 7 days) after early discontinuation.
4)
Only to be performed if V2a and V2b will not take place on the same day.
5)
The first intake of opicapone will take place on the day of V2b, at least 1 hour before or after the last daily 
dose of L-dopa/DDCI.
6)
In females of childbearing potential.

SAP_001.pdf: 
Randomised, double-blind, placebo-controlled, clinical study to evaluate the effect of
opicapone 50 mg on Parkinson’s disease patients with end-of-dose motor fluctuations
and associated pain.
Sponsor Project Code: BIA-91067-404
Scope Project Code: 0230BI30.MPB
STATISTICAL ANALYSIS PLAN
Sponsor:
Bial - Portela & Ca, S.A.
À Av. da Siderurgia Nacional
4745-457 Coronado (S. Romão e S.Mamede), Portugal
Phone: +351 229866100
Fax:     +351 229866192
CRO:
SCOPE International AG
Konrad-Zuse-Ring 18
68163 Mannheim, Germany
Version:
Final 1.0 (21-MAY-2024)
The information provided in this document is strictly confidential. No part of this document may be reproduced, 
transmitted or copied in any form nor its contents disclosed to the third parties without prior written consent of 
Bial - Portela & Ca, S.A. or a nominated representative.
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 2 of 49
Effective date: 15.09.2020
DOCUMENT REVISION HISTORY
Version Draft 0.1 (18-MAR-2022): Document was created.
Version Draft 0.2 (06-FEB-2023): Document was updated according to Sponsor’s comments. Major 
changes:
-
Primary efficacy analysis model from ANCOVA changed to MMRM, under the assumption 
that data are missing at random (MAR).
-
Multiple imputation method under the assumption that data are missing not at random (MNAR) 
will be used instead of last observation carried forward (LOCF) approach within the sensitivity 
analysis.
-
Secondary efficacy endpoints will be analysed using MMRM in those continuous endpoints 
where 3 post-baseline visits are planned to be collected.
-
Added improvement analysis for CGIC and PGIC: number of responses (improved vs. not 
improved) will be compared among two treatment groups using Fisher’s exact test.
-
Rescue medication adherence will be calculated.
Version Draft 0.3 (05-MAY-2023): Document was updated according to Sponsor’s comments. Major 
changes:
-
Added specification in full analysis set definition that patients must have at least one post-
baseline assessment.
-
COVID-19 related protocol deviations will not be provided.
-
Details for sensitivity analysis of rescue medication will be specified during blind data review 
meeting.
-
New shift tables added for morning dystonia.
Version Draft 0.4 (30-NOV-2023): Document was updated according to Sponsor’s comments. Major 
changes:
-
EDV visit will be used for analysis only if no more than 3 days have passed since the IP was 
discontinued.
-
In addition, IP compliance by periods will be calculated.
-
Added new listing - Listing 16.2.3.6.2 Hauser’s Parkinson’s Disease Diary for Analysis
Version Draft 0.5 (16-MAY-2024): Document was updated. The following major changes were made:
-
Randomised set added as analysis set.
-
Hauser’s Parkinson disease diary will be analysed using visit windows.
-
Subgroups and subgroup analysis added.
-
Last IP intake date imputation rules provided for partially or fully missing last IP intake date.
-
Compliance by periods will not be calculated.
-
Sensitivity analysis of rescue medication impact to the primary efficacy endpoint will be 
conducted if more than 10% of subjects were using tramadol during the last 30 days prior to 
the primary endpoint.
-
Periods for rescue diary analysis agreed.
Version Final 1.0 (21-MAY-2024): Document was finalised. Minor changes were made.
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 3 of 49
Effective date: 15.09.2020
TABLE OF CONTENTS
DOCUMENT REVISION HISTORY.................................................................................................2
TABLE OF CONTENTS .....................................................................................................................3
LIST OF ABBREVIATIONS AND KEY TERMS............................................................................5
INTRODUCTION.................................................................................................................................7
1.
VISIT SCHEDULE......................................................................................................................8
2.
OBJECTIVES AND DESIGN...................................................................................................10
2.1
STUDY OBJECTIVES .............................................................................................................10
2.1.1
Primary Objective.......................................................................................................10
2.1.2
Secondary Objectives..................................................................................................10
2.2
STUDY ENDPOINTS ..............................................................................................................10
2.2.1
Primary Efficacy Endpoints........................................................................................10
2.2.2
Secondary Efficacy Endpoints ....................................................................................10
2.2.3
Safety Endpoints .........................................................................................................10
2.3
OVERALL STUDY DESIGN....................................................................................................11
2.4
RANDOMISATION.................................................................................................................11
2.5
TREATMENTS.......................................................................................................................11
2.6
SAMPLE SIZE........................................................................................................................12
2.7
BLINDING.............................................................................................................................12
3.
ANALYSIS SETS AND SUBGROUPS....................................................................................13
3.1
ANALYSIS SETS....................................................................................................................13
3.2
SUBGROUPS .........................................................................................................................13
4.
GENERAL DEFINITIONS AND NAMING CONVENTIONS ............................................14
4.1
GENERAL METHODOLOGY AND PRESENTATION OF THE RESULTS......................................14
4.2
STATISTICAL OUTPUT LAYOUT ...........................................................................................14
4.3
TREATMENT GROUP NAMES AND LABELS ..........................................................................14
4.4
VISIT NAMES AND LABELS..................................................................................................15
4.5
STUDY DAY NUMBERING ....................................................................................................15
4.6
STUDY PERIODS...................................................................................................................15
4.7
BASELINE AND ENDPOINT VALUE.......................................................................................15
4.8
VISIT WINDOWS...................................................................................................................16
4.9
CODING SYSTEMS AND CONVENTIONS................................................................................16
4.9.1
Coding of Adverse Events and Medical History.........................................................16
4.9.2
Coding of Medications................................................................................................16
4.10
HANDLING OF MISSING DATA.............................................................................................17
5.
STATISTICAL ANALYSIS: DEFINITIONS, DERIVATIONS, CALCULATIONS AND 
METHODOLOGY.....................................................................................................................18
5.1
PATIENT DISPOSITION..........................................................................................................18
5.1.1
Disposition and Withdrawals......................................................................................18
5.1.2
Protocol Deviations....................................................................................................19
5.1.3
Inclusion/Exclusion.....................................................................................................19
5.2
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................................19
5.2.1
Demographics.............................................................................................................19
5.2.2
Neurological History ..................................................................................................20
5.2.3
Medical History ..........................................................................................................20
5.3
PRIOR AND CONCOMITANT MEDICATIONS..........................................................................21
5.4
EXPOSURE TO IP AND RESCUE MEDICATION AND COMPLIANCE........................................22
5.4.1
Exposure to IP ............................................................................................................22
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5.4.2
IP Compliance ............................................................................................................23
5.4.3
Exposure to Rescue Medication..................................................................................24
5.5
EFFICACY ANALYSIS ...........................................................................................................24
5.5.1
Primary Efficacy Analysis...........................................................................................24
5.5.2
Analysis of Secondary Variables ................................................................................26
5.5.2.1
Total Score and Domain 4 of KPPS ...........................................................................26
5.5.2.2
Movement Disorder Society-sponsored Non-motor Rating Scale ..............................27
5.5.2.3
Movement Disorder Society-sponsored Unified Parkinson’s Disease Rating Scale..28
5.5.2.4
Parkinson’s Disease Questionnaire............................................................................28
5.5.2.5
Clinical Global Impression of Change and Patient’s Global Impression of Change.29
5.5.2.6
Hauser’s Parkinson Disease Diary ............................................................................29
5.5.2.7
Morning Dystonia.......................................................................................................31
5.5.2.8
Use of Rescue Medication...........................................................................................31
5.6
SAFETY ANALYSIS...............................................................................................................32
5.6.1
Adverse Events............................................................................................................32
5.6.2
Vital Signs...................................................................................................................33
5.6.3
Physical Examination .................................................................................................34
5.6.4
Neurological Examination..........................................................................................34
5.6.5
Clinical Laboratory Evaluation..................................................................................34
6.
BLIND DATA REVIEW ...........................................................................................................36
7.
INTERIM ANALYSIS...............................................................................................................39
8.
CHANGES TO THE ANALYSIS AS LAID DOWN IN THE PROTOCOL AND 
MODIFICATIONS ....................................................................................................................40
9.
REFERENCES...........................................................................................................................41
10.
APPENDICES ............................................................................................................................42
10.1
TABLES ................................................................................................................................42
10.2
LISTINGS ..............................................................................................................................46
10.3
FIGURES...............................................................................................................................48
11.
SIGNATURES............................................................................................................................49
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LIST OF ABBREVIATIONS AND KEY TERMS
Abbreviation
Description of abbreviation
AE
Adverse event
ALT/GPT
Alanine aminotransferase / glutamic-pyruvic transaminase
AST/GOT
Aspartate aminotransferase / glutamic-oxaloacetic transaminase
BDR
Blind data review
BMI
Body mass index
BUN
Blood urea nitrogen
CGIC
Clinical Global Impression of Change
CK
Creatine kinase
CS
Clinically significant
DDCI
Dopa decarboxylase inhibitor
eCRF
Electronic case report form
EDV
Early discontinuation visit
EOS
End of study
FAS
Full analysis set
FU
Follow-up
H
Higher
hCG
Human chorionic gonadotropin
HLGT
High level group term
HLT
High level term
IP
Investigational product
IWRS
Interactive web response system
KPPS
King’s Parkinson’s Disease Pain Scale
L
Lower
L-DOPA
Levodopa
LLT
Lowest level term
LOCF
Last observation carried forward
LS
Least squares
MAR
Missing at random
max
Maximum
MCH
Mean corpuscular/cellular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
MDS-NMS
Movement Disorder Society-sponsored Non-motor Rating Scale
MDS-UPDRS
Movement Disorder Society-sponsored Unified Parkinson’s Disease Rating 
Scale
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
min
Minimum
MMRM
Mixed model for repeated measures
MNAR
Missing not at random
n
Number of observations/ frequency count
PD
Parkinson’s disease
PDQ-8
Parkinson’s Disease Questionnaire
PGIC
Patient’s Global Impression of Change
PPS
Per-protocol set
PT
Preferred term
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
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Abbreviation
Description of abbreviation
SOC
System organ class
SS
Safety set
TLF
Tables, listings, figures
WBC
White blood cell
WHO
World Health Organization
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INTRODUCTION
This statistical analysis plan (SAP) contains a more technical and detailed elaboration of the principal 
features of the statistical analyses as described in the clinical study protocol and its modifications:
Final Protocol Version(s), Date(s):
Final 1.0, 04-JUN-2020
Protocol Amendment Date(s):
Final 1.0 Germany, 03-DEC-2020
Final 2.0 Germany, 19-FEB-2021
Final 2.0, Phase III, 04-JUL-2022 (for Poland)
Final 2.0 Czech Republic, 17-OCT-2022
The SAP includes detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data, and it is structured according to different data types.
The SAP will supersede all the statistical considerations previously described into the Clinical Trial 
Protocol. The SAP will be finalised and signed-off prior to unblinding the study.
All analysis data sets and statistical output will be produced by the statistics department using SAS for 
Windows (SAS Institute Inc., Cary, NC, USA) [1] version 9.4 or higher. The actual version used will 
be documented in the Validation Plan for Statistical Programming.
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1.
VISIT SCHEDULE
Visit no./name
V1
V2a1
V2b
V32
V4
V5
V6/
EDV3
FU
Screening
Double-blind treatment period
Follow-up
Baseline
End of 
Study
Day
-7 (±2)
5-6 days 
after V1
1
8 (±2)
29 (±2) 85 (±4) 169 (±4)
183 
(±4)
On-site visit  / telephone contact 







Initiation procedures
Informed consent
z
Demographics
z
Height and weight
z
Medical/neurological history
z
Previous medications/therapies
z
In-/exclusion criteria
z
z
Modified Hoehn & Yahr staging at ON
z
Review of Hauser’s PD diary
z
z4
z
z
z
Instructions on use and delivery of 
Hauser’s PD diary
z
z4
z
z
z
Urine pregnancy test6
z
z
z
z
Medication
Concomitant medications/therapies
z
z
z
z
z
z
z
Record L-DOPA/DDCI dose
z
z
z
z
z
z
z
Adjust L-DOPA/DDCI dose, if 
necessary
z
z
z
Randomisation (1:1)
z
IP dispensing 
z
z
z
Dispensing rescue medication
z
z
z
Instructions on use and dispensing of 
rescue medication diary.
z
Review of rescue medication diary
z
z
z
Drug accountability (IP and rescue 
medication)
z
z
z
First IP administration5
z
Efficacy
KPPS
z
z
z
z
z
MDS-NMS
z
z
z
z
MDS-UPDRS Part I and II
z
MDS-UPDRS Part III and IV
z
z
z
z
PDQ-8 
z
z
z
z
Early morning dystonia 
z
z
z
z
CGIC
z
z
z
PGIC
z
z
z
Safety
Record adverse events
z
z4
z
z
z
z
z
z
Vital signs (blood pressure, heart rate)
z
z
z
z
z
Physical and neurological examinations
z
z
z
Blood samples for routine laboratory
z
z
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CGIC: Clinical Global Impression of Change; DDCI: Dopa decarboxylase inhibitor; EDV: early discontinuation 
visit; FU: Follow-up; KPPS: King’s Parkinson’s Disease Pain Scale; L-DOPA: levodopa; IP: investigational 
product; MDS-NMS: Movement Disorder Society-sponsored Non-motor Rating Scale; MDS-UPDRS: Movement
Disorder Society-sponsored Unified Parkinson’s Disease Rating Scale; PD: Parkinson’s disease; PDQ-8: 
Parkinson’s Disease Questionnaire; PGIC: Patient’s Global Impression of Change.
1) If self-rating diary (Hauser’s PD diary) entries are non-compliant, the patient will be re-trained on correct use
of the diary and V2b will be postponed for 3 to 4 days. If the patient completed the diary satisfactorily, V2b is to 
be performed immediately, at the same day.
2) If L-DOPA/DDCI adjustment is deemed necessary, an unscheduled on-site visit for dose adjustment may be
performed at the investigator’s discretion. After L-DOPA/DDCI adjustment, either the phone call should be
repeated up to 7 days after dose adjustment or V4 should be performed, whatever applies first.
3) An EDV should be performed as soon as possible (not exceeding 7 days) after early discontinuation.
4) Only to be performed if V2a and V2b will not take place on the same day.
5) The first intake of opicapone will take place on the day of V2b, at least 1 hour before or after the last daily dose 
of L-DOPA/DDCI.
6) In females of childbearing potential.
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2.
OBJECTIVES AND DESIGN
2.1
Study Objectives
2.1.1
Primary Objective
The primary objective of this study is to investigate the efficacy of 50 mg opicapone when administered
with the existing treatment of L-DOPA plus a DDCI, in Parkinson’s disease (PD) patients with end-of
dose motor fluctuations and associated pain.
2.1.2
Secondary Objectives
The secondary objectives of this study are:
x
to investigate the efficacy of opicapone 50 mg in reducing further symptoms
x
to investigate the safety and tolerability of opicapone 50 mg once daily
2.2
Study Endpoints
2.2.1
Primary Efficacy Endpoints
The primary efficacy endpoint of this study is change from baseline in Domain 3 (fluctuation-related
pain) of King’s Parkinson’s Disease Pain Scale (KPPS).
2.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints of this study are:
x
change from baseline in Domain B (anxiety) of Movement Disorder Society-sponsored Non-
motor Rating Scale (MDS-NMS)
x
change from baseline in Domain A (depression) of MDS-NMS
x
change from baseline in Domain K (sleep and wakefulness) of MDS-NMS
x
change from baseline in total score of MDS-NMS
x
change from baseline in Domain 4 (nocturnal pain) of KPPS
x
change from baseline in total score of KPPS
x
change from baseline in Movement Disorder Society-sponsored Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS) Part III and IV
x
change from baseline in Parkinson’s Disease Questionnaire (PDQ-8)
x
Clinical Global Impression of Change (CGIC)
x
Patient’s Global Impression of Change (PGIC)
x
change from baseline in functional status via Hauser’s PD diary
x
changes from baseline in morning dystonia
x
frequency of use of rescue medication
2.2.3
Safety Endpoints
The safety endpoints of this study are:
x
incidence of adverse events (AEs) including serious adverse events (SAEs); relatedness to 
opicapone and severity will also be evaluated
x
changes from baseline in vital signs
x
changes from baseline in physical and neurological examinations
x
changes from baseline in routine laboratory parameters
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2.3
Overall Study Design
This is a randomised, double-blind, placebo-controlled, multi-centre, parallel group, interventional 
clinical study in PD patients with end-of-dose motor fluctuations and associated pain. The study consists 
of a 1-week screening period, a 24-weeks double-blind treatment period and 2 weeks of follow-up 
period.
At Visit 1, the patient will complete initiation procedures. Moreover, the patient will be provided with 
a paper-based self-rating diary (Hauser’s PD diary) and will be instructed how to complete it.
Completion of Hauser’s PD diary entries will be reviewed at Visit 2a. In case the patient completed the 
diary satisfactorily the investigator will immediately continue with Visit 2b at the same day. If diary 
entries are non-compliant (i.e. more than 3 missing entries per day in the 3 days prior to Visit 2a), the 
patient will be re-trained on the correct use of the diary and Visit 2b will be postponed for 3 to 4 days.
At Visit 2b (Day 1) and if eligibility is confirmed, the patient will be randomised to 50 mg opicapone 
or placebo once daily (1:1) and start treatment in addition to current treatment with L-DOPA/DDCI.
Opicapone enhances the effects of L-DOPA. Hence, it may be necessary to reduce the patient’s 
L-DOPA/DDCI dose within the first days or weeks of opicapone treatment. If dose decrease of 
L-DOPA/DDCI is deemed necessary, it may be adjusted by phone at Visit 3 or an unscheduled on-site 
visit may be performed at the investigator’s discretion. The dosage of L-DOPA/DDCI should not be 
changed from Visit 4 through the end of the study.
No new anti-PD drugs should be started during the study and any that are ongoing at the start of the 
study must be kept at a stable dose throughout the study, unless for safety reasons. No new pain 
medication should be started during the study except the allowed rescue medication. 
Patients who discontinue study participation prematurely will be asked to come to the site for an early 
discontinuation visit (EDV) as soon as possible (not exceeding 7 days after early discontinuation).
2.4
Randomisation
Randomisation will follow a 1:1 allocation rate for each of the treatment arms (50 mg opicapone or 
placebo). No stratification factors were considered for randomisation.
At Visit 1, each patient will be assigned in a chronological order via electronic case report form (eCRF)
to a patient unique number within the study. The patient number will be transferred by the site staff to 
the interactive web response system (IWRS). At Visit 2b, after confirming that the patient is eligible 
for entry into the treatment phase, the site staff will contact the IWRS in order to get the appropriate 
medication number from the system.
Patient recruitment will be competitive. It is possible for clinical study sites with a high recruitment rate 
to enrol more patients. Other clinical study sites could be slow at enrolling.
2.5
Treatments
Each patient will continue with his/her current daily L-DOPA/DDCI dose (3 to 8 daily doses) and will 
additionally take one capsule of IP (opicapone 50 mg as test product of this study or matching placebo) 
once daily for the duration of 24 weeks, starting in the evening of Visit 2b.
Table 1: IP Description
Name of IP
Opicapone
Placebo
Dosage form
Hard capsule
Hard capsule
Active ingredient
Opicapone (BIA 9-1067), (2,5-dichloro-
3-[5-{3,4-dihydroxy-5-nitrophenyl}-
1,2,4-oxadiazol-3-yl]-4,6-
dimethylpyridine 1-oxide)
Not applicable
Strength/concentration
50 mg
Not applicable
The last IP intake will take place in the evening prior to Visit 6. The IP should be taken once daily at 
bedtime, at least 1 hour before or after the last daily dose of L-DOPA/DDCI. The patients will be 
instructed to swallow the capsule whole with a glass of water.
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In case one dose of IP is missed, the next dose should be taken as scheduled. The patient should not 
take a double dose to make up for the missed dose.
Patients are allowed to use rescue medication provided by sponsor:
x
paracetamol (500 mg tablets; 4 g (3 g for German sites) per day at maximum) (unless patient 
already receives tramadol)
x
tramadol (50 mg capsules; 400 mg per day at maximum).
Concomitant use of both types of rescue medication during the same day is not allowed. In case the 
patient needs to switch to tramadol, an unscheduled visit for dispensation of tramadol may be performed 
as required.
2.6
Sample Size
For the primary endpoint (change from baseline in Domain 3 of KPPS), a difference to placebo of 3.0 
is regarded as clinically meaningful and from a former study (Rascol O et al 2016; DOI: 
10.1002/jcph.678) a standard deviation of 5.8 can be assumed in both arm groups. With a two-sided 
significance level α of 0.05, a power of 80%, a 1:1 treatment allocation ratio and with the 
abovementioned assumptions, 2 x 60 = 120 evaluable patients are required. An approximate drop-out 
rate of 15% is assumed, therefore 140 patients need to be randomised.
Post-BDRM note: 144 patients were screened and 127 were randomised. Sample size differs from 
planned because study was early terminated. As the drop-out rate was less than 15%, the early 
termination will not have an impact. A total of 120 evaluable patients were required and 122 subjects 
belong to the full analysis set.
2.7
Blinding
Opicapone and placebo capsules will be identical in size, colour, taste and appearance. The packaging 
and labelling will not allow for any distinction between test and reference drug.
No person involved in conducting the study may have access to the randomisation code before the blind 
is officially broken.
Unblinding will not be done unless an actual emergency occurs, and knowledge of the patient’s 
allocated treatment arm affects his/her medical treatment. If possible, before breaking the blind the 
principal investigator or an authorised delegate consults with the SCOPE 24/7 medical contact to 
ascertain the necessity of breaking the code. The result of unblinding should be kept confidential and 
will not be recorded in the eCRF.
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3.
ANALYSIS SETS AND SUBGROUPS
3.1
Analysis Sets
The Enrolled Set will be defined as all patients who signed informed consent.
The Randomised Set will be defined as all randomised patients.
The Safety Set (SS) will be defined as all patients randomised who took at least one dose of IP. Subjects 
will be analysed according to actual treatment taken.
The Full Analysis Set (FAS) will be defined as all patients who were randomised and who had at least 
one post-baseline assessment of primary efficacy measurement. Subjects will be analysed according to 
randomised treatment.
The Per-Protocol Set (PPS) will be defined as all patients who were included into the FAS and had no 
major protocol deviations that could have an influence on the primary efficacy endpoint. Subjects will 
be analysed according to randomised treatment. Patients that will belong to or will be excluded from
the PPS will be discussed case-by-case by reviewing protocol deviations during Blind Data Review 
(BDR) meeting.
3.2
Subgroups
The following subgroups are defined for primary efficacy analysis:
x
Age group (years): ≤ 65, > 65
x
Modified Hoehn and Yahr Staging: 1 – 2 and 2.5 - 3
x
PD duration (years): ≤ 5, > 5
x
Motor-fluctuations (wearing-off) duration (years): < 2, ≥ 2
x
L-DOPA total dose at baseline (mg): < 600, ≥600.
The primary statistical model will be used for each subgroup analysis. Details are provided in Section 
5.5.1.
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4.
GENERAL DEFINITIONS AND NAMING CONVENTIONS 
In order to avoid ambiguity during the analysis, a number of definitions and conventions for data 
handling are described here.
4.1
General Methodology and Presentation of the Results
The default summary statistics for quantitative (continuous) variables will be 
-
the number of patients (n),
-
the number of patients with missing data (nmiss),
-
mean,
-
standard deviation (SD), 
-
median,
-
first quartile (Q1) and third quartile (Q3),
-
minimum (min) and maximum (max).
Mean, median, and the quartiles will be presented to one more decimal place than the raw value. The 
minimum and maximum values will be presented with the same decimal precision as the raw value. SD 
will be reported to two decimal places greater than the original value.
For qualitative (categorical) variables, the frequency count (n) and percentage (%) of patients with non-
missing data per category will be the default frequency tabulations. Where appropriate and present, the 
number of missing values will be displayed as “Missing” category.
Percentage values such as proportions are to be presented to one decimal place, for example, 52.3%.
The denominator used for calculation of the percentages will be specified in a footnote to the tables for 
clarification.
4.2
Statistical Output Layout
All titles and column headers (consisting of one or several words) will be capitalised; articles, 
prepositions, and conjunctions, and “To” in infinitives will not be capitalised, except they are at the 
beginning of titles or headers.
All pages will be numbered according to the table/listing/figure to which the page belongs to. Every 
table/listing/figure will be numbered from page 1, “Page X of Y” at the bottom of each page.
The definition of baseline and endpoint value will be described in a footnote in every table, listing, 
figure (TLF) where applicable. Other important definitions will also be presented if necessary.
Dates will be listed in the format: yyyy-mm-dd (e.g. 2003-11-20). Times will be listed in the format: 
hh:mm (e.g. 13:15) or in the format hh:mm:ss if seconds are collected. When date and time are collected, 
these are listed in the format: yyyy-mm-ddThh:mm (e.g. 2003-11-20T09:15), yyyy-mm-ddThh, or 
yyyy-mm-ddThh:mm:ss.
Partial missing dates will be listed in the format yyyy-mm (e.g. 2013-11) if only day is missing or in 
the format yyyy (e.g. 2013) if month and day are missing.
Missing data including missing dates or times will be displayed in listings as blank fields, unless 
otherwise specified.
Listings will be sorted by patient number and visit number where applicable, unless specified otherwise.
4.3
Treatment Group Names and Labels
Statistical output will be presented by treatment group and the treatment labels to be used in the tables, 
listings and figures are defined in Table 2 below.
Table 2: Treatment Group Labels
Description
Label in TLFs
Placebo
Placebo
Opicapone 50 mg
Opicapone 50 mg
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4.4
Visit Names and Labels
The names to be used in the analysis datasets and the labels to be used in the tables, listings and figures 
for the different study visits are defined in Table 3 below.
Table 3: Visit Labels
Name
Description
Label in TLFs
Visit 1
Screening visit
Visit 1
Visit 2a
Visit 2a
Visit 2b
Baseline visit
Visit 2b
Visit 3
Visit 3
Visit 4
Visit 4
Visit 5
Visit 5
Visit 6/EDV
End of study visit
Visit 6/EDV*
Follow-up Visit
Follow-up
Follow-up
Unscheduled visits will be labelled as “Unscheduled Visit X.Y”, where X is the previous attended 
scheduled visit, and Y is the number of consecutive unscheduled visits. For example, two unscheduled 
visits after Visit 2b would be labelled as Unscheduled Visit 2b.1 and Unscheduled Visit 2b.2.
* This label is applicable for safety analysis. For efficacy analysis and for data split by periods EDV 
will be assigned as defined in Section 4.8.
4.5
Study Day Numbering
All assessment dates will be related to the date of first IP intake. The date of first IP intake is referred 
to as Day 1. Day –1 is the day preceding Day 1 and Day 0 will not be defined. The numbering is such 
that Day –2 is the day before Day -1, Day 2 is the day after the first IP intake, etc. 
4.6
Study Periods
Baseline period
The baseline period will be defined as the period from informed consent signature date to the first IP 
intake.
Treatment period
The period from the date of first IP intake to the date of last IP intake is defined as the treatment period.
Follow-up period
The follow-up period is a period lasting from the end of the treatment period until study termination 
date.
4.7
Baseline and Endpoint Value
Baseline value
The baseline value for a variable is defined as the last non-missing value collected before the first IP 
intake on the day of Visit 2b.
If a different baseline value will be used, it will be defined in the respective subsection.
Endpoint value
The endpoint value for a variable is defined as value recorded at Visit 6/EDV.
EDV usage rule is defined in Section 4.8.
If a different endpoint value will be used, it will be defined in that subsection.
Absolute change from baseline will be calculated as
ܣܾݏ݋݈ݑݐ݁ܥ݄݂ܽ݊݃݁ݎ݋݉ܤܽݏ݈݁݅݊݁ܽݐܸ݅ݏ݅ݐܺൌܸ݈ܽݑ݁ܽݐܸ݅ݏ݅ݐܺെܤܽݏ݈ܸ݈݁݅݊݁ܽݑ݁
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4.8
Visit Windows
No visit windowing will be applied, and all data will be analysed using the nominal visit number for 
safety analysis.
Use of EDVs Data
Data collected at EDV will be used for efficacy analysis, only if EDV assessments were performed no 
later than 3 days after last IP intake. The EDV which follows the rule will be assigned to the closest 
scheduled post-baseline analysis visit by target day (same visit windows as in Table 4). If the EDV is
assigned to already performed scheduled visit, then non-missing assessment which is closest to the 
target day will be selected for the analysis. Other visits will be used according to analysis time windows 
as in Table 4..
This rule will be used for the total scores and subscores of KPPS, MDS-NMS, MDS-UPDRS and 
PDQ-8 analysis, as well as for the Clinical Global Impression of Change (CGIC), Patient’s Global 
Impression of Change (PGIC) and morning dystonia.
EDV data will be assigned to the closest scheduled post-baseline analysis visit by target day if period 
analysis is needed for change of L-DOPA, rescue diary.
Post-BDRM note:
x
All EDVs allocation to scheduled visit were reviewed case-by-case during the BDR and no 
modifications were needed.
x
The Hauser’s PD diary data will be analysed using analysis windows. Within each analysis time 
window three diary entries closest to the target day will be used for the analysis. See the table 
below for slotting:
Table 4: Visit Slotting
Visit
Visit Schedule (Protocol)
Target Day
Analysis Time Window
Visit 3
8 days ± 2
8
2 to 18
Visit 4
29 days ± 2
29
19 to 56
Visit 5
85 days ± 4
85
57 to 127
Visit 6
169 days ± 4
169
128 to 200
It will be checked that diary filling days for EDV do not exceed 3 days after the last IP intake. If it does 
exceed, those days will not be used in the analysis.
Data from Visit 3 will not be used for efficacy analysis.
4.9
Coding Systems and Conventions
4.9.1
Coding of Adverse Events and Medical History
Adverse event (AE) and medical history investigator terms are assigned to a lowest level term (LLT) 
and a preferred term (PT) and will be classified by high level term (HLT), high level group term (HLGT) 
and system organ class (SOC) according to the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 23.1 [2].
4.9.2
Coding of Medications
Medications are classified according to active drug substance using the World Health Organization
(WHO) drug dictionary WHODrug Global, March 2020 version [3]. The WHO drug code has 11 digits. 
The generic name is defined by the first 6 of the 11 digits. In addition, the Anatomical Therapeutic 
Chemical (ATC) classes are assigned to the drug code. In this study, ATC codes are defined to the 4th
level.
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4.10
Handling of Missing Data
For the primary analysis, missing change from baseline to Visit 6 in Domain 3 of KPPS will be handled 
with mixed model for repeated measures (MMRM) assuming the data is missing at random (MAR).
This missingness mechanism assumes the unobserved data are similar to the observed data. For 
sensitivity purpose, multiple imputation (MI) approach under the assumption that data are missing not 
at random (MNAR) will be used for primary efficacy endpoint. More details about the MI approach 
will be presented in Section 5.5.1.
MI approach will not be performed for secondary efficacy endpoints. 
Missing data regarding safety endpoints will not be imputed and only observed data will be reported 
and analysed.
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5.
STATISTICAL ANALYSIS: DEFINITIONS, DERIVATIONS, CALCULATIONS AND 
METHODOLOGY
5.1
Patient Disposition
5.1.1
Disposition and Withdrawals
The following disposition data will be collected:
-
date of informed consent
-
did the patient complete the study as scheduled (yes, no)
-
reason for premature study termination
Screening failures will be all patients who have been enrolled in the study (informed consent signed) 
but discontinue the study prior to randomisation due to whatever reason.
Withdrawals will be all patients who have been enrolled and, for whatever reason, discontinue the 
study prematurely after randomisation.
Completers will be all patients who completed the treatment phase (from Visit 2b to Visit 6) as 
scheduled, even if no follow-up visit was performed.
Subgroups as defined in Section 3.2 will be summarised.
The following statistical output will be provided:
Table 15.1.1.1 Analysis Sets – Enrolled Set
The number and percentage of patients included in the enrolled, randomised, safety, full analysis and 
per-protocol sets will be provided. Percentages will be based on the number of patients in the 
randomised set.
Table 15.1.1.2 Reasons for Exclusions from Analysis Sets – Randomised Set
The number and percentage of patients excluded from the safety, full analysis and per-protocol sets will 
be provided. Percentages will be based on the number of patients in the randomised set. The reasons of 
exclusion from the analysis sets will be incorporated into the table.
Table 15.1.2 Screening Failures – Enrolled Set
Counts and percentages of patients who discontinued the study during the screening phase prior to 
randomisation will be summarised by reasons associated with the discontinuation. Percentages will be 
based on the number of patients in the enrolled set.
Table 15.1.4 Patient Disposition – Safety Set
Counts and percentages of patients who completed the treatment phase as scheduled or as withdrawals 
during the treatment phase will be summarised. Reasons for discontinuation will be included. 
Percentages will be based on the number of patients in the safety set.
Table 15.1.5 Number of Patients by Country and Site – Randomised Set
Counts and percentages of patients in each country and site. Percentages will be based on the number 
of patients in the respective analysis set.
Table 15.1.6 Number of Patients by Visit – Safety Set
Counts and percentages of patients attending each scheduled visit will be presented. Percentages will 
be based on the number of patients in the safety set.
Table 15.1.7.1 Summary of Subgroups – Full Analysis Set
Table 15.1.7.2 Summary of Subgroups – Per-Protocol Set
Counts and percentages of patients in each subgroup will be presented. Percentages will be based on 
the number of patients in the respective analysis set.
Figure 15.1.1 Flow Chart of Patient Disposition – Enrolled Set
The number of enrolled, randomised patients and completers will be displayed. The number of 
screening failures and withdrawals as well as their reasons will also be summarised.
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Figure 15.1.2 Flow Chart of Analysis Sets – Enrolled Set
The number of patients in each analysis set will be displayed.
Listing 16.2.1.1 Patient Disposition – Safety Set
Patients who enter the treatment period and complete the study as scheduled or as withdrawal will be 
listed. Reasons for premature study termination will be displayed for withdrawals.
Listing 16.2.1.2 Screening Failures – Enrolled Set
Patients who discontinued the study prior to the randomisation will be listed. Reasons associated with 
the discontinuation will be displayed.
Listing 16.2.1.3 Patient Visits – Enrolled Set
All visit dates will be listed by patient.
Listing 16.2.1.4 Exclusions from Analysis Sets – Enrolled Set
Patients excluded from any analysis set and corresponding reasons for exclusion will be listed.
Listing 16.2.1.5 Patient Allocation to Treatments – Randomised Set
Randomisation codes and treatment allocations will be listed for all randomised patients.
5.1.2
Protocol Deviations
Protocol deviations are deviations from the procedures outlined in the clinical study protocol or from 
subsequent protocol-related instructions like missed evaluations, incorrect timing of evaluations, non-
compliance with IP and intake of prohibited medications or any non-adherence to the clinical study
protocol that impacts patient’s rights, safety or welfare.
Major protocol deviations will be summarised. Protocol deviations will be evaluated as major or minor 
during Blind Data Review (BDR) (See Section 6).
The following statistical output will be provided:
Table 15.1.3 Major Protocol Deviations – Full Analysis Set
The number and percentage of patients with major protocol deviations will be summarised by treatment 
and overall. The categories of major protocol deviations will be included. Percentages will be based on 
the number of patients in the respective analysis set.
Listing 16.2.1.6 Major Protocol Deviations – Safety Set
Patients with major protocol deviations will be listed.
5.1.3
Inclusion/Exclusion
The study specific inclusion/exclusion criteria are presented in Section 9.2 and 9.3 of the clinical study 
protocol. For each criterion, as appropriate, a response of “Yes/No/NA (only for exclusion criterion no. 
17)” is to be obtained at screening and checked again prior to randomisation at Visit 2b.
The following statistical output will be provided:
Listing 16.2.1.7 Inclusion Criteria Not Met and Exclusion Criteria Met – Enrolled Set
Inclusion criteria which were not met and exclusion criteria which were met will be listed.
5.2
Demographic and Other Baseline Characteristics
5.2.1
Demographics
The following demographic characteristics will be presented:
-
Age
-
Gender (Male, Female)
-
Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian 
or Other Pacific Islander, White, Unknown)
-
Childbearing potential
-
Height (cm)
-
Weight (kg).
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Body mass index (BMI) will be calculated as:
ܤܯܫሺȀ݉ଶሻൌ
ௐ௘௜௚௛௧ሺ௞௚ሻ
ு௘௜௚௛௧ሺ௠ሻమ   and presented to 1 decimal precision.
The following statistical output will be presented:
Table 15.1.8.1 Demographics and Baseline Characteristics – Safety Set
Table 15.1.8.2 Demographics and Baseline Characteristics – Full Analysis Set
Table 15.1.8.3 Demographics and Baseline Characteristics – Per-Protocol Set
Demographic data, weight, height and BMI will be summarised for each treatment group in the specified
set. Overall summary will also be included. Percentages for categorical variables will be based on the
number of patients in the respective analysis set.
Listing 16.2.1.8 Demographics and Baseline Characteristics – Enrolled Set
Demographic and baseline characteristic data will be listed for patients in the enrolled set.
5.2.2
Neurological History
The following information about the PD history and status at baseline will be collected:
-
Date of PD diagnosis
-
Start date of wearing-off motor fluctuations
-
Start date of PD associated pain
-
Modified Hoehn & Yahr staging at ON (stages: 0, 1, 1.5, 2, 2.5, 3, 4, 5)
Time since diagnosis, time since wearing-off motor fluctuations and time since associated pain will 
be calculated as follows:
Time since parameter (years) = (Visit 1 date - Date of parameter)/365.25
In case of incomplete date, one of the following will be imputed: 
-
The 15th day of the month will be used if the month and year are available, but the day is 
missing.
-
If year is available, but month and day are missing, 2nd of July will be imputed. If the year of 
the incomplete date coincides with the year of Visit 1, then the 1st of January will be imputed.
-
If the year is missing, time since will not be calculated.
The following statistical output will be presented:
Table 15.1.9.1 Summary of Neurological History – Safety Set
Table 15.1.9.2 Summary of Neurological History – Full Analysis Set
Table 15.1.9.3 Summary of Neurological History – Per-Protocol Set
Time since diagnosis, time since wearing-off motor fluctuations, time since PD associated pain and 
modified Hoehn & Yahr staging will be summarised in the respective analysis set.
Listing 16.2.1.9 Neurological History – Enrolled Set
Parkinson’s disease characteristic data will be listed for patients in the enrolled set.
5.2.3
Medical History
Medical history encompasses relevant prior or ongoing relevant diseases, conditions, hospitalisation 
and surgical procedures. Medical history records are collected at Visit 1.
Medical history of the patients includes:
-
Medical condition/procedure
-
Start date
-
Stop date
-
Ongoing
-
Treatment used (yes, no)
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Medical history is classified as:
-
Prior conditions are the conditions which started and ended prior to Visit 1.
-
Ongoing conditions are the conditions which are marked as ongoing at Visit 1 or with a stop 
date at or after Visit 1
If the stop date of a medical history condition is incomplete or missing, it will be assumed to be ongoing 
except if the incomplete stop date indicates that the condition stopped prior to Visit 1.
The following statistical output will be provided:
Table 15.1.10.1.1 Prior Medical Conditions – Safety Set
Table 15.1.10.1.2 Prior Medical Conditions – Full Analysis Set
Table 15.1.10.2.1 Ongoing Medical Conditions – Safety Set
Table 15.1.10.2.2 Ongoing Medical Conditions – Full Analysis Set
Medical history will be summarised displaying counts and percentages of patients having at least one 
medical condition and will be presented by primary System Organ Class (SOC) and by Preferred Term 
(PT) within SOC. SOCs and PT within SOC are to be sorted by descending order of overall incidence. 
Patients with two or more occurrences of the same condition (as qualified by its PTs) will be counted 
only once for the respective PT. Percentages will be based on the number of patients in the respective 
analysis set.
Listing 16.2.1.10 Medical History – Enrolled Set
Medical history conditions will be listed for patients in the enrolled set.
5.3
Prior and Concomitant Medications
Prior and concomitant medications and therapies are documented in the eCRF.
The following information is collected:
-
Medication/ therapy
-
Indication
-
Route
-
Total daily dose
-
Units
-
Frequency
-
Start date of medication
-
Stop date of medication
-
Ongoing (yes, no)
Medications will be classified as ‘prior’, ‘concomitant’ or ‘post-treatment’ based on start/stop dates:
-
Prior medications are defined as those medications starting and ending prior to the first IP 
intake.
-
Concomitant medications are defined as medications started at or after first IP intake but 
before the last IP intake and include medications started prior to the first IP intake but 
continued after the first IP intake.
-
Post-treatment medications are defined as medications/therapies which started after the last 
IP intake.
If the start or stop date of a medication is incomplete or missing, it will be assumed to be concomitant 
except if the incomplete start or stop date indicates that the medication stopped prior to the first IP 
intake or started after the last IP intake.
Moreover, tramadol taken within 30 days before the endpoint will be summarised separately.
Additionally, L-DOPA/DDCI medication usage will be documented at Visit 1 and afterwards any 
change will be documented, if applicable. The following data are collected:
-
Start date of L-DOPA/DDCI treatment
-
Medication/ therapy
-
Indication
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Route
-
Total daily dose
-
Units
-
Frequency
-
Start date of medication
-
Stop date of medication
-
Ongoing (yes, no)
-
L-DOPA/DDCI dose adjusted since previous visit
-
Slow release formulation:
x
Time of intake (morning, during day-time, evening)
x
Total daily dose
x
Units
L-DOPA/DDCI dose could be adjusted until Visit 4.
The following statistical output will be provided:
Table 15.1.11.1.1 Prior Medications – Safety Set
Table 15.1.11.1.2 Prior Medications – Full Analysis Set
Table 15.1.11.2.1 Concomitant Medications – Safety Set
Table 15.1.11.2.2 Concomitant Medications – Full Analysis Set
Table 15.1.11.3.1 L-DOPA/DDCI Medication – Safety Set
Table 15.1.11.3.2 L-DOPA/DDCI Medication – Full Analysis Set
The number and percentage of patients with at least one medication within each ATC 2nd level subgroup 
and substance name (or combination of substances) will be presented by treatment and overall for the 
respective set. The ATC 2nd level subgroups and substance names within ATC 2nd level subgroup will 
be ordered by descending overall incidence.
Table 15.1.11.4 Tramadol Taken Within 30 Days Before the Endpoint – Safety Set
Number of subjects using tramadol within 30 days before the endpoint will be counted in safety set, full 
analysis set and per-protocol. Percentage will be based on each analysis set.
Table 15.1.11.5.1 Change of L-DOPA/DDCI Medication – Safety Set
Table 15.1.11.5.2 Change of L-DOPA/DDCI Medication – Full Analysis Set
Table 15.1.11.5.3 Change of L-DOPA/DDCI Medication – Per-Protocol Set
Change of L-DOPA/DDCI dose by adjustment type from Visit 2b to Visit 4, and from Visit 4 to Visit 
6 will be presented for patients in the specified analysis set. Moreover, L-DOPA/DDCI dose per day 
and number of intakes will be summarised at all visits.
Listing 16.2.1.11 Medications – Enrolled Set
All medications, prior, concomitant and subsequent, will be listed for patients in the enrolled set.
Listing 16.2.1.12.1 L-DOPA/DDCI Medications – Enrolled Set
L-DOPA/DDCI medications will be listed for patients in the enrolled set.
Listing 16.2.1.12.2 Change of L-DOPA/DDCI Medications – Safety Set
L-DOPA/DDCI adjustment will be listed for patients in the safety set.
5.4
Exposure to IP and Rescue Medication and Compliance
5.4.1
Exposure to IP
Exposure data from eCRF include:
-
Date/ Time of the first IP intake
-
Date of last IP intake
-
Start/ Stop interruption date
-
IP interruption cause (AE number)
Following information will be delivered by IWRS provider:
-
Kit no.
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


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-
Number of dispensed/ returned IP capsules
Post-BDRM note:
It was decided that in case of a partial or missing last IP intake date the following imputation rules will 
be applied:
•
In case of a partially missing last IP intake date the last visit date (excluding follow-up visit) 
minus 1 day or the last day of month whichever is earlier will be used.
•
In case of a completely missing last IP intake date the last visit date (excluding follow-up visit) 
minus 1 day will be used.
The list of imputed last IP dates is provided below:
•
Subject: 44402 – Date: 2021-10-28
•
Subject: 48401 – Date: 2021-08-15
•
Subject: 48502 – Date: 2022-09-30
The overall treatment duration and actual treatment duration in days will be calculated as follows:
Overall treatment duration (days) = Date of last IP intake – Date of first IP intake + 1
Actual treatment duration (days) = Overall treatment duration – Total interruption duration
Each not overlapping treatment interruption duration will be calculated as:
Stop date of interruptioni - Start date of interruptioni + 1
If treatment duration overlaps, then not already calculated days will be added to interruption duration.
The following statistical output will be provided:
Table 15.1.12.1.1 Treatment Duration – Safety Set
Table 15.1.12.1.2 Treatment Duration – Full Analysis Set
Table 15.1.12.1.3 Treatment Duration – Per-Protocol Set
The default summary statistics of treatment duration will be presented.
Listing for exposure and IP interruption data will be present with compliance data in Section Error! 
Reference source not found..
5.4.2
IP Compliance
Treatment compliance will be calculated as:
ܱݒ݁ݎ݈݈ܽܿ݋݉݌݈݅ܽ݊ܿ݁ሺΨሻൌሺܰ݋݂ܿܽ݌ݏݑ݈݁ݏ݀݅ݏ݌݁݊ݏ݁݀െܰ݋݂ܿܽ݌ݏݑ݈݁ݏݎ݁ݐݑݎ݊݁݀ሻ
ܱݒ݁ݎ݈݈ܽݐݎ݁ܽݐ݉݁݊ݐ݀ݑݎܽݐ݅݋݊
ൈͳͲͲ
Post-BDRM note: The listing of all subjects who lost at least one IP kit including explanation and 
decision can be found in Appendix 3. This appendix will be used to correct drug accountability data.
If from the explanation presented in the PD log/ query it is not possible to identify the lost number of 
capsules, compliance will not be calculated. In case a subject discontinued the study due to lost to 
follow-up reason, lost kits will be counted as not used.
Compliance will be categorised as:
-
< 80%
-
≥ 80% and ≤ 120%
-
> 120%
-
Missing
The following statistical output will be provided:
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


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Table 15.1.12.2.1 Treatment Compliance – Safety Set
Table 15.1.12.2.2 Treatment Compliance – Full Analysis Set
Table 15.1.12.2.3 Treatment Compliance – Per-Protocol Set
The default summary statistics of compliance will be presented by treatment group and overall. The 
number and percentage of patients within each compliance category (< 80%, ≥ 80%, ≤ 120%, > 120%
and Missing) will also be summarised. Percentages will be based on the number of patients in the
corresponding analysis set.
Listing 16.2.2.1 Exposure to IP and Treatment Compliance – Safety Set
Drug accountability data as well as their overall compliance will be displayed for each patient in the 
safety set.
5.4.3
Exposure to Rescue Medication
The rescue medication (paracetamol or tramadol) will be dispensed at Visit 2b, Visit 4 and Visit 5.
Following information will be delivered by IWRS provider:
-
Type of rescue medication
-
Number of dispensed/ returned rescue medication tablets/ capsules
Detailed description of usage of rescue medication is provided in Section 5.5.2.8.
The following statistical output will be provided:
Listing 16.2.2.2 Exposure to Rescue Medication – Safety Set
Drug accountability of rescue medication data will be displayed for each patient in the safety set.
5.5
Efficacy Analysis
Efficacy analysis of the primary endpoint will be based on the FAS and PPS (under MAR assumption 
for primary evaluation and MNAR for sensitivity purposes). The efficacy of the secondary endpoints 
will be based on the FAS and PPS.
5.5.1
Primary Efficacy Analysis
The King’s Parkinson’s Disease Pain Scale (KPPS) evaluates the burden (global and bedside) and 
characterises various phenotypes of pain in PD. Its seven domains include 14 items, each item scored 
by severity (0-3) multiplied by frequency (0-4), resulting in subscores of 0 to 12. The total possible 
KPPS score (0 to 168) represents the symptomatic burden by pain. The questionnaire will be fill out on 
Visit 1, Visit 2b, Visit 4, Visit 5 and Visit 6/EDV.
The primary efficacy endpoint of this study is the change from baseline to Visit 6/EDV in the Domain 3 
of KPPS. The Domain 3 is about fluctuation-related pain and consists of 3 questions and the total 
possible Domain 3 score ranges from 0 to 36. The primary efficacy endpoint will be analysed using a 
two-sided alpha 0.05 using a mixed model for repeated measures (MMRM) assuming the unobserved 
data is missing at random (MAR) to demonstrate differences in the fluctuation-related pain score 
between opicapone 50 mg and placebo in addition to current treatment with L-DOPA/DDCI for PD
patients with end-of dose motor fluctuations and associated pain.
The following statistical hypotheses will be tested:
H0: μT = μC
H1: μT ≠μC
where μT is mean change in Domain 3 of KPPS from baseline in the opicapone treatment arm and μC is 
mean change in Domain 3 of KPPS from baseline in the placebo arm. For the rational used under the
sample size and hypotheses see section 2.6.
Only subjects without missing baseline score will be used for analysis using MMRM. The MMRM is 
longitudinal approach which analyse data as collected (including missing values). Analyses will include 
the fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the 
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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continuous, fixed covariates of baseline score. The two-sided test estimated results with alpha level of 
0.05 will be provided. 
An unstructured variance structure will be used to model the within-patient errors. If this analysis fails 
to converge, the following structures will be tested in order defined below until model convergence is 
reached:
-
Heterogeneous Toeplitz
-
Heterogeneous autoregressive
-
Toeplitz
-
Autoregressive
-
Compound symmetry
-
Variance components
The Kenward-Roger approximation will be used to estimate degrees of freedom.
Following SAS code will be used to fit MMRM model:
PROC MIXED DATA = <DATASET>;
CLASS <TREATMENT> <VISIT> <SUBJECT ID>;
MODEL <CHANGE FROM BASELINE> = <TREATMENT> <VISIT> <BASELINE>
<TREATMENT>*<VISIT> / S DDFM=KENROG;
REPEATED <VISIT> / TYPE=<UN> SUBJECT=<SUBJECT ID>;  
LSMEANS <TREATMENT>*<VISIT> / CL PDIFF;
RUN;
Moreover, exploratory analysis of each subgroup as defined in Section 3.2 will be performed. The 
primary model as described above will be used by each subgroup. In addition, forest plots will be
generated representing the difference of LS Means and corresponding 95% CI.
For sensitivity purposes, missing data for the primary efficacy endpoint will be imputed using MI under 
the missing not at random (MNAR) assumption by creating control-based pattern imputation, assuming 
that those subjects who have missing data will behave as if they were taking placebo (worst-case 
scenario). The missing efficacy endpoint data at Visit 4, Visit 5, Visit 6 will be imputed using pattern 
mixture models. The regression method will be used which fits a regression model. Based on the fitted 
regression model, a new regression model is simulated and used to impute the missing values for each 
variable. The number of imputations will be at least 100.
The variables to be used in the MI are treatment, baseline score, and observed values at appropriate 
visits. Observations from the placebo group will be used to impute the missing data.
The following SAS code will be used for imputations: 
PROC MI DATA=<DATASET> SEED=14442 NIMPUTE=100 OUT=<OUTPUT DATASET>
ROUND =. . 1 1 1
MINIMUM =. . 0 0 0
MAXIMUM =. . 36 36 36;
CLASS <TREATMENT>;
FCS REG(/ DETAILS);
MNAR MODEL (<VISIT 4> <VISIT 5> <VISIT 6> /
MODELOBS=(<TREATMENT>=”PLACEBO”));
VAR <BASELINE VALUE> <VISIT 4> <VISIT 5> <VISIT 6>;
RUN;
The MMRM model described earlier will be applied to each of the imputed datasets, and the resulting 
least squares (LS) means/LS means differences and including their respective standard errors will be 
aggregated and further evaluated using the following SAS statements:
PROC MIANALYZE DATA = <DATASET>;
MODELEFFECTS <LS MEAN ESTIMATES/LS MEAN DIFFERENCE ESTIMATES>; 
STDERR <LS MEAN STANDARD ERRORS/LS MEAN DIFFERENCE STANDARD ERRORS>;
RUN;
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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Additional sensitivity analysis of rescue medication impact to the primary efficacy endpoint will be 
performed. MMRM model will be used for analysis. Details will be specified during BDR meeting.
Post-BDRM note: It was decided that sensitivity analysis of rescue medication impact to the primary 
efficacy endpoint will be conducted if more than 10% of subjects were using tramadol during the last 
30 days prior to the primary endpoint. As in total only 12 subjects used tramadol 30 days before 
V6/EDV the sensitivity analysis will not be performed as 12 out of 122 subjects correspond to 9.8%.
The following statistical output will be provided:
Table 15.2.1.1.1.1 Summary of KPPS – Full Analysis Set
Table 15.2.1.1.1.2 Summary of KPPS – Per-Protocol Set
The KPPS domains and total scores will be summarised by visit, including changes from baseline, using 
default summary statistics.
Table 15.2.1.1.2.1 Summary of the Domain 3 of KPPS by Subgroup – Full Analysis Set
Table 15.2.1.1.2.2 Summary of the Domain 3 of KPPS by Subgroup – Per-Protocol Set
The KPPS domain 3 score will be summarised using default summary statistics by each subgroup and 
visit, including changes from baseline.
Table 15.2.1.2.1.1 Analysis of the Domain 3 of KPPS – Full Analysis Set
Table 15.2.1.2.1.2 Analysis of the Domain 3 of KPPS – Per-Protocol Set
Table 15.2.1.2.2.1 Analysis of the Domain 3 of KPPS (MI) – Full Analysis Set
Table 15.2.1.2.2.2 Analysis of the Domain 3 of KPPS (MI) – Per-Protocol Set
Table 15.2.1.2.3.1 Analysis of the Domain 3 of KPPS by Subgroup – Full Analysis Set
Table 15.2.1.2.3.2 Analysis of the Domain 3 of KPPS by Subgroup – Per-Protocol Set
The LS means associated with treatments and treatment differences will be presented with 95% 
confidence intervals and corresponding p-value for each visit for the Domain 3 of KPPS.
Figure 15.2.1.1 Domain 3 of KPPS Change from Baseline LS-Means by Visit – Full Analysis Set 
Figure 15.2.1.2 Domain 3 of KPPS Change from Baseline LS-Means by Visit – Per-Protocol Set 
A line chart with error bars will be used to display the LS-means and 95% confidence intervals.
Figure 15.2.2.1 Forest Plot of Domain 3 of KPPS by Subgroup – Full Analysis Set 
Figure 15.2.2.2 Forest Plot of Domain 3 of KPPS by Subgroup – Per-Protocol Set 
Forest plots will be used to display difference of LS Means and 95% CI for Visit 6 by each subgroup. 
Primary model difference of LS Means, and 95% CI will be included as well.
Listing 16.2.3.1 KPPS – Enrolled Set 
KPPS data and total score will be displayed for each patient in the enrolled set.
5.5.2
Analysis of Secondary Variables
The secondary variables will be tested in an exploratory manner and p-values will not be considered 
confirmatory. No multiplicity adjustments will be conducted. Same MMRM models with MAR 
assumption defined for the primary analysis will be fitted for the next secondary efficacy endpoints: 
total score and Domain 4 of KPSS, Domain A, Domain B, Domain K and total score of MDS-NMS, 
MDS-UPDRS part III and part IV separately, and PDQ-8. The LS means associated with treatments 
and treatment differences will be presented with 95% confidence intervals and corresponding p-values 
for each visit.
5.5.2.1
Total Score and Domain 4 of KPPS
The KPPS questionnaire description, summary and listing are already presented in Section 5.5.1.
Domain 4 consists of 2 questions about nocturnal pain.
Change from baseline in total score and Domain 4 score will be analysed using MMRM as described 
in Section 5.5.1.
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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The following statistical output will be provided:
Table 15.2.2.1.1 Analysis of the Domain 4 of KPPS – Full Analysis Set
Table 15.2.2.1.2 Analysis of the Domain 4 of KPPS – Per-Protocol Set
Table 15.2.2.2.1 Analysis of KPPS Total Score – Full Analysis Set
Table 15.2.2.2.2 Analysis of KPPS Total Score – Per-Protocol Set
The LS means associated with treatments and treatment differences will be presented with 95% 
confidence intervals and corresponding p-values.
5.5.2.2
Movement Disorder Society-sponsored Non-motor Rating Scale
The Movement Disorder Society-sponsored Non-motor Rating Scale (MDS-NMS) consists of 
13 domains: depression (A), anxiety (B), apathy (C), psychosis (D), impulse control and related 
disorders (E), cognition (F), orthostatic hypertension (G), urinary (H), sexual (I), gastrointestinal (J), 
sleep and wakefulness (K), pain (L), other (M). In addition, a subscale for non-motor fluctuations to 
assess changes in non-motor symptoms in relation to the timing of anti-PD medications across 8 
domains. 
The MDS-NMS will be filled out at Visit 2b, Visit 4, Visit 5 and Visit 6/EDV.
Each questionnaire item is scored for frequency and severity:
-
Frequency:
0
Never
1
Rarely
2
Sometimes
3
Frequently
4
Majority of time
-
Severity
0
Not present
1
Minimal
2
Mild
3
Moderate
4
Severe
Then item score is calculated as frequency multiplied by severity. A domain total score will be 
calculated as sum of all items. If any item score is missing, then corresponding domain score will not 
be calculated.
The total score will be calculated by summing the domains from A to M. In case, where any domain 
score is missing, then total score will not be calculated.
The lower total scores represent better quality of life.
Change from baseline in total score, domain A (depression), domain B (anxiety) and domain K (sleep 
and wakefulness) score will be analysed using MMRM as described in Section 5.5.1.
The following statistical output will be provided:
Table 15.2.3.1.1 Summary of MDS-NMS – Full Analysis Set
Table 15.2.3.1.2 Summary of MDS-NMS – Per-Protocol Set
The MDS-NMS domains and total scores will be summarised by visit, including changes from baseline, 
using default summary statistics.
Table 15.2.3.2.1 Analysis of MDS-NMS – Full Analysis Set
Table 15.2.3.2.2 Analysis of MDS-NMS – Per-Protocol Set
The LS means associated with treatments and treatment differences will be presented with 95% 
confidence intervals and corresponding p-values for each visit using MDS-NMS total score, Domain 
A, Domain B and Domain K score.
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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Listing 16.2.3.2 MDS-NMS – Enrolled Set 
MDS-NMS each question of domain, domain and total scores will be displayed for each patient in the 
enrolled set.
5.5.2.3
Movement Disorder Society-sponsored Unified Parkinson’s Disease Rating Scale
The Movement Disorder Society-sponsored Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) 
consists of 4 parts:
x
Part IA and IB: Non-Motor Aspects of Experiences of Daily Living (nM-EDL) (13 questions)
x
Part II: Motor Aspects of Experiences of Daily Living (M-EDL) (13 questions)
x
Part III: Motor Examination (33 items based on 18 questions)
x
Part IV: Motor Complications (6 questions).
Part I and Part II will be filled out only once at Visit 2b. Part III and Part IV will be filled out at Visit 2b, 
Visit 4, Visit 5 and Visit 6/EDV. Every item can be scored on a 5-point scale: 0 (“normal”), 1 (“slight”), 
2 (“mild”), 3 (“moderate”), 4 (“severe”), with higher scores indicating more severe impairment. The 
maximum total MDS-UPDRS score is 260, indicating the worst possible disability from PD.
The total score for each part will be calculated as the sum of each item. According to Goetz et al. [4], 
valid score for the MDS-UPDRS parts can be calculated if the respective part contains a number of 
missing values less than or equal to the following:
x
Part I – 1
x
Part II – 1
x
Part III – 3
x
Part IV – 0
For patients with partially missing data, a prorated score will be calculated by taking the mean of the 
observed scores and multiplying it by the total number of items in each part. The prorated score will be 
rounded to the nearest whole number. Otherwise, total score for that part will be set to missing.
Change from baseline in Part III and Part IV will be analysed using MMRM as described in Section 
5.5.1
The following statistical output will be provided:
Table 15.2.4.1.1 Summary of MDS-UPDRS – Full Analysis Set
Table 15.2.4.1.2 Summary of MDS-UPDRS – Per-Protocol Set
The MDS-UPDRS parts and total scores will be summarised by visit, including changes from baseline, 
using default summary statistics.
Table 15.2.4.2.1 Analysis of MDS-UPDRS Part III/IV Total Score – Full Analysis Set
Table 15.2.4.2.2 Analysis of MDS-UPDRS Part III/IV Total Score – Per-Protocol Set
The LS means associated with treatments and treatment differences will be presented with 95% 
confidence intervals and corresponding p-values.
Listing 16.2.3.3.1 MDS-UPDRS – Enrolled Set 
MDS-UPDRS items and total scores will be displayed for each patient in the enrolled set.
Listing 16.2.3.3.2 MDS-UPDRS Part III Additional Information – Enrolled Set 
MDS-UPDRS part III additional information about medication, clinical state, dyskinesias impact, 
Hoehn and Yahr stage will be displayed for each patient in the enrolled set.
5.5.2.4
Parkinson’s Disease Questionnaire
The Parkinson’s Disease Questionnaire (PDQ-8) will be filled out at Visit 2b, Visit 4, Visit 5 and Visit 
6/EDV. The questionnaire contains eight aspects: mobility, activities of daily live, emotional well-
being, stigma, social support, cognitions, communication and bodily discomfort. Every question is rated 
on a 5-point scale: 0 (“never”), 1 (“occasionally”), 2 (“sometimes”), 3 (“often”), 4 (“always or cannot 
do at all”). The PDQ-8 index will be calculated as follows:
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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PDQ-8 index ൌ
ௌ௨௠௢௙௜௧௘௠௦
ெ௔௫௜௠௨௠௣௢௦௦௜௕௟௘௦௖௢௥௘ൈͳͲͲ,
where the maximum possible score is 32. If one item answer is missing, then PDQ-8 index will not be 
calculated. The higher index scores indicate more difficulty due to having PD.
Change from baseline in PDQ-8 index will be analysed as described in Section 5.5.1.
The following statistical output will be provided:
Table 15.2.5.1.1 Summary of PDQ-8 Index – Full Analysis Set
Table 15.2.5.1.2 Summary of PDQ-8 Index – Per-Protocol Set
The PDQ-8 index will be summarised by visit, including changes from baseline, using default summary 
statistics.
Table 15.2.5.2.1 Analysis of PDQ-8 Index – Full Analysis Set
Table 15.2.5.2.2 Analysis of PDQ-8 Index – Per-Protocol Set
The LS means associated with treatments and treatment differences will be presented with 95% 
confidence intervals and corresponding p-values.
Listing 16.2.3.4 PDQ-8 – Enrolled Set
PDQ-8 items and index will be displayed for each patient in the enrolled set.
5.5.2.5
Clinical Global Impression of Change and Patient’s Global Impression of Change
The Clinical Global Impression of Change (CGIC) scale requires the investigator to assess how much 
the patient’s overall status has improved or worsened since the start of the study. The Patient’s Global 
Impression of Change (PGIC) consists of a general evaluation of patient own overall status in 
comparison to the start of the study. Both questionnaires will be evaluated at Visit 4, Visit 5 and 
Visit 6/EDV. 
The CGIC and PGIC will be rated on a 7-point scale: 1 (“very much improved”), 2 (“much improved”), 
3 (“minimally improved”), 4 (“no change”), 5 (“minimally worse”), 6 (“much worse”), 7 (“very much 
worse”).
Improvement analysis will be performed. Parameters will be categorised into 2 groups based on 
response given: improved (which include answers from 1 to 3) and not improved (answers from 4 to 7).
The number of responses (improved vs. not improved) will be compared among two treatment groups 
using Fisher’s exact test. The following SAS code will be used:
PROC FREQ DATA = <DATASET>;
TABLES <TREATMENT>*<CATEGORY> / FISHER OR;
RUN;
The following statistical output will be provided:
Table 15.2.6.1.1 Summary of CGIC and PGIC – Full Analysis Set
Table 15.2.6.1.2 Summary of CGIC and PGIC – Per-Protocol Set
CGIC and PGIC will be summarised for each visit where assessments were made.
Table 15.2.6.2.1 Improvement Analysis of CGIC and PGIC – Full Analysis Set
Table 15.2.6.2.2 Improvement Analysis of CGIC and PGIC – Per-Protocol Set
Improvement groups of CGIC and PGIC will be summarised for each visit where assessments were 
made. Odds ratio, 95% CI and P-values of Fisher’s exact test by visit will be provided. 
Listing 16.2.3.5 CGIC and PGIC – Safety Set 
The CGIC and PGIC data will be displayed for each patient in the safety set.
5.5.2.6
Hauser’s Parkinson Disease Diary
Functional status will be assessed via the Hauser’s PD diary. Patient’s will categorise their status every 
half-hour interval of the 24-hour day as: asleep, OFF, ON without dyskinesia, ON with non-troublesome 
dyskinesia, ON with trouble dyskinesia. The diary must be completed on the 3 days before Visit 2a, 
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
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Effective date: 15.09.2020
Visit 2b (only if diary is not completed as instructed [more than 3 missing entries per day] at Visit 2a), 
Visit 4, Visit 5 and Visit 6/EDV.
The average ON/OFF-times of the last 3 diary days within 7 days before Visit 2a/ Visit 2b will be 
considered as the baseline value.
The average ON/OFF-time at each post-baseline visit will be calculated based on 3 diary entries closest 
to the target day within the analysis time window as defined in Section 4.8
The diary day begins at 6 AM and ends at 5:30 AM of the next day.
Percentage ON/OFF-time at baseline and each visit will be calculated as the ON/OFF-time as defined 
above, divided by the total time awake (calculated as the addition of all 30-minute periods in each day 
where the patient has recorded any state other than asleep).
If only diary data from less than 3 days are available for visit, the mean of the data from the available 
days will be used.
Handling of missing data:
If a day has less than 8 hours assessable waking time that day will be set to missing. In all other cases 
and in case of inconsistencies in the data, the following rules will be applied:
x
If multiple states are recorded for one 30-minute period, the 30 minutes of the period will be 
equally divided among the multiple states, i.e. time with state X = 30 minutes / number of states 
recorded for this period.
x
If a single entry of 30 minutes is missing within a day, adjacent available diary values carried 
forward and backward will be used for imputation of the missing record, i.e. 15 minutes will 
be allocated to the state of the adjacent periods, each. If any of the adjacent periods had multiple 
states recorded, these 15 minutes will be equally divided among the multiple states.
x
If the first or last 30 minutes period of a day is missing, the state recorded immediately after or 
prior to this period, respectively, will be used for imputation of the missing record, using the 
same algorithm as described above.
x
If two or more consecutive 30 minutes periods are missing within a day, these will not be 
imputed but set to missing.
Additionally, ON without troublesome dyskinesia will be summarised as ON with non-troublesome
dyskinesia + ON without dyskinesia and ON-time will be summarised as ON without dyskinesia + ON 
with non-troublesome dyskinesia + ON with troublesome dyskinesia.
Responder analysis will be performed as:
x
OFF-time responders: 1 hour or more reduction in OFF-time from baseline to each post-
baseline visits.
x
ON-time responders: 1 hour or more increase in ON-time from baseline to each post-baseline 
visit.
In addition, 1.5, 2, 2.5 hours reduction in OFF-time and increase in ON-time from baseline to all 
post-baseline visits will be calculated.
The following statistical output will be provided:
Table 15.2.7.1.1 Summary of Functional Status (Time in Minutes) – Full Analysis Set
Table 15.2.7.1.2 Summary of Functional Status (Time in Minutes) – Per-Protocol Set
OFF, ON, ON with troublesome dyskinesia, ON without troublesome dyskinesia, ON with non-
troublesome dyskinesia, ON without dyskinesia, asleep and change from baseline will be summarised 
for baseline and endpoint.
Table 15.2.7.2.1 Summary of Functional Status (Percentage) – Full Analysis Set
Table 15.2.7.2.2 Summary of Functional Status (Percentage) – Per-Protocol Set
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6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


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Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 31 of 49
Effective date: 15.09.2020
OFF, ON, ON with troublesome dyskinesia, ON without troublesome dyskinesia, ON with non-
troublesome dyskinesia, ON without dyskinesia and change from baseline will be summarised for 
baseline and endpoint.
Table 15.2.7.3.1 Responder Analysis of OFF-time and ON-time – Full Analysis Set
Table 15.2.7.3.2 Responder Analysis of OFF-time and ON-time – Per-Protocol Set
OFF-time reduction and ON-time increase from baseline to each post-baseline visit will be summarised 
by defined responder categories.
Listing 16.2.3.6.1 Hauser’s Parkinson’s Disease Diary – Enrolled Set
Hauser’s Parkinson’s Disease Diary data will be listed for each patient in enrolled set.
Listing 16.2.3.6.2 Hauser’s Parkinson’s Disease Diary Analysis Parameters – Enrolled Set
Hauser’s Parkinson’s Disease Diary analysis parameters will be listed for each patient in enrolled set 
by analysis visit.
5.5.2.7
Morning Dystonia
Patients will be asked if they experienced any morning dystonia within the last week before Visit 2b, 
Visit 4, Visit 5 and Visit 6/EDV.
The following statistical output will be provided:
Table 15.2.8.1.1 Summary of Morning Dystonia – Full Analysis Set
Table 15.2.8.1.2 Summary of Morning Dystonia – Per-Protocol Set
Morning dystonia evaluation will be summarised for each visit at which the assessment was performed.
Table 15.2.8.2.1 Shift Table of Morning Dystonia – Full Analysis Set
Table 15.2.8.2.2 Shift Table of Morning Dystonia – Per-Protocol Set
Shift tables will be provided showing changes between Visit 2b (baseline) and all post-baseline visits
in the number and frequency of patients with morning dystonia (yes) and without morning dystonia 
(no). Patients with missing data will be presented as part of a “missing” category.
Listing 16.2.3.7 Morning Dystonia – Enrolled Set
Morning dystonia data will be displayed for each patient at all applicable visits in the enrolled set.
5.5.2.8
Use of Rescue Medication
The intake of rescue medication will be recorded in a patient diary. Starting with Visit 2b, the patients 
will receive a rescue medication diary and will be trained to daily record if any rescue medication was 
taken or not. In case of intake, the name of the rescue medication (paracetamol or tramadol) and the 
number of tablets/capsules taken have to be recorded.
The frequency of rescue medication intakes will be summarised by type of rescue medication, by overall
and periods as described below:
-
overall – from first IP intake day to the day before Visit 6/EDV
-
from first IP to Visit 4 - from first IP intake day to the day before Visit 4
-
from Visit 4 to Visit 5 - from Visit 4 day to the day before Visit 5
-
from Visit 5 to Visit 6 - from Visit 5 day to the day before Visit 6
-
within 30 days before Visit 4 (this period could contain less than 30 days)
-
within 30 days before Visit 5
-
within 30 days before Visit 6.
If both medications are used on the same day, then both will be used for calculation. If duplicated entries 
are present the worst case will be applied for the analysis, i.e. in case a record with and without rescue 
medication intake is documented in the diary, the record with rescue medication intake will be used.
Additionally, diary adherence by overall and periods will be calculated as:
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݁݊݀݀ܽݐ݁݋݂݌݁ݎ݅݋݀െݏݐܽݎݐ݀ܽݐ݁݋݂݌݁ݎ݅݋݀൅ͳ
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
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Effective date: 15.09.2020
The frequency of rescue medication intakes and diary adherence will be summarised using data from 
first IP intake day to the day before Visit 6/EDV. Other collected data outside this period will be listed.
The following statistical output will be provided:
Table 15.2.9.1.1 Summary of Usage Frequency of Rescue Medication – Full Analysis Set
Table 15.2.9.1.2 Summary of Usage Frequency of Rescue Medication – Per-Protocol Set
Usage frequency of rescue medication will be summarised by type of rescue medication, by overall and
periods.
Table 15.2.9.2.1 Summary of Rescue Medication Diary Adherence – Full Analysis Set
Table 15.2.9.2.2 Summary of Rescue Medication Diary Adherence – Per-Protocol Set
Rescue medication adherence will be summarised by overall and periods.
Listing 16.2.3.8 Use of Rescue Medication – Safety Set
Use of rescue medication data will be displayed for each patient in the safety set.
5.6
Safety Analysis
The SS will be used for the analysis of safety data.
5.6.1
Adverse Events
AEs will be coded according to latest MedDRA® Version 23.1.
Adverse event data includes:
-
adverse event name
-
onset date/time and stop date
-
action taken with study medication (dose not changed, dose increased, dose reduced, drug 
interrupted, drug withdrawn, not applicable, unknown)
-
other actions (none, medication required, tests required, hospitalisation required or prolonged, 
withdrawn from study, other – specified)
-
outcome of event (recovered/resolved, recovering/resolving, not recovered/not resolved,
recovered/resolved with sequelae, fatal, unknown)
-
seriousness (yes or no)
-
severity (mild, moderate, severe)
-
relationship (unrelated, unlikely possible, probable, definite)
All AEs will be presented in listings.
Summaries of AE will include AEs defined as treatment-emergent adverse events (TEAEs), defined 
as AEs with the first onset or worsening after the first IP intake until 14 days after the last IP intake.
If the start date of an AE is incomplete or missing, it will be assumed to be treatment-emergent except 
if the incomplete start date or the stop date indicates that the event started prior to the first IP intake or 
later than 14 days after last IP intake.
Adverse events will be further assigned to the following categories:
-
Serious Adverse Events (SAEs): defined as AEs considered by the investigator as serious, 
including AEs with an unknown or missing seriousness assessment.
-
Related TEAEs: AEs assessed as “Possible”, “Definite” or “Probable” to IP, including 
events with missing IP relationship assessment.
-
Unrelated TEAEs: AEs assessed as “Unrelated” or “Unlikely” to IP.
-
Severe TEAEs: AEs assessed as “Severe” in intensity, including events with missing 
severity assessments.
-
TEAEs leading to discontinuation: AEs for which “Action taken with IP” is indicated as 
“drug withdrawn” or “other actions taken” is “withdrawn from study”.
-
TEAEs leading to death: AEs documented as having a “fatal” outcome.
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
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The following statistical output will be provided: 
Table 15.3.1.1 Overall Summary of TEAEs – Safety Set
An overview of TEAEs: 
-
TEAEs
-
Ongoing TEAEs at EOS
-
Non-serious TEAEs
-
Serious TEAEs
-
Related TEAEs
-
Related Serious TEAEs
-
Severe TEAEs
-
TEAEs leading to discontinuation
-
Related TEAEs leading to discontinuation
-
Serious TEAEs leading to discontinuation
-
TEAEs leading to death
will be displayed by treatment and overall for the patients in the safety set.
Table 15.3.1.2 Incidence of TEAEs – Safety Set
Table 15.3.1.3 Incidence of Non-Serious TEAEs – Safety Set
Table 15.3.1.4 Incidence of Serious TEAEs – Safety Set
Table 15.3.1.5 Incidence of Related TEAEs – Safety Set
Table 15.3.1.6 Incidence of Related Serious TEAEs – Safety Set
Table 15.3.1.7 Incidence of TEAEs Leading to Discontinuation – Safety Set
Table 15.3.1.8 Incidence of TEAEs Leading to Death – Safety Set
TEAEs will be summarised by treatment and overall by displaying the numbers of AEs, as well as
counts and percentages of patients having experienced AEs. Percentages will be based on the number 
of patients in the safety set. SOCs and PTs within each SOC will be ordered by descending number of 
AEs in the total column.
Table 15.3.1.9 Incidence of TEAEs by Severity – Safety Set
Table 15.3.1.10 Incidence of TEAEs by Relationship – Safety Set
TEAEs will be summarised as above within each severity/relationship category.
Listing 16.2.4.1.1 Adverse Events: MedDRA Coding
MedDRA SOC and PTs assigned to each reported AE name will be displayed.
Listing 16.2.4.1.2 Adverse Events: General – Enrolled Set
Listing 16.2.4.1.3 Non-Serious Adverse Events – Safety Set
Listing 16.2.4.1.4 Serious Adverse Events – Safety Set
Listing 16.2.4.1.5 AEs Leading to Discontinuation – Safety Set
Listing 16.2.4.1.6 AEs Leading to Death – Safety Set
All AEs will be displayed by patient including the PT of an AE, onset datetime and stop date, duration 
and other characteristics of AEs.
5.6.2
Vital Signs
Following vital signs will be collected at Visit 1, Visit 2b, Visit 4, Visit 5 and Visit 6/EDV in 
siting/standing/supine position:
-
systolic blood pressure 
-
diastolic blood pressure
-
heart rate
The following statistical output will be provided:
Table 15.3.2 Summary of Vital Signs – Safety Set
Vital sign parameters will be summarised including change from baseline at each visit where 
assessments were made by treatment and overall.
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
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Effective date: 15.09.2020
Listing 16.2.4.2 Vital Signs – Enrolled Set
Vital signs data will be listed.
5.6.3
Physical Examination
Physical examinations are performed at Visit 1, Visit 5 and Visit 6/EDV on relevant body systems 
(appearance, skin, eyes, ears-nose-throat, lungs-chest, heart, abdomen, extremities, other). Clinical 
significance (CS) (yes/no) of any abnormal physical examination finding is assessed by the investigator.
The following statistical output will be presented:
Table 15.3.3.1 Summary of Physical Examination Findings – Safety Set
The number and percentage of patients with normal, abnormal, or CS abnormal physical examinations 
findings will be displayed by treatment and overall. Percentages will be based on the number of patients 
with data available at the specified visit.
Table 15.3.3.2 Shift Table of Physical Examination Findings – Safety Set
Shift tables will be provided showing changes between Visit 1 and each post-baseline visit where 
assessments were made in the number and frequency of patients with normal, abnormal, and clinically 
relevant abnormal physical examinations findings. Patients with missing data will be presented as part 
of a “Missing” category.
Listing 16.2.4.3 Physical Examinations – Enrolled Set
Physical examination findings will be listed.
5.6.4
Neurological Examination 
Neurological examinations are performed at Visit 1, Visit 5 and Visit 6/EDV on:
-
mental status
-
cranial nerves
-
motor system
-
sensory system
-
reflexes
-
co-ordination
Clinical significance (yes/no) of any abnormal neurological examination finding is assessed by the 
investigator.
The following statistical output will be presented:
Table 15.3.4.1 Summary of Neurological Examination Findings – Safety Set
The number and percentage of patients with normal, abnormal, or CS abnormal neurological 
examinations findings will be displayed. Percentages will be based on the number of patients with data 
available at the specified visit.
Table 15.3.4.2 Shift Table of Neurological Examination Findings – Safety Set
Shift tables will be provided showing changes between Visit 1 and each post-baseline visit where 
assessments were made in the number and frequency of patients with normal, abnormal, and clinically 
relevant abnormal neurological examinations findings. Patients with missing data will be presented as 
part of a “Missing” category.
Listing 16.2.4.4 Neurological Examinations – Enrolled Set
Neurological examination findings will be listed.
5.6.5
Clinical Laboratory Evaluation
Clinical laboratory values (haematology, biochemistry) are collected at Visit 1 and Visit 6/EDV for 
each laboratory parameter.
If re-test results are available, then the last test result on that visit will be used for the analysis.
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Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
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Effective date: 15.09.2020
Urine samples (in females of childbearing potential only) for pregnancy tests will be collected and 
analysed on-site via dip-stick analysis at Visit 1, Visit 2b, Visit 5 and Visit 6/EDV.
The following parameters are collected:
Haematology: haemoglobin, haematocrit, red blood cell (RBC) count, mean corpuscular volume 
(MCV), mean corpuscular/cellular haemoglobin, (MCH), mean corpuscular haemoglobin concentration 
(MCHC), white blood cell (WBC) count, differential WBC count (neutrophiles, lymphocytes, 
monocytes, eosinophiles, basophiles), platelet count.
Biochemistry: albumin, alanine aminotransferase / glutamic-pyruvic transaminase (ALT/GPT), 
aspartate aminotransferase / glutamic-oxaloacetic transaminase (AST/GOT), blood urea nitrogen 
(BUN), chloride, creatine kinase (CK), creatinine, glucose, potassium, sodium, bicarbonate.
Pregnancy test: urine human chorionic gonadotropin (hCG) dipstick analysis.
Haematology and biochemistry test results are assigned an LH classification according to whether the 
value is lower (L) than or higher (H) than the reference range for that parameter as provided by the 
corresponding laboratory.
The following statistical output will be provided:
Table 15.3.5.1.1 Summary of Clinical Laboratory Tests: Haematology – Safety Set
Table 15.3.5.1.2 Summary of Clinical Laboratory Tests: Biochemistry – Safety Set
The default summary statistics of clinical laboratory test results will be presented by treatment and 
overall at Visit 1 and Visit 6/EDV. The absolute change from baseline will be presented as well.
Table 15.3.5.2.1 Clinical Laboratory Tests: Incidence of Haematology Abnormalities – Safety Set
Table 15.3.5.2.2 Clinical Laboratory Tests: Incidence of Biochemistry Abnormalities – Safety Set
The number and percentage of patients with Low, Normal or High categories of each laboratory 
parameter will be displayed by treatment and overall. Percentages will be based on the number of 
patients at the specified visit.
Table 15.3.5.3.1 Clinical Laboratory Tests: Shift Table of Haematology Results – Safety Set
Table 15.3.5.3.2 Clinical Laboratory Tests: Shift Table of Biochemistry Results – Safety Set
Shift tables showing changes in the number and frequency of patients with respect to the normal range
between Visit 1 and Visit 6/EDV will be provided. Patients with missing data will be presented as part 
of a “Missing” category.
Listing 16.2.4.5.1 Laboratory Data: Haematology – Enrolled Set
Listing 16.2.4.5.2 Laboratory Data: Biochemistry – Enrolled Set
Safety laboratory test results will be listed.
Listing 16.2.4.5.3 Laboratory Data: Pregnancy Test – Enrolled Set
Urine pregnancy (dipstick) data will be listed.
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
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Effective date: 15.09.2020
6.
BLIND DATA REVIEW
A BDR will be performed after data entry and following a database lock. The following goals are 
defined for the BDR:
-
to identify major/minor protocol deviations
-
to identify patients that are not eligible for the per-protocol population
-
to identify protocol deviations that may affect the primary endpoint
-
review of rescue medication data
-
to discuss any open data issues
All decisions made during the BDR will be documented in the BDR report before the closure of the 
database and the randomisation code release.
An appropriate clinical study team, including a physician, will review potential protocol deviations and 
relevant information regarding those deviations to determine a possible impact on efficacy endpoints. 
An assessment will be made as to the effect of each of the possible deviations to determine if it is 
considered major or minor. The status, major or minor, of each protocol deviation will be documented 
in the BDR report. A patient may have one or more major protocol deviations resulting in the exclusion 
of that patient from the per-protocol analysis set.
Protocol deviations of the following categories will be reviewed during the BDR.
Inclusion Criteria at Visit 1
No.
Inclusion Criteria Deviation
Major/ 
Minor/ 
Case by 
case review
PD#01.
1. Able to comprehend and willing to sign an informed consent form and to 
comply with all aspects of the study.
Case by case
PD#02.
2. Male or female patients aged 30 years or older.
Protocol Germany
2. Male or female patients aged 50 to 85 years.
Case by case
PD#03.
3. Experiencing PD associated pain for at least 4 weeks prior to V1.
Case by case
PD#04.
4. Diagnosed with idiopathic PD according to the UK Parkinson’s Disease 
Society Brain Bank Clinical Diagnostic Criteria (2006) or according to 
MDS Clinical Diagnostic Criteria (2015).
Case by case
PD#05.
5. Disease severity Stages I-III (modified Hoehn & Yahr staging) at ON.
Case by case
PD#06.
6. Treated with 3 to 8 intakes per day of L-DOPA/DDCI (which may 
include a slow-release formulation), on a stable regimen for at least 4 weeks 
before V1.
Case by case
PD#07.
7. In case of any other anti-PD-treatment, it should be on a stable regimen 
for at least 4 weeks before V1, and not likely to need any adjustment until 
V6.
Case by case
PD#08.
8. No changes in chronic treatment regimen for pain within the last 4 weeks 
before V1. This includes medication (including but not limited to 
paracetamol, opioids, nonsteroidal anti-inflammatory drugs [NSAIDS], 
antidepressants, anticonvulsants and corticosteroids) and non-medication 
therapies (including but not limited to transcutaneous electrical nerve 
stimulation and bioelectrical therapy).
Case by case
PD#09.
9. Signs of “wearing-off” phenomenon (end-of-dose motor fluctuations) 
with average total daily OFF time while awake of at least 1.5 hours, 
excluding the early morning pre-first dose OFF, despite optimal anti-PD 
therapy (based on investigator’s assessment).
Case by case
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6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
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Effective date: 15.09.2020
No.
Inclusion Criteria Deviation
Major/ 
Minor/ 
Case by 
case review
PD#10.
10. Domain 3 of KPPS ≥ 12.
Case by case
PD#11.
11. For females: Postmenopausal for at least 2 years before V1, surgically 
sterile for at least 6 months before V1, or practicing effective contraception 
until V6. Female patients who request to continue with oral contraceptives 
must be willing to use non-hormonal methods of contraception in addition 
during the course of this study.
For males: Male patients who are sexually active with a partner of 
childbearing potential must use, with their partner, a condom plus an 
approved method of highly effective contraception during the treatment 
period until V6.
Protocol Germany
11. For females: Postmenopausal for at least 2 years before V1 or surgically 
sterile for at least 6 months before V1.
For males: Male patients who are sexually active with a partner of 
childbearing potential must use, with their partner, a condom plus an 
approved method of highly effective contraception during the treatment 
period until V6.
Protocol Czech Republic
11. For females: Postmenopausal for at least 2 years before V1, surgically
sterile for at least 6 months before V1, or practicing highly effective 
contraception until V6. Female patients who request to continue with oral 
contraceptives must be willing to use non-hormonal methods of 
contraception in addition during the course of this study.
For males: Male patients who are sexually active with a partner of 
childbearing potential must use, with their partner, a condom plus an 
approved method of highly effective contraception during the treatment 
period until V6.
Case by case
Inclusion Criteria at Visit 2b
No.
Exclusion Criteria Deviation
Major/ 
Minor/ 
Case by 
case review
PD#12.
12. Have filled-in self-rating diary in accordance with the diary instructions 
and with ≥ 3 missing entries per day, in the 3 days preceding V2a/V2b.
Case by case
PD#13.
13. With at least 1.5 OFF hours per day, excluding the early morning 
pre-first dose OFF period (i.e. the time between wake-up and response to 
the first L-DOPA/DDCI dosage), as recorded in at least 2 of the 3 days in 
the self-rating diary for the 3 days preceding V2a/V2b.
Case by case
PD#14.
14. Results of the screening laboratory tests are considered acceptable by 
the investigator (i.e. not clinically relevant for the well-being of the patient 
or for the purpose of the study).
Case by case
PD#15.
15. Domain 3 of KPPS ≥ 12.
Case by case
PD#16.
16. Adequate compliance to relevant (PD and pain related) concomitant 
medication during the screening period (based on the investigator’s 
judgment).
Case by case
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Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 38 of 49
Effective date: 15.09.2020
Exclusion Criteria
No.
Exclusion Criteria Deviation
Major/ 
Minor/ 
Case by 
case review
PD#17.
1. Non-idiopathic PD (atypical parkinsonism, secondary [acquired or 
symptomatic] parkinsonism, Parkinson-plus syndrome).
Case by case
PD#18.
2. Severe and/or unpredictable OFF periods, according to investigator 
judgement.
Case by case
PD#19.
3. Major/prominent non-PD-related pain (e.g. due to malignant disease).
Case by case
PD#20.
4. Treatment with prohibited medication: entacapone, tolcapone, 
monoamine oxidase (MAO) inhibitors (except selegiline up to 10 mg/day 
in oral formulation or 1.25 mg/day in buccal absorption formulation, 
rasagiline up to 1 mg/day or safinamide up to 100 mg/day), or antiemetics 
with antidopaminergic action (except domperidone) within the last 4 weeks 
before V1.
Case by case
PD#21.
5. Previous or planned (during the entire study duration) L-
DOPA/carbidopa intestinal gel infusion, deep brain stimulation or 
stereotactic surgery (e.g. pallidotomy, thalamotomy).
Case by case
PD#22.
6. Treatment with apomorphine within the last 4 weeks before V1 or likely 
to be needed at any time until V6.
Case by case
PD#23.
7. Previous or current use of opicapone.
Case by case
PD#24.
8. Use of any other IP, currently or within the 3 months (or within 5 half-
lives of the IP, whichever is longer) before V1.
Case by case
PD#25.
9. Past (within the past year) or present history of suicidal ideation or 
suicide attempts.
Case by case
PD#26.
10. Current or previous (within the past year) alcohol or substance abuse 
excluding caffeine or nicotine.
Case by case
PD#27.
11. Phaeochromocytoma, paraganglioma, or other catecholamine secreting 
neoplasms.
Case by case
PD#28.
12. Known hypersensitivity to the excipients of IP (including lactose 
intolerance, galactose intolerance, Lapp lactase deficiency or glucose-
galactose malabsorption) or of rescue medication.
Case by case
PD#29.
13. History of neuroleptic malignant syndrome or non-traumatic 
rhabdomyolysis.
Case by case
PD#30.
14. History of severe hepatic impairment (Child-Pugh Class C).
Case by case
PD#31.
15. Previous history of psychosis or psychiatric disorders, including severe 
major depression.
Case by case
PD#32.
16. Any medical condition that might place the patient at increased risk or 
interfere with assessments.
Case by case
PD#33.
17. For females: Pregnant or breastfeeding.
Protocol Germany
Not Applicable.
Case by case
PD#34.
18. Employees of the investigator, study centre, sponsor, clinical research 
organisation and study consultants, when employees are directly involved 
in this study or other studies under the direction of this investigator or study 
centre, and their family members.
Minor
PD#35.
19. Persons committed to an institution by virtue of an order issued either 
by the judicial or other authorities.
Minor
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
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6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 39 of 49
Effective date: 15.09.2020
Additional study conduct deviations
No.
Deviation
Major/ 
Minor/ 
Case by 
case review
PD#36.
IP treatment compliance <80% or >120%
Case by case
PD#37.
Intake of prohibited medications
Case by case
PD#38.
Visits performed not according to the study protocol schedule
Case by case
PD#39.
Missing efficacy assessments
Case by case
PD#40.
The dosage of L-DOPA/DDCI changed from Visit 4 to the Visit 6/EDV or 
dosage of L-DOPA/DDCI increased more than baseline dose level from 
Visit 2b to Visit 6/EDV.
Case by case
PD#41.
PDs from the global Protocol deviations log that may significantly affect 
the primary study objective and are not covered by other listings
Case by case
PD#42.
Paracetamol and tramadol taken on the same day according to rescue 
medication diary.
Case by case
Reference listings will be made available to facilitate the review of the protocol deviations. The specific 
content and format of listings to be reviewed during the BDR meeting (including any additional 
requirements that may be necessary to aid in review) will be determined outside the scope of this SAP.
7.
INTERIM ANALYSIS
No interim analysis is planned for this study.
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 40 of 49
Effective date: 15.09.2020
8.
CHANGES TO THE ANALYSIS AS LAID DOWN IN THE PROTOCOL AND 
MODIFICATIONS
The following changes were made to the analysis as laid down in the clinical study protocol and protocol 
modification(s):
-
The primary hypothesis was changed from H0: μT – μC ≤ 3 scores, H1: μT – μC > 3 scores to 
H0: μT = μC, H1: μT ≠μC.
-
The primary efficacy analysis model was changed from ANCOVA to MMRM.
-
Imputation using LOCF approach will not be used. For sensitivity purpose, multiple imputation 
(MI) approach under the assumption that data are missing not at random (MNAR) will be used.
-
Endpoint of change from baseline in Domain B (anxiety) of Movement Disorder Society-
sponsored Non-motor Rating Scale (MDS-NMS) will be referred to as secondary endpoint 
instead of key secondary endpoint.
-
Hauser’s Parkinson disease diary baseline definition changed. Instead of using the last 3 days 
before the visit, it was agreed to use the last 3 diary days within 7 days before Visit 2a/ Visit 2b.
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 41 of 49
Effective date: 15.09.2020
9.
REFERENCES
1.
SAS® Institute Inc., Cary, North Carolina, United States of America, Version 9.4.
2.
MedDRA – Medical Dictionary for Regulated Activities. International Federation of 
Pharmaceutical Manufacturers Associations (IFPMA), c/o TRW, VAR1/8A/MSSO, 12011 
Sunset Hills Road, Reston, VA 20190-3285, USA, 23.1.
3.
WHO – Drug Dictionary. World Health Organization Collaborating Center for International 
Drug Monitoring, P.O. Box 26, S-751 03 Uppsala, Sweden, March 2020.
4.
Goetz CG, Luo S, Wang L, Tilley BC, LaPelle NR, Stebbins GT. Handling missing values in 
the MDS-UPDRS. Movement Disorders. 2015;30(12):1632-1638.
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 42 of 49
Effective date: 15.09.2020
10. APPENDICES
Shells for tables, listings, and figures are available in the following attachments:
1. BIA-91067-404_Table_Shells_Final_1.0_20240521.docx
2. BIA-91067-404_Listing_Shells_Final_1.0_20240521.docx
3. BIA-91067-404_Figure_Shells_Final_1.0_20240521.docx
10.1
Tables
Appendix tables defined below will be provided in separate .rtf files for each output.
No
Table Identifier, Title
Output File
Baseline Characteristics 
1
Table 15.1.1.1 Analysis Sets – Enrolled Set
BIA-91067-404-T-150101010000-sets-es.rtf
2
Table 15.1.1.2 Reasons for Exclusion from Analysis Sets 
– Randomised Set
BIA-91067-404-T-150101020000-sets-excl-rs.rtf
3
Table 15.1.2 Screening Failures – Enrolled Set
BIA-91067-404-T-150102000000-sf-es.rtf
4
Table 15.1.3 Major Protocol Deviations – Full Analysis 
Set
BIA-91067-404-T-150103000000-pd-fas.rtf
5
Table 15.1.4 Patient Disposition – Safety Set
BIA-91067-404-T-150104000000-ds-ss.rtf
6
Table 15.1.5 Number of Patients by Country and Site –
Randomised Set
BIA-91067-404-T-150105000000-cntr-site-rn.rtf
7
Table 15.1.6 Number of Patients by Visit – Safety Set
BIA-91067-404-T-150106000000-visit-ss.rtf
8
Table 15.1.7.1 Summary of Subgroups – Full Analysis 
Set
BIA-91067-404-T-150107010000-subgr-fas.rtf
9
Table 15.1.7.2 Summary of Subgroups – Per-Protocol 
Set
BIA-91067-404-T-150107020000-subgr-pps.rtf
10
Table 15.1.8.1 Demographics and Baseline 
Characteristics – Safety Set
BIA-91067-404-T-150108010000-dm-basechar-ss.rtf
11
Table 15.1.8.2 Demographics and Baseline 
Characteristics – Full Analysis Set
BIA-91067-404-T-150108020000-dm-basechar-
fas.rtf
12
Table 15.1.8.3 Demographics and Baseline 
Characteristics – Per-Protocol Set
BIA-91067-404-T-150108030000-dm-basechar-
pps.rtf
13
Table 15.1.9.1 Summary of Neurological History –
Safety Set
BIA-91067-404-T-150109010000-neuro-h-ss.rtf
14
Table 15.1.9.2 Summary of Neurological History – Full 
Analysis Set
BIA-91067-404-T-150109020000-neuro-h-fas.rtf
15
Table 15.1.9.3 Summary of Neurological History – Per-
Protocol Set
BIA-91067-404-T-150109030000-neuro-h-pps.rtf
16
Table 15.1.10.1.1 Prior Medical Conditions – Safety Set
BIA-91067-404-T-150110010100-mh-pr-ss.rtf
17
Table 15.1.10.1.2 Prior Medical Conditions – Full 
Analysis Set
BIA-91067-404-T-150110010200-mh-pr-fas.rtf
18
Table 15.1.10.2.1 Ongoing Medical Conditions – Safety 
Set
BIA-91067-404-T-150110020100-mh-ong-ss.rtf
19
Table 15.1.10.2.2 Ongoing Medical Conditions – Full 
Analysis Set
BIA-91067-404-T-150110020200-mh-ong-fas.rtf
20
Table 15.1.11.1.1 Prior Medications – Safety Set
BIA-91067-404-T-150111010100-prmed-ss.rtf
21
Table 15.1.11.1.2 Prior Medications – Full Analysis Set
BIA-91067-404-T-150111010200-prmed-fas.rtf
22
Table 15.1.11.2.1 Concomitant Medications – Safety Set
BIA-91067-404-T-150111020100-cm-ss.rtf
23
Table 15.1.11.2.2 Concomitant Medications – Full 
Analysis Set
BIA-91067-404-T-150111020200-cm-fas.rtf
24
Table 15.1.11.3.1 L-DOPA/DDCI Medication – Safety 
Set
BIA-91067-404-T-150111030100-ldopa-ddci-ss.rtf
25
Table 15.1.11.3.2 L-DOPA/DDCI Medication – Full 
Analysis Set
BIA-91067-404-T-150111030200-ldopa-ddci-fas.rtf
26
Table 15.1.11.4 Tramadol Taken Within 30 Days Before 
the Endpoint – Safety Set
BIA-91067-404-T-150111040000-tramadol30-ss.rtf
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6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 43 of 49
Effective date: 15.09.2020
No
Table Identifier, Title
Output File
27
Table 15.1.11.5.1 Change of L-DOPA/DDCI Medication 
– Safety Set
BIA-91067-404-T-150111050100-ldopa-ddci-chg-
ss.rtf
28
Table 15.1.11.5.2 Change of L-DOPA/DDCI Medication 
– Full Analysis Set
BIA-91067-404-T-150111050200-ldopa-ddci-chg-
fas.rtf
29
Table 15.1.11.5.3 Change of L-DOPA/DDCI Medication 
– Per-Protocol Set
BIA-91067-404-T-150111050300-ldopa-ddci-chg-
pps.rtf
30
Table 15.1.12.1.1 Treatment Duration – Safety Set
BIA-91067-404-T-150112010100-trtdur-ss.rtf
31
Table 15.1.12.1.2 Treatment Duration – Full Analysis 
Set
BIA-91067-404-T-150112010200-trtdur-fas.rtf
32
Table 15.1.12.1.3 Treatment Duration – Per-Protocol Set
BIA-91067-404-T-150112010300-trtdur-pps.rtf
33
Table 15.1.12.2.1 Treatment Compliance – Safety Set
BIA-91067-404-T-150112020100-trtcompl-ss.rtf
34
Table 15.1.12.2.2 Treatment Compliance – Full Analysis 
Set
BIA-91067-404-T-150112020200-trtcompl-fas.rtf
35
Table 15.1.12.2.3 Treatment Compliance – Per-Protocol 
Set
BIA-91067-404-T-150112020300-trtcompl-pps.rtf
Efficacy Data
36
Table 15.2.1.1.1.1 Summary of KPPS – Full Analysis 
Set
BIA-91067-404-T-150201010101-kpps-fas.rtf
37
Table 15.2.1.1.1.2 Summary of KPPS – Per-Protocol Set
BIA-91067-404-T-150201010102-kpps-pps.rtf
38
Table 15.2.1.1.2.1 Summary of the Domain 3 of KPPS 
by Subgroup – Full Analysis Set
BIA-91067-404-T-150201010201-sub-kpps-fas.rtf
39
Table 15.2.1.1.2.2 Summary of the Domain 3 of KPPS 
by Subgroup – Per-Protocol Set
BIA-91067-404-T-150201010202-sub-kpps-pps.rtf
40
Table 15.2.1.2.1.1 Analysis of the Domain 3 of KPPS –
Full Analysis Set
BIA-91067-404-T-150201020101-kpps-d3-mmrm-
fas.rtf
41
Table 15.2.1.2.1.2 Analysis of the Domain 3 of KPPS –
Per-Protocol Set
BIA-91067-404-T-150201020102-kpps-d3-mmrm-
pps.rtf
42
Table 15.2.1.2.2.1 Analysis of the Domain 3 of KPPS 
(MI) – Full Analysis Set
BIA-91067-404-T-150201020201-kpps-d3-mmrm-
mi-fas.rtf
43
Table 15.2.1.2.2.2 Analysis of the Domain 3 of KPPS 
(MI) – Per-Protocol Set
BIA-91067-404-T-150201020202-kpps-d3-mmrm-
mi-pps.rtf
44
Table 15.2.1.2.3.1 Analysis of the Domain 3 of KPPS by 
Subgroup – Full Analysis Set
BIA-91067-404-T-150201020301-sub-kpps-d3-
mmrm-fas
45
Table 15.2.1.2.3.2 Analysis of the Domain 3 of KPPS by 
Subgroup – Per-Protocol Set
BIA-91067-404-T-150201020302-sub-kpps-d3-
mmrm-pps
46
Table 15.2.2.1.1 Analysis of the Domain 4 of KPPS –
Full Analysis Set
BIA-91067-404-T-150202010100-kpps-d4-mmrm-
fas.rtf
47
Table 15.2.2.1.2 Analysis of the Domain 4 of KPPS –
Per-Protocol Set
BIA-91067-404-T-150202010200-kpps-d4-mmrm-
pps.rtf
48
Table 15.2.2.2.1 Analysis of KPPS Total Score – Full 
Analysis Set
BIA-91067-404-T-150202020100-kpps-tot-mmrm-
fas.rtf
49
Table 15.2.2.2.2 Analysis of KPPS Total Score – Per-
Protocol Set
BIA-91067-404-T-150202020200-kpps-tot-mmrm-
pps.rtf
50
Table 15.2.3.1.1 Summary of MDS-NMS – Full 
Analysis Set
BIA-91067-404-T-150203010100-mds-nms-fas.rtf
51
Table 15.2.3.1.2 Summary of MDS-NMS – Per-Protocol 
Set
BIA-91067-404-T-150203010200-mds-nms-pps.rtf
52
Table 15.2.3.2.1 Analysis of MDS-NMS – Full Analysis 
Set
BIA-91067-404-T-150203020100-mds-nms-a-fas.rtf
53
Table 15.2.3.2.2 Analysis of MDS-NMS – Per-Protocol 
Set
BIA-91067-404-T-150203020200-mds-nms-a-pps.rtf
54
Table 15.2.4.1.1 Summary of MDS-UPDRS – Full 
Analysis Set
BIA-91067-404-T-150204010100-mds-updrs-fas.rtf
55
Table 15.2.4.1.2 Summary of MDS-UPDRS – Per-
Protocol Set
BIA-91067-404-T-150204010200-mds-updrs-pps.rtf
56
Table 15.2.4.2.1 Analysis of MDS-UPDRS Part III/IV 
Total Score – Full Analysis Set
BIA-91067-404-T-150204020100-mds-updrs-a-fas.rtf
57
Table 15.2.4.2.2 Analysis of MDS-UPDRS Part III/IV 
Total Score – Per-Protocol Set
BIA-91067-404-T-150204020200-mds-updrs-a-
pps.rtf
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 44 of 49
Effective date: 15.09.2020
No
Table Identifier, Title
Output File
58
Table 15.2.5.1.1 Summary of PDQ-8 Index – Full 
Analysis Set
BIA-91067-404-T-150205010100-pdq8-fas.rtf
59
Table 15.2.5.1.2 Summary of PDQ-8 Index – Per-
Protocol Set
BIA-91067-404-T-150205010200-pdq8-pps.rtf
60
Table 15.2.5.2.1 Analysis of PDQ-8 Index – Full 
Analysis Set
BIA-91067-404-T-150205020100-pdq8-a-fas.rtf
61
Table 15.2.5.2.2 Analysis of PDQ-8 Index – Per-
Protocol Set
BIA-91067-404-T-150205020200-pdq8-a-pps.rtf
62
Table 15.2.6.1.1 Summary of CGIC and PGIC – Full 
Analysis Set
BIA-91067-404-T-150206010100-cgic-pgic-fas.rtf
63
Table 15.2.6.1.2 Summary of CGIC and PGIC – Per-
Protocol Set
BIA-91067-404-T-150206010200-cgic-pgic-pps.rtf
64
Table 15.2.6.2.1 Improvement Analysis of CGIC and 
PGIC – Full Analysis Set
BIA-91067-404-T-150206020100-cgic-pgic-a-fas.rtf
65
Table 15.2.6.2.2 Improvement Analysis of CGIC and 
PGIC – Per-Protocol Set
BIA-91067-404-T-150206020200-cgic-pgic-a-pps.rtf
66
Table 15.2.7.1.1 Summary of Functional Status (Time in 
Minutes) – Full Analysis Set
BIA-91067-404-T-150207010100-func-min-fas.rtf
67
Table 15.2.7.1.2 Summary of Functional Status (Time in 
Minutes) – Per-Protocol Set
BIA-91067-404-T-150207010200-func-min-pps.rtf
68
Table 15.2.7.2.1 Summary of Functional Status 
(Percentage) – Full Analysis Set
BIA-91067-404-T-150207020100-func-perc-fas.rtf
69
Table 15.2.7.2.2 Summary of Functional Status 
(Percentage) – Per-Protocol Set
BIA-91067-404-T-150207020200-func-perc-pps.rtf
70
Table 15.2.7.3.1 Responder Analysis of OFF-time and 
ON-time – Full Analysis Set
BIA-91067-404-T-150207030100-func-resp-fas.rtf
71
Table 15.2.7.3.2 Responder Analysis of OFF-time and 
ON-time – Per-Protocol Set
BIA-91067-404-T-150207030200-func-resp-pps.rtf
72
Table 15.2.8.1.1 Summary of Morning Dystonia – Full 
Analysis Set
BIA-91067-404-T-150208010100-morn-dyst-fas.rtf
73
Table 15.2.8.1.2 Summary of Morning Dystonia – Per-
Protocol Set
BIA-91067-404-T-150208010200-morn-dyst-pps.rtf
74
Table 15.2.8.2.1 Shift Table of Morning Dystonia – Full 
Analysis Set
BIA-91067-404-T-150208020100-morn-dyst-shift-
fas.rtf
75
Table 15.2.8.2.2 Shift Table of Morning Dystonia – Per-
Protocol Set
BIA-91067-404-T-150208020200-morn-dyst-shift-
pps.rtf
76
Table 15.2.9.1.1 Summary of Usage Frequency of 
Rescue Medication – Full Analysis Set
BIA-91067-404-T-150209010100-rescdiary-use-
fas.rtf
77
Table 15.2.9.1.2 Summary of Usage Frequency of 
Rescue Medication – Per-Protocol Set
BIA-91067-404-T-150209010200-rescdiary-use-
pps.rtf
78
Table 15.2.9.2.1 Summary of Rescue Medication Diary 
Adherence – Full Analysis Set
BIA-91067-404-T-150209020100-rescdiary-adh-
fas.rtf
79
Table 15.2.9.2.2 Summary of Rescue Medication Diary 
Adherence – Per-Protocol Set
BIA-91067-404-T-150209020200-rescdiary-adh-
pps.rtf
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 45 of 49
Effective date: 15.09.2020
No
Table Identifier, Title
Output File
Safety Data
80
Table 15.3.1.1 Overall Summary of TEAEs – Safety Set
BIA-91067-404-T-150301010000-teaesum-ss.rtf
81
Table 15.3.1.2 Incidence of TEAEs – Safety Set
BIA-91067-404-T-150301020000-teae-ss.rtf
82
Table 15.3.1.3 Incidence of Non-Serious TEAEs –
Safety Set
BIA-91067-404-T-150301030000-teae-nonser-ss.rtf
83
Table 15.3.1.4 Incidence of Serious TEAEs – Safety Set
BIA-91067-404-T-150301040000-tesae-ss.rtf
84
Table 15.3.1.5 Incidence of Related TEAEs – Safety Set
BIA-91067-404-T-150301050000-teae-rel-ss.rtf
85
Table 15.3.1.6 Incidence of Related Serious TEAEs –
Safety Set
BIA-91067-404-T-150301060000-tesae-rel-ss.rtf
86
Table 15.3.1.7 Incidence of TEAEs Leading to 
Discontinuation – Safety Set
BIA-91067-404-T-150301070000-teae-disc-ss.rtf
87
Table 15.3.1.8 Incidence of TEAEs Leading to Death –
Safety Set
BIA-91067-404-T-150301080000-teae-death-ss.rtf
88
Table 15.3.1.9 Incidence of TEAEs by Severity – Safety 
Set
BIA-91067-404-T-150301090000-teae-bysev-ss.rtf
89
Table 15.3.1.10 Incidence of TEAE by Relationship –
Safety Set
BIA-91067-404-T-150301100000-teae-byrel-ss.rtf
90
Table 15.3.2 Summary of Vital Signs – Safety Set
BIA-91067-404-T-150302000000-vs-ss.rtf
91
Table 15.3.3.1 Summary of Physical Examination 
Findings – Safety Set
BIA-91067-404-T-150303010000-pe-ss.rtf
92
Table 15.3.3.2 Shift Table of Physical Examination 
Findings – Safety Set
BIA-91067-404-T-150303020000-pe-shift-ss.rtf
93
Table 15.3.4.1 Summary of Neurological Examination 
Findings – Safety Set
BIA-91067-404-T-150304010000-neuro-ss.rtf
94
Table 15.3.4.2 Shift Table of Neurological Examination 
Findings – Safety Set
BIA-91067-404-T-150304020000-neuro-shift-ss.rtf
95
Table 15.3.5.1.1 Summary of Clinical Laboratory Tests: 
Haematology – Safety Set
BIA-91067-404-T-150305010100-lbh-ss.rtf
96
Table 15.3.5.1.2 Summary of Clinical Laboratory Tests: 
Biochemistry – Safety Set
BIA-91067-404-T-150305010200-lbb-ss.rtf
97
Table 15.3.5.2.1 Clinical Laboratory Tests: Incidence of 
Haematology Abnormalities –  Safety Set
BIA-91067-404-T-150305020100-lbh-abnorm-ss.rtf
98
Table 15.3.5.2.2 Clinical Laboratory Tests: Incidence of 
Biochemistry Abnormalities – Safety Set
BIA-91067-404-T-150305020200-lbb-abnorm-ss.rtf
99
Table 15.3.5.3.1 Clinical Laboratory Tests: Shift Table 
of Haematology Results – Safety Set
BIA-91067-404-T-150305030100-lbh-shift-ss.rtf
100
Table 15.3.5.3.2 Clinical Laboratory Tests: Shift Table 
of Biochemistry Results – Safety Set
BIA-91067-404-T-150305030200-lbb-shift-ss.rtf
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 46 of 49
Effective date: 15.09.2020
10.2
Listings
Appendix listings defined below will be provided in separate .rtf files for each output. 
No
Listing Identifier, Title
Output File
Demographic and Study Population Data
1
Listing 16.2.1.1 Patient Disposition – Safety Set
BIA-91067-404-L-1602010100-ds-ss
2
Listing 16.2.1.2 Screening Failures – Enrolled Set
BIA-91067-404-L-1602010200-sf-es
3
Listing 16.2.1.3 Patient Visits – Enrolled Set
BIA-91067-404-L-1602010300-visit-es
4
Listing 16.2.1.4 Exclusions from Analysis Sets –
Enrolled Set
BIA-91067-404-L-1602010400-sets-excl-es
5
Listing 16.2.1.5 Patient Allocation to Treatments –
Randomised Set
BIA-91067-404-L-1602010500-aloc-trt-rn
6
Listing 16.2.1.6 Major Protocol Deviations – Safety Set
BIA-91067-404-L-1602010600-pd-ss
7
Listing 16.2.1.7 Inclusion Criteria Not Met and 
Exclusion Criteria Met – Enrolled Set
BIA-91067-404-L-1602010700-ie-es
8
Listing 16.2.1.8 Demographics and Baseline 
Characteristics – Enrolled Set
BIA-91067-404-L-1602010800-dm-basechar-es
9
Listing 16.2.1.9 Neurological History – Enrolled Set
BIA-91067-404-L-1602010900-neuro-h-es
10
Listing 16.2.1.10 Medical History – Enrolled Set
BIA-91067-404-L-1602011000-mh-es
11
Listing 16.2.1.11 Medications – Enrolled Set
BIA-91067-404-L-1602011100-cm-es
12
Listing 16.2.1.12.1 L-dopa/DDCI Medications –
Enrolled Set
BIA-91067-404-L-1602011201-ldopa-ddci-es
13
Listing 16.2.1.12.2 Change of L-dopa/DDCI 
Medications – Safety Set
BIA-91067-404-L-1602011202-ldopa-ddci-chg-ss
14
Listing 16.2.2.1 Exposure to IP and Treatment 
Compliance – Safety Set
BIA-91067-404-L-1602020100-ex-trtcompl-ss
15
Listing 16.2.2.2 Exposure to Rescue Medication – Safety 
Set
BIA-91067-404-L-1602020200-ex-rescmed-ss
Efficacy Data
16
Listing 16.2.3.1 KPPS – Enrolled Set
BIA-91067-404-L-1602030100-kpps-es
17
Listing 16.2.3.2 MDS-NMS – Enrolled Set
BIA-91067-404-L-1602030200-mds-nms-es
18
Listing 16.2.3.3.1 MDS-UPDRS – Enrolled Set
BIA-91067-404-L-1602030301-mds-updrs-es
19
Listing 16.2.3.3.2 MDS-UPDRS Part III Additional 
Information – Enrolled Set
BIA-91067-404-L-1602030302-mds-updrs-add-es
20
Listing 16.2.3.4 PDQ-8 – Enrolled Set
BIA-91067-404-L-1602030400-pdq8-es
21
Listing 16.2.3.5 CGIC and PGIC – Safety Set
BIA-91067-404-L-1602030500-cgic-pgic-ss
22
Listing 16.2.3.6.1 Hauser’s Parkinson’s Disease Diary –
Enrolled Set
BIA-91067-404-L-1602030601-pd-diary-es
23
Listing 16.2.3.6.2 Hauser’s Parkinson’s Disease Diary 
Analysis Parameters – Enrolled Set
BIA-91067-404-L-1602030602-pd-diary-a-es
24
Listing 16.2.3.7 Morning Dystonia – Enrolled Set
BIA-91067-404-L-1602030700-morn-dyst-es
25
Listing 16.2.3.8 Use of Rescue Medication – Safety Set
BIA-91067-404-L-1602030800-rescmed-ss
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 47 of 49
Effective date: 15.09.2020
No
Listing Identifier, Title
Output File
Safety Data
26
Listing 16.2.4.1.1 Adverse Events: MedDRA Coding
BIA-91067-404-L-1602040101-aecod
27
Listing 16.2.4.1.2 Adverse Events: General – Enrolled 
Set
BIA-91067-404-L-1602040102-ae-es
28
Listing 16.2.4.1.3 Non-Serious Adverse Events – Safety 
Set
BIA-91067-404-L-1602040103-ae-nonser-ss
29
Listing 16.2.4.1.4 Serious Adverse Events – Safety Set
BIA-91067-404-L-1602040104-sae-ss
30
Listing 16.2.4.1.5 AEs Leading to Discontinuation –
Safety Set
BIA-91067-404-L-1602040105-ae-disc-ss
31
Listing 16.2.4.1.6 AEs Leading to Death – Safety Set
BIA-91067-404-L-1602040106-ae-death-ss
32
Listing 16.2.4.2 Vital Signs – Enrolled Set
BIA-91067-404-L-1602040200-vs-es
33
Listing 16.2.4.3 Physical Examinations – Enrolled Set
BIA-91067-404-L-1602040300-pe-es
34
Listing 16.2.4.4 Neurological Examinations – Enrolled 
Set
BIA-91067-404-L-1602040400-neuro-es
35
Listing 16.2.4.5.1 Laboratory Data: Haematology –
Enrolled Set
BIA-91067-404-L-1602040501-lbh-es
36
Listing 16.2.4.5.2 Laboratory Data: Biochemistry –
Enrolled Set
BIA-91067-404-L-1602040502-lbb-es
37
Listing 16.2.4.5.3 Laboratory Data: Pregnancy Test –
Enrolled Set
BIA-91067-404-L-1602040503-preg-test-es
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 48 of 49
Effective date: 15.09.2020
10.3
Figures 
Appendix figures defined below will be provided in separate .rtf files for each output. 
No
Figure Identifier, Title
Output File
Demographic and Study Population Data
1
Figure 15.1.1 Flow Chart of Subject Disposition –
Enrolled Set
BIA-91067-405-F-150101-ds-es.rtf
2
Figure 15.1.2 Flow Chart of Analysis Sets – Enrolled Set
BIA-91067-405-F-150102-sets-es.rtf
Efficacy Data
4
Figure 15.2.1.1 Domain 3 of KPPS Change from 
Baseline LS-Means by Visit – Full Analysis Set
BIA-91067-405-F-150201-kpps-d3-mmrm-fas.rtf
5
Figure 15.2.1.2 Domain 3 of KPPS Change from 
Baseline LS-Means by Visit – Per-Protocol Set
BIA-91067-405-F-150201-kpps-d3-mmrm-pps.rtf
6
Figure 15.2.2.1 Forest Plot of Domain 3 of KPPS by 
Subgroup – Full Analysis Set
BIA-91067-405-F-150202-kpps-d3-forest-sub-fas.rtf
7
Figure 15.2.2.1 Forest Plot of Domain 3 of KPPS by 
Subgroup – Per-Protocol Set
BIA-91067-405-F-150202-kpps-d3-forest-sub-fas.rtf
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


Sponsor: Bial - Portela & Ca, S.A.
Protocol no. BIA-91067-404
Statistical Analysis Plan, Version Final 1.0
21-MAY-2024
I-DM-011SAP
Page 49 of 49
Effective date: 15.09.2020
11. SIGNATURES
_______________________________ ______________________
Signature
Date
Author:
Rasa Gaupsaite
Statistician, Scope International AG
_______________________________ ______________________
Signature
Date
Reviewer:
Jurgita Kavalne
Principal Statistician, Scope International AG
_______________________________ ______________________
Signature
Date
Reviewer:
Angelika Seedorf
Medical Writer, Scope International AG
_______________________________ ______________________
Signature
Date
Reviewer:
Miriam Reinhard
Project Manager, Scope International AG
Note: Sarah Kern is signing on behalf of Miriam Reinhard
_______________________________ ______________________
Signature
Date
Sponsor:
Raquel Costa
Senior Clinical Operations Manager, Bial – Portela & Ca, S.A.
_______________________________ ______________________
Signature
Date
Sponsor:
Guillermo Castilla
Senior Biostatistician, Bial - Portela & Ca, S.A.
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20
6CFA34F09AFEE39A4D91C56E9BBD0603F135E1CD566B62F7CCC6713B18912D20


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B
6
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