Clinical trial NCT03194217
Conditions: Excessive Daytime Sleepiness Parkinson Disease
Sponsor: BenevolentAI Bio
Start date: 2017-11-10; Completion date: 2019-05-28
Enrollment: 244 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase 2b study is designed as multicentre, multinational, randomized, double blind, parallel group and placebo controlled with three doses of Bavisant (0.5, 1, and 3 mg/d) in subjects with excessive daytime sleepiness with Parkinson's disease.

Detailed description:
Phase 2b study will be conducted with the aim of investigating the efficacy and safety of three fixed doses of Bavisant (0.5, 1 and 3 mg/d) compared to placebo for the treatment of excessive daytime sleepiness (EDS) in subjects with Parkinson's disease.

Arms: arm 1: Experimental treatment arm 2: Placebo comparator arm 3: Experimental treatment arm 4: Experimental treatment
Interventions: intervention 1: BEN-2001 intervention 2: Placebo
Intervention descriptions: intervention 1: Bavisant dihydrochloride monohydrate for oral use intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
 
 
 
 
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Confidential 
1.0 
Title Page 
 
Protocol No. 
BB-2001-201b 
EudraCT No. 
2017-000877-35 
Title: 
Dose finding phase IIb study of Bavisant to evaluate its safety and 
effiCacy in treAtment of exceSsive daytime sleePiness (EDS) in 
PARkinson’s Disease (PD). CASPAR study. 
Study Sponsor: 
BenevolentAI Bio 
4-8 Maple Street 
W1T 5HD, London, UK 
Tel +44 2037 819 360 
Dr. Leo James 
Medical Director (contract)  
e-mail: leo.james@benevolent.ai  
 
Amendment History 
    Date 
Amendment Number Amendment Type  
05 April 2017 
Initial version 
Not applicable 
20 June  2017 
01 
Non-substantial 
03 July  2017 
02 
Non-substantial 
23 August 2017 
03 
Substantial 
07 November 2018 04 
Non-substantial 
 
 
 
 
 
 
 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents. 
 
Confidential Information 
No use or disclosure outside BenevolentAI Bio is permitted without prior written authorisation 
from BenevolentAI Bio. 




 
 
 
 
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Confidential 
INVESTIGATOR AGREEMENT  
 
I confirm that I have read and that I understand this protocol, the investigator brochure, and other 
product information provided by the sponsor. I agree to conduct this study in accordance with the 
requirements of this protocol and also protect the rights, safety, privacy, and well-being of study 
subjects in accordance with the following: 
 
 
The ethical principles that have their origin in the Declaration of Helsinki. 
 
International Conference on Harmonisation Harmonised Tripartite Guideline for Good 
Clinical Practice E6. 
 
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 
Regulatory requirements for reporting serious adverse events defined in this protocol. 
 
Terms outlined in the Clinical Study Site Agreement.  
 
 
 
 
 
Signature of Investigator 
Date 
 
 
Investigator Name (print or type) 
 
 
 
Investigator’s Title 
 
 
 
Name of Facility 
 
 
 
Location of Facility (City) 
 
 
 
 


 
 
 
 
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REASON FOR NON SUBSTANTIAL AMENDMENT 04 
 
This amended study protocol is prepared to update the sponsor’s postal address, medical director, 
study statistician, and the setup arranged for the 24h emergency contact: 
 
BenevolentAI Bio: New postal address. 
 
Dr. Patrick Keohane, Chief Medical Officer, replaced by Dr. Leo James, Medical Director 
(contract) 
 
Sara Prada, Statistician, replaced by Eduardo Sobreviela, Statistician 
 
24h emergency contact: Split between business hours weekdays, and non-business hours 
and weekends 
Detailed changes are summarized in the following table: 
 
 
Section 
Page 
Old text 
New text 
Heading 
All 
Amendment 03, Final Version 1.0 
Amendment 04, Final Version 
1.0 
 
All 
23/Aug/2017 
06/Nov/2018 
Cover 
1 
BenevolentAI Bio 
40 Churchway 
W1 1LW, London, UK 
Tel +44 20 3096 0720 
Dr. Patrick Keohane 
Chief Medical Officer 
e-mail: 
patrick.keohane@benevolent.ai  
BenevolentAI Bio 
4-8 Maple Street 
W1T 5HD, London, UK 
Tel +44 2037 819 360 
Dr. Leo James 
Medical Director (contract) 
e-mail: leo.james@benevolent.ai  
Signature page 
2 
DR. PATRICK KEOHANE 
CHIEF MEDICAL OFFICER 
 
PEJU OSHISANYA 
SENIOR PROJECT MANAGER 
 
SARA PRADA 
STATISTICIAN 
DR. LEO JAMES 
MEDICAL DIRECTOR 
(CONTRACT) 
 
ADEPEJU OSHISANYA 
DIRECTOR, CLINICAL 
PROGRAMME LEADER 
 
EDUARDO SOBREVIELA 
STATISTICIAN 
Reason for non 
substantial 
amendment 04 
4 
<<blank>> 
<<New section with details of 
the non substantial amendment 
04>> 
3.0 Table of 
contents 
26 
<<blank>> 
<<updated>> 


 
 
 
 
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18.1 
Administrative 
Information – 
Contacts 
99 
24h emergency contact 
Linical (CRA / MM)  
BEN01.medical.emergency@lini
cal.com  
Dr. Isabel Caballero (+34 610 134 
109) 
Dr. Carlos Hortelano (+34 670 
836 340) 
Dr. Patrick Keohane (+44 782 
6854 866) 
Emergency contact 
Business hours weekdays (08:00 
to 16:00 CET) 
Linical (CRA / MM)  
BEN01.medical.emergency@lini
cal.com  
Dr. Isabel Caballero (+34 610 
134 109) 
Dr. Carlos Hortelano (+34 670 
836 340) 
 
18.1 
Administrative 
Information – 
Contacts 
99 
<<blank>> 
24h emergency contact 
Non business hours and 
weekends 
Czech Republic 296849801
 
+441204684560 
Germany 08005891887
 
+441235239958 
Italy 0236007792 
 
+441228899357 
Poland 124207010 
 
 
+441204684450 
Spain  966990007 
 
 
+441204684092 
United Kingdom 01242649524
 
+441242649524 
USA  18666151825
 
+441204684544 
 
 


 
 
 
 
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REASON FOR SUBSTANTIAL AMENDMENT 03 
 
This amended study protocol is prepared to include the requests from the FDA regarding the 
safety review of IND 133435 in order for the study to be considered Safe to Proceed: 
 
C-SSRS: Columbia-Suicide Severity Rating Scale will be assessed at all study visits 
(including follow-up visits where adverse events are also assessed), and not just screening 
and Visit 3 following the FDA Guidance for Industry – Suicidal Ideation and Behavior: 
Prospective Assessment of Occurrence in Clinical Trials(1). 
 
BPRS+ (Brief Psychiatric Rating Scale positive subscale) will be included to monitor 
psychotic symptoms at all study visits (including follow-up visits where adverse events 
are also assessed), based that patients with Parkinson’s disease are known to be at higher 
risk of psychosis than the general population. 
 
HAM-D will be assessed at all study visits (including follow-up visits), and not just 
screening and Visit 3, based that patients with Parkinson’s disease are known to be at 
higher risk of depression. 
 
Follow-up procedures are described for a positive finding on the C-SSRS, or an elevated 
HAM-D or psychosis scale score. 
 
Vital signs (including blood pressure and heart rate) will be assessed at all study visits 
(including follow-up visits), as patients with Parkinson’s disease are known to commonly 
exhibit orthostatis and other cardiovascular changes. 
The statistical section of the protocol has been updated to: 
 
Consider the intent to treat population as the main population for the efficacy analysis 
and the per protocol population also as a sensitivity analysis. 
 
Include the region as a factor for the ANCOVA model 
 
Include sensitivity analyses (mixed-effect model with repeated measures, MCP-Mod 
approach, Rank ANCOVA model. 
 
Consider missing data in the 6-week ESS evaluation as a treatment failure. 
 
Consider three regions for the stratification: USA, Western Europe, and Eastern Europe 
Additionally, some text passages were clarified and errors were corrected in the study protocol 
corresponding to the following: 
 
Update on the patient reported and clinician reported outcome instruments 
 
Cross references were updated 
 
E-mail address of Linical Safety department for SAE reporting updated to 
BEN01.safetydesk@linical.com  
 
E-mail 
address 
of 
24h 
emergency 
contact 
updated 
to 
BEN01.medical.emergency@linical.com  
Detailed changes are summarized in the following table: 
 
 


 
 
 
 
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Section 
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Heading 
All 
Amendment 02, Final Version 
1.0 
Amendment 03, Final Version 1.0 
 
All 
03/Jul/2017 
23/Aug/2017 
Reason for 
substantial 
amendment 03 
4 
<<blank>> 
<<New section with details of the 
substantial amendment 03>> 
Summary – Main 
Criteria for 
Inclusion 
18 
(3) Subjects with previous 
diagnosis of Parkinson's 
disease (following the UK 
Parkinson’s disease society 
brain bank clinical diagnostic 
criteria. 
(3) Subjects with previous diagnosis of 
Parkinson's disease (following the UK 
Parkinson’s disease society brain bank 
clinical diagnostic criteria)* of 
minimum 3 months before informed 
consent date. 
Summary – Main 
Criteria for 
Exclusion 
19 
<<blank>> 
<<New criterion #3>> 
(3) 
Subjects with a need of referral 
to a trained mental health professional 
based on their suicidal ideation (C-
SSRS with an answer of ‘yes’ to any of 
the 6 questions)   
Summary – Main 
Criteria for 
Exclusion 
19 
Exclusion criteria (3) – (17) 
Exclusion criteria (4) to (18) 
Summary - Main 
Criteria for 
Evaluation and 
Analysis: Primary 
variable: 
20 
ESS mean absolute change 
from baseline to the end of the 
6-week treatment period will 
be analysed with an ANCOVA 
model, with the baseline ESS 
as a covariate, and treatment as 
a factor. A non-parametric 
ANCOVA model (as rank 
ANCOVA model) will be 
implemented in case the 
assumptions for the previous 
analysis are not met. Least-
squared (LS) absolute mean 
changes will be presented by 
treatment group together with 
their corresponding 95% 
confidence interval. Paired-
comparisons will be performed 
without any multiplicity 
adjustment.  
ESS mean absolute change from 
baseline to the end of the 6-week 
treatment period will be analysed with 
an ANCOVA model, with the baseline 
ESS as a covariate, region and 
treatment as a factor. Missing data in 
the 6-week ESS evaluation will be 
considered as a treatment failure , that 
is imputing the missing ESS reduction 
as 0. Least-squared (LS) absolute mean 
changes will be presented by treatment 
group together with their corresponding 
95% confidence interval. Paired-
comparisons will be performed without 
any multiplicity adjustment.   
As sensitivity analyses: 
a) A mixed-effect model with repeated 
measures (MMRM) approach will be 
used, under the missing at random 
framework carried out using an 
adequate contrast at Week 2 or Week 6, 
accordingly. The model will include 
fixed categorical effects of treatment 
group, region, visit and treatment-by-
visit interaction as well as the 
continuous fixed covariates of mean 
baseline ESS. This MMRM model will 


 
 
 
 
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As sensitivity analyses, both a 
Last Observation Carried 
Forward (LOCF) imputation 
for missing data, and a mixed-
effect model with repeated 
measures (MMRM) approach 
will be used, under the missing 
at random framework carried 
out using an adequate contrast 
at Week 2 or Week 6, 
accordingly. The model will 
include fixed categorical 
effects of treatment group, 
visit and treatment-by-visit 
interaction as well as the 
continuous fixed covariates of 
mean baseline ESS. This 
MMRM model will be run 
with an unstructured 
correlation matrix to model the 
within-subject errors. 
be run with an unstructured correlation 
matrix to model the within-subject 
errors. 
b) MCP-Mod approach will be applied 
to identify the most suitable dose-
response curve. Further details about 
the curve selection and validation 
procedures being used will be stated in 
the Statistical Analysis Plan. 
c) Similar to the  primary analysis a 
Rank ANCOVA will be modelled in 
order to provide evidence of the 
treatment effect in case of violation of 
normality assumption. 
d) Primary Analysis, and sensitivity 
analysis as described above will be 
performed in the Per Protocol 
Population. 
Summary – 
Secondary 
variables 
20 
HAM-D (6 week), C-SSRS (6 
week) 
HAM-D (2-week and 6-week) 
Summary – 
Secondary 
variables 
20 
Physical examination changes, 
vital signs changes, laboratory 
tests changes, cardiovascular 
changes, and ocular changes 
findings will be described for 
the different treatment groups 
and assessed as either 
clinically or non-clinically 
significant findings. 
Physical examination changes, vital 
signs changes, laboratory tests changes, 
cardiovascular changes, ocular 
changes, suicidal ideation (C-SSRS) 
findings, and positive psychotic 
symptoms (BPRS+) findings will be 
described for the different treatment 
groups and assessed as either clinically 
or non-clinically significant findings. 
3.0 Table of 
contents 
22 
<<blank>> 
<<updated>> 
4.0 List of 
abbreviations and 
definition of terms 
27 
<<blank>> 
BPRS+ – Brief Psychiatric Rating 
Scale positive subscale 
6.2.2 Secondary 
Endpoint(s) 
33 
• Mean absolute change in the 
depression HAM-D score from 
screening/baseline to the end 
of the the 6-week treatment 
period. 
•Mean absolute change in the 
depression HAM-D score from 
screening/baseline to the end of the the 
2-week and 6-week treatment period 
and safety follow-up. 
6.2.2 Secondary 
Endpoints 
33 
<<blank>> 
• Incidence of suicidal ideation (C-
SSRS) findings from 
screening/baseline to the end of the 2-
week and the 6-week treatment period 
and safety follow-up 
• Incidence of positive psychotic 


 
 
 
 
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symptoms (BPRS+) findings from 
screening/baseline to the end of the 2-
week and the 6-week treatment period 
and safety follow-up 
7.1 Overall Study 
Design and Plan: 
Description 
35 
There is a 6 weeks treatment 
period, starting on Day 1, 
followed by a safety follow-up 
call made at least 4 weeks after 
completion of the treatment 
period. Additional 
unscheduled visits may be 
required based on the 
investigators' judgement at the 
end of study visit or at the 
safety phone call. For early 
termination, all the 
assessments of the treatment 
week 6 visit should be 
performed, if possible, 
including the safety follow-up 
call 4 weeks after the last IMP 
administration. 
There is a 6 weeks treatment period, 
starting on Day 1, followed by a safety 
follow-up at least 4 weeks after 
completion of the treatment period. 
Additional unscheduled visits may be 
required based on the investigators' 
judgement at the end of study visit or at 
the safety follow-up. For early 
termination, all the assessments of the 
treatment week 6 visit should be 
performed, if possible, including the 
safety follow-up 4 weeks after the last 
IMP administration. 
Figure 1 
36 
<<Figure 1>> 
<<updated to include C-SSRS, HAM-
D, and BPRS+ at screening, visit 2, 
visit 3, and follow-up>> 
7.2 Discussion of 
Study Design, 
including the 
Choice of Control 
Groups 
37 
[…] have no clinical evidence 
of depression, cognitive 
impairment, or fatigue). 
[…] have no clinical evidence of 
suicidal ideation, depression, cognitive 
impairment, or fatigue). 
7.2 Discussion of 
Study Design, 
including the 
Choice of Control 
Groups 
37 
<<blank>> 
[…] need of referral to a trained mental 
health professional based on their 
suicidal ideation (C-SSRS with an 
answer of ‘yes’ to any of the 6 
questions), […] 
7.2 Discussion of 
Study Design, 
including the 
Choice of Control 
Groups 
37 
The suicide risk will be 
assessed (C-SSRS) both before 
and after treatment 
administration following the 
the FDA Guidance for Industry 
on Suicidal Ideation and 
Behavior(3) 
The suicide risk will be assessed (C-
SSRS) before and after treatment 
administration at all study visits 
including follow-up following the the 
FDA Guidance for Industry on Suicidal 
Ideation and Behavior(1). BPRS+ (Brief 
Psychiatric Rating Scale) positive 
subscale to monitor psychotic 
symptoms and HAM-D to monitor 
depression will be assessed at all study 
visits (including follow-up) based that 
patients with Parkinson’s disease are 
known to be at higher risk of psychosis 
and depression than the general 


 
 
 
 
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population. Follow-up procedures will 
be described for a positive finding on 
the C-SSRS, or an elevated HAM-D or 
psychosis scale score. Vital signs 
(including blood pressure and heart 
rate) will be assessed at all study visits 
(including follow-up) as patients with 
Parkinson’s disease are known to 
commonly exhibit orthostatis and other 
cardiovascular changes. 
8.1 Inclusion 
Criteria 
40 
(3) Subjects with previous 
diagnosis of Parkinson's 
disease (following the UK 
Parkinson’s disease society 
brain bank clinical diagnostic 
criteria. 
(3) Subjects with previous diagnosis of 
Parkinson's disease (following the UK 
Parkinson’s disease society brain bank 
clinical diagnostic criteria)* of 
minimum 3 months before informed 
consent date. 
8.2 Exclusion 
Criteria 
41 
<<blank>> 
<<New criterion #3>> 
(3) 
Subjects with a need of referral 
to a trained mental health professional 
based on their suicidal ideation (C-
SSRS with an answer of ‘yes’ to any of 
the 6 questions)   
8.2 Exclusion 
Criteria 
41 
Exclusion criteria (3) – (17) 
Exclusion criteria (4) to (18) 
8.3 Prior and 
Concomitant 
Therapy 
42 
At a minimum, the following 
medications will be prohibited 
at any time during the study 
(see exclusion criterion #7): 
At a minimum, the following 
medications will be prohibited at any 
time during the study (see exclusion 
criterion #8): 
8.4 Efficacy and 
Safety 
Assessments / 
Variables 
43 
<<reference to follow-up 
safety call>> 
<<reference to follow-up visit>> 
8.4.1.7 Vital signs 
44 
<<assessed at screening and 
visit 3 (day 42)>> 
<<assessed at all study visits 
(screening, visit 2 (day 14), visit 3 (day 
42) or early termination, and follow-up. 
8.4.1.7 Vital signs 
44 
Blood pressure (both systolic 
and diastolic and heart rate) 
will be assessed but this is 
considered for this protocol as 
specific cardiovascular 
assessment (see later) 
Blood pressure (both systolic and 
diastolic and heart rate) will be 
assessed at the same visits but this is 
considered for this protocol as specific 
cardiovascular assessment (see later) 
8.4.1.8 
Contraception and 
Pregnancy 
Avoidance 
45 
<<blank>> 
All potential participate in this clinical 
trial that are of child bearing potential 
MUST use adequate contraception 
methods; this should be one highly 
reliable method (such as intrauterine 
device, sterilisation of one of the 
partners, hormonal birth control 
methods) plus one supplementary 


 
 
 
 
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barrier method (such as condom, 
diaphragm) with a spermicide. 
8.4.1.9 Pregnancy 
46 
All pregnancies from subjects 
on active study drug will be 
followed up to final outcome, 
using the pregnancy form. 
All pregnancies from female subjects, 
or female partner of a male subjects on 
active study drug will be followed up to 
final outcome, using the pregnancy 
form. 
8.4.1.15 
Clinician-
Reported 
Outcome 
Instruments 
51 
<<blank>> 
<<inclusion of C-SSRS and BPRS+>> 
8.4.1.15.3 HAM-
D 
53 
<<assessed at screening and 
visit 3 (day 42)>> 
<<assessed at all study visits 
(screening, visit 2 (day 14), visit 3 (day 
42) or early termination, and follow-up. 
8.4.1.15.3 HAM-
D 
53 
<<blank>> 
Subjects with a HAM-D score ≥ 17 at 
screening will be considered as 
excluded from the study. Any positive 
finding on the HAM-D during the 
study will be followed based on usual 
clinical practice of the participant sites. 
8.4.1.15.4 C-
SSRS 
53 
<<assessed at screening and 
visit 3 (day 42)>> 
<<assessed at all study visits 
(screening, visit 2 (day 14), visit 3 (day 
42) or early termination, and follow-up. 
8.4.1.15.4 C-
SSRS 
54 
<<blank>> 
Subjects with a need of referral to a 
trained mental health professional 
based on their suicidal ideation (C-
SSRS with an answer of ‘yes’ to any of 
the 6 questions) will be considered as 
excluded from the study. Any positive 
finding on the C-SSRS during the study 
will be followed based on usual clinical 
practice of the participant sites. 
8.4.1.15.5 BPRS+ 
54 
<<blank>> 
<<New section describing BPRS+ and 
assessment at all study visits including 
follow-up>> 
8.4.2 Study 
Procedures 
56 
<<blank>> 
Screening: BPRS+ 
Randomisation: Vital signs 
Visit 2: vital signs, C-SSRS, HAM-D, 
BPRS+ 
Visit 3: BPRS+ 
8.4.2 Study 
Procedures 
 
59 
Follow-up Period (+Day 28 
±2) 
During the following up period 
the eye examination post dose 
on Day 42 will be conducted 
and a follow-up safety call will 
be performed 28 days after the 
Follow-up Period (+Day 28 ±2) 
During the following up period the eye 
examination post dose on Day 42 will 
be conducted and a follow-up safety 
visit will be performed 28 days after 
the last IMP administration where the 
vital signs (including hear rate and 


 
 
 
 
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last IMP administration. The 
eye examination should be 
performed before the follow up 
safety call. Additional 
unscheduled visits may be 
arranged as needed for the 
management of eye 
examination findings and / or 
adverse event findings. 
blood pressure), C-SSRS, HAM-D, and 
BPRS+ will be assessed. The eye 
examination should be performed 
before the follow up visit. Additional 
unscheduled visits may be arranged as 
needed for the management of eye 
examination findings and / or adverse 
event findings. 
8.4.2 Study 
Procedures – 
Unscheduled 
visits 
58 
<<blank>> 
Other scales: C-SSRS, HAM-D and 
BPRS+ 
8.4.5 Secondary 
Variables 
60 
• Mean absolute change in the 
depression HAM-D score from 
screening/baseline to the end 
of the the 6-week treatment 
period. 
• Mean absolute change in the 
depression HAM-D score from 
screening/baseline to the end of the the 
2-week and 6-week treatment period 
and safety follow-up. 
8.4.7 Safety 
Variables 
61 
<<blank>> 
• Incidence of suicidal ideation (C-
SSRS) findings from 
screening/baseline to the end of the 2-
week and the 6-week treatment period 
and safety follow-up 
• Incidence of positive psychotic 
symptoms (BPRS+) findings from 
screening/baseline to the end of the 2-
week and the 6-week treatment period 
and safety follow-up 
8.6.6 Method of 
Assigning 
Subjects to 
Treatment Groups 
65 
A computer-generated 
randomisation scheme will be 
provided by Nuvisan 
according to Sponsor 
specification. 
A computer-generated randomisation 
scheme by region will be provided by 
Nuvisan according to Sponsor 
specification. 
8.6.6 Method of 
Assigning 
Subjects to 
Treatment Groups 
65 
The randomisation will be 
stratified by the 
polysomnography and the 
MWT assessment which will 
be performed to a subset of 
subjects (around 50%). The 
information on whether the 
subject will do the 
polysomnography and the 
MWT assessment will be 
collected first and the 
randomisation will be 
performed based on this 
information. A first block of 
medication according to the 
randomisation scheme created 
The randomisation will be stratified by 
region,  the polysomnography and the 
MWT assessment which will be 
performed to a subset of subjects 
(around 50%). The information on 
whether the subject will do the 
polysomnography and the MWT 
assessment will be collected first and 
the randomisation will be performed 
based on this information. A first block 
of medication according to the 
randomisation scheme created for the 
corresponding region will be provided 
to each site. 


 
 
 
 
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will be provided to each site. 
9.7.1 Serious 
Adverse Events 
74 
<<blank>> 
The Medical Manager at Linical will 
review the reported documentation for 
any medical clarification. 
9.7.1 Serious 
Adverse Events 
74 
safetydesk@linical.com 
BEN01.safetydesk@linical.com 
11.1. Statistical 
and analytical 
plans 
77 
The main population for the 
efficacy analysis will be the 
Per Protocol (PP) Population 
defined as all the subjects of 
the intent to treat population 
(ITT) who do not perform any 
major protocol deviation. 
The main population for the efficacy 
analysis will be the intent to treat 
population (ITT). The per protocol 
population (PP) will be analysed also 
as a sensitivity analysis. 
11.1.4 Primary 
Efficacy Analyses 
77 
ESS mean absolute change 
from baseline to the end of the 
6-week treatment period will 
be analysed with an ANCOVA 
model, with the baseline ESS 
as a covariate, and treatment as 
a factor. A non-parametric 
ANCOVA model (as rank 
ANCOVA model) will be 
implemented in case the 
assumptions for the previous 
analysis are not met. Least-
squared (LS) absolute mean 
changes will be presented by 
treatment group together with 
their corresponding 95% 
confidence interval. Paired-
comparisons will be performed 
without any multiplicity 
adjustment.  
As sensitivity analyses, both a 
Last Observation Carried 
Forward (LOCF) imputation 
for missing data, and a mixed-
effect model with repeated 
measures (MMRM) approach 
will be used, under the missing 
at random framework carried 
out using an adequate contrast 
at Week 2 or Week 6, 
accordingly. The model will 
include fixed categorical 
effects of treatment group, 
visit and treatment-by-visit 
interaction as well as the 
continuous fixed covariates of 
ESS mean absolute change from 
baseline to the end of the 6-week 
treatment period will be analysed with 
an ANCOVA model, with the baseline 
ESS as a covariate, region and 
treatment as a factor. Missing data in 
the 6-week ESS evaluation will be 
considered as a treatment failure , that 
is imputing the missing ESS reduction 
as 0. Least-squared (LS) absolute mean 
changes will be presented by treatment 
group together with their corresponding 
95% confidence interval. Paired-
comparisons will be performed without 
any multiplicity adjustment.   
As sensitivity analyses: 
a) A mixed-effect model with repeated 
measures (MMRM) approach will be 
used, under the missing at random 
framework carried out using an 
adequate contrast at Week 2 or Week 6, 
accordingly. The model will include 
fixed categorical effects of treatment 
group, region, visit and treatment-by-
visit interaction as well as the 
continuous fixed covariates of mean 
baseline ESS. This MMRM model will 
be run with an unstructured correlation 
matrix to model the within-subject 
errors. 
b) MCP-Mod approach will be applied 
to identify the most suitable dose-
response curve. Further details about 
the curve selection and validation 
procedures being used will be stated in 
the Statistical Analysis Plan. 


 
 
 
 
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mean baseline ESS. This 
MMRM model will be run 
with an unstructured 
correlation matrix to model the 
within-subject errors. 
c) Similar to the  primary analysis a 
Rank ANCOVA will be modelled in 
order to provide evidence of the 
treatment effect in case of violation of 
normality assumption. 
d) Primary Analysis, and sensitivity 
analysis as described above will be 
performed in the Per Protocol 
Population. 
11.1.5 Secondary 
Efficacy Analyses 
77 
[…] and HAM-D (6-week), 
MoCA (6-week), C-SSRS (6-
week), and FSS (6-week). 
[…] HAM-D (2-week, 6-week and 
follow-up), MoCA (6-week), and FSS 
(6-week). 
11.1.7 Safety 
Analyses 
78 
Physical examination changes, 
vital signs changes, laboratory 
tests changes, cardiovascular 
changes, and ocular changes 
will be described for the 
different treatment groups […] 
Physical examination changes, vital 
signs changes, laboratory tests changes, 
cardiovascular changes, ocular 
changes, suicidal ideation (C-SSRS) 
findings, and positive psychotic 
symptoms (BPRS+) findings will be 
described for the different treatment 
groups […] 
11.5 Handling of 
dropouts or 
missing data 
79 
As sensitivity analyses, both a 
Last Observation Carried 
Forward (LOCF) imputation 
for missing data, and a mixed-
effect model with repeated 
measures (MMRM) approach 
will be used, under the missing 
at random framework carried 
out using an adequate contrast 
at Week 2 or Week 6, 
accordingly. The model will 
include fixed categorical 
effects of treatment group, 
visit and treatment-by-visit 
interaction as well as the 
continuous fixed covariates of 
mean baseline ESS. This 
MMRM model will be run 
with an unstructured 
correlation matrix to model the 
within-subject errors. 
For the primary analysis ESS missing 
at 6-weeks will be inputed under the 
treatment failure approach. 
As sensitivity analyses, a mixed-effect 
model with repeated measures 
(MMRM) approach will be used, under 
the missing at random framework 
carried out using an adequate contrast 
at Week 2 or Week 6, accordingly. The 
model will include fixed categorical 
effects of treatment group, visit and 
treatment-by-visit interaction as well as 
the continuous fixed covariates of mean 
baseline ESS. This MMRM model will 
be run with an unstructured correlation 
matrix to model the within-subject 
errors. 
11.3 
Randomisation 
Methods 
81 
One single randomisation list 
will be performed to guarantee 
a ratio of 1:1:1:1 for the 
treatment groups. 
Three regions will be defined: USA, 
Western Europe and Eastern Europe. 
Regionally randomization list will be 
performed to guarantee a ratio of 
1:1:1:1 for the treatment groups by 
region. 
17.0 Reference 
List 
92 
<<blank>> 
<<updated>> 


 
 
 
 
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18.1 
Administrative 
Information – 
Contacts 
96 
24h emergency contact  
BEN01-medical-
emergency@linical.com 
24h emergency contact  
BEN01.medical.emergency@linical.com 
18.10 BPRS+ 
119 
<<blank>> 
<<new appendix>> 
18.11-18.15 
121 
<<old references 18.10 to 
18.14>> 
<<new references 18.11 to 18.15>> 
18.15 Schedule of 
Assessments 
139 
<<blank>> 
<<updated to: 
- include vital signs with heart rate and 
blood pressure at screening, V2, V3, 
FUP 
- HAM-D, C-SSRS, BPRS+ at 
screening, V2, V3, FUP 
- change follow-up call to follow-up 
visit>> 
 
 
 


 
 
 
 
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REASON FOR NONSUBSTANTIAL AMENDMENT 02 
 
This amended study protocol is prepared to remove the LOCS III assessment (Lens Opacities 
Classification System III) from the ocular examination in the study. As this is a six week study 
the likelihood of observing cataract development in humans is very low and conducting the LOCS 
III assessment does not add value. In order to reduce the patient burden and focus on the ocular 
safety assessment, the LOCS III assessment is removed; but safety eye examination will remain 
both at Screening and during the follow-up period after the 6-week treatment period.  
Additionally, some text passages were clarified and errors were corrected in the study protocol 
corresponding to the following: 
 
No data monitoring committee will be used in this study. 
 
Cross references were updated 
Detailed changes are summarized in the following table: 
 
Section 
Page 
Old text 
New text 
Heading 
All 
Amendment 01, Final Version 1.0 
Amendment 02, Final Version 1.0 
 
All 
20/Jun/2017 
03/Jul/2017 
Reason for 
nonsubstantial 
amendment 02 
4 
<<blank>> 
<<New section with details of the 
nonsubstantial amendment 02>> 
3.0 Table of 
contents 
13 
<<blank>> 
<<updated>> 
6.2.2 Secondary 
Endpoint(s) 
25 
Incidence of slit lamp 
examination findings 
Incidence of eye exam findings 
7.1 Overall Study 
Design and Plan: 
Description 
27 
<<Figure 1>> 
<<updated figure to rename ‘slit 
lamp examination’ with ‘eye 
exam’>> 
8.4.1.13 Slit Lamp 
Examination 
39 
8.4.1.13 Eye Examination 
<<updated section to replace ‘slit 
lamp examination’ with ‘eye 
examination’ 
8.4.2 Study 
Procedures 
Screening 
assessments 
(Day -28 to Day -8) 
45 
Slit lamp examination and full 
ocular check 
Eye examination 
8.4.2 Study 
Procedures 
Treatment Visit 3 
(Day 42 ±3) 
47 
Slit lamp examination and full 
ocular check (should be 
performed after the last treatment 
on Day 42 and before the follow 
up safety call) 
Eye examination (should be 
performed after the last treatment 
on Day 42 and before the follow up 
safety call) 
8.4.2 Study 
Procedures 
Follow-up Period 
(+Day 28 ±2) 
48 
During the following up period 
the slit lamp examination post 
dose on Day 42 will be conducted 
and a follow-up safety call will be 
During the following up period the 
eye examination post dose on Day 
42 will be conducted and a follow-
up safety call will be performed 28 


 
 
 
 
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performed 28 days after the last 
IMP administration. The slit lamp 
examination should be performed 
before the follow up safety call. 
Additional unscheduled visits 
may be arranged as needed for the 
management of slit lamp 
examination findings and / or 
adverse event findings. 
days after the last IMP 
administration. The eye 
examination should be performed 
before the follow up safety call. 
Additional unscheduled visits may 
be arranged as needed for the 
management of eye examination 
findings and / or adverse event 
findings. 
8.4.2 Study 
Procedures 
Unscheduled Visit 
48 
Unscheduled visits may be 
arranged following investigators' 
judgement for Slit lamp 
examination, or adverse event 
findings identified either at the 
end of study or during the follow-
up period. 
Unscheduled visits may be arranged 
following investigators' judgement 
for eye examination, or adverse 
event findings identified either at 
the end of study or during the 
follow-up period. 
8.4.2 Study 
Procedures 
Telephone Contacts 
48 
Sites will maintain telephone 
contacts with subjects during the 
study as reminders for the study 
logistics, including the safety slit 
lamp assessment during follow-
up. 
Sites will maintain telephone 
contacts with subjects during the 
study as reminders for the study 
logistics, including the safety eye 
examination during follow-up. 
8.4.7 Safety 
Variables 
50 
Incidence of slit lamp 
examination findings 
Incidence of eye examination 
findings 
9.7.3 Data 
Monitoring 
Committee 
64 
<<blank>> 
<<New section>> 
No data monitoring committee will 
be used in this study. 
18.14 Schedule of 
Assessments 
123 
Slit lamp examination and ocular 
check 
Eye examination 
18.14 Schedule of 
Assessments 
123 
(1) All subjects will receive a 
phone-call safety follow-up from 
the site 28 days after last study 
visit performed. 
Additional unscheduled visits 
may be arranged in case of slit 
lamp examination, ECG, or 
adverse event findings. 
(1) All subjects will receive a 
phone-call safety follow-up from 
the site 28 days after last study 
visit performed. 
Additional unscheduled visits may 
be arranged in case of eye 
examination, ECG, or adverse event 
findings. 
18.14 Schedule of 
assessments 
123 
(7) The slit lamp examination 
should be performed after the last 
treatment on Day 42 and before 
the follow up safety call. 
(7) The eye examination should be 
performed after the last treatment 
on Day 42 and before the follow up 
safety call. 
 
 
 


 
 
 
 
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REASON FOR NONSUBSTANTIAL AMENDMENT 01 
 
This amended study protocol is prepared to include the Columbia-Suicide Severity Rating Scale 
(C-SSRS)(2, 3) following the US FDA Guidance document on the prospective assessment of 
occurrence of suicidal ideation and behavior in clinical trials(1), and to clarify some text passages 
and correct some errors in the study protocol corresponding to the following: 
 
Inclusion of the C-SSRS assessment both at screening and Visit 3 (week 6) 
 
Inclusion of the C-SSRS assessment as another secondary objective 
 
Insertion of a new Appendix for the C-SSRS information 
 
Update of the study figure to describe the C-SSRS assessment both at screening and Visit 
3 (week 6) 
 
Update of the Schedule of assessment to include the C-SSRS assessment both at screening 
and Visit 3 (week 6), and a new column between Visit 2 and Visit 3 to precise the start 
of the GENEActive® assessment. 
 
Update of references with the inclusion of new references regarding the C-SSRS and the 
US FDA guidance document. 
 
Cross references were updated 
Detailed changes are summarized in the following table: 
 
Section 
Page 
Old text 
New text 
Heading 
All 
Final Version 1.0 
Amendment 01, Final Version 1.0 
 
All 
05/Apr/2017 
20/Jun/2017 
Reason for 
nonsubstantial 
amendment 01 
4 
<<blank>> 
<<New section with details of the 
nonsubstantial amendment 01>> 
Synopsis 
Secondary variables 
9 
<<blank>> 
C-SSRS (6 week) 
3.0 Table of 
contents 
11 
<<blank>> 
<<updated>> 
4.0 List of 
abbreviations and 
definition of terms 
16 
<<blank>> 
C-SSRS: Columbia-Suicide 
Severity Rating Scale 
6.2.2. Secondary 
Endpoint(s) 
23 
<<blank>> 
Mean absolute change in the 
suicidal ideation and behaviour C-
SSRS score from screening/baseline 
to the end of the 6-week treatment 
period. 


 
 
 
 
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7.1 Overall Study 
Design and Plan: 
Description 
24 
Key inclusion / exclusion criteria 
will be verified to determine 
subject eligibility at the screening, 
baseline periods and prior to 
randomization. 
Key inclusion / exclusion criteria 
will be verified to determine subject 
eligibility at the screening, baseline 
periods and prior to randomisation., 
including the suicide risk 
assessment following the FDA 
Guidance for Industry on Suicidal 
Ideation and Behavior(3). 
Figure 1 
25 
<<Figure 1>> 
<<New figure to update the C-
SSRS assessment both at screening 
and Visit 3 (week 6)>> 
7.2 Discussion of 
Study Design, 
including the 
Choice of Control 
Groups 
26 
<<blank>> 
The suicide risk will be assessed 
(C-SSRS) both before and after 
treatment administration following 
the the FDA Guidance for Industry 
on Suicidal Ideation and 
Behavior(3). 
8.4.1.15.4 
Columbia-Suicide 
Severity Rating 
Scale (C-SSRS) 
41 
<<Blank>> 
New section 
8.4.1.15.5 Rater 
Qualification and 
Certification 
41 
8.4.1.16 Rater Qualification and 
Certification 
8.4.1.15.5 Rater Qualification and 
Certification 
8.4.1.15.6 
Maintenance of 
Wakefulness Test 
(MWT) 
42 
8.4.1.17 Maintenance of 
Wakefulness Test (MWT) 
8.4.1.15.6 Maintenance of 
Wakefulness Test (MWT) 
8.4.1.15.7 
Polysomnography 
42 
8.4.1.18 Polysomnography 
8.4.1.15.7 Polysomnography 
8.4.1.15.8 Free 
Living Activity 
43 
8.4.1.19 Free Living Activity 
8.4.1.15.8 Free Living Activity 
8.4.2 Study 
Procedures 
43 
<<Blank>> 
<<C-SSRS included in the 
Screening assessments>> 
8.4.2 Study 
Procedures 
45 
<<Blank>> 
<<C-SSRS included in the Visit 3 
(week 6) assessments>> 
11.1.5 Secondary 
Efficacy Analyses 
64 
<<Blank>> 
C-SSRS (6 week) 
17.0 Reference List 
77 
<<Blank>> 
<<3 new references inserted>> 
18.11 Columbia-
Suicide Severity 
Rating Scale (C-
SSRS) 
109 
<<Blank>> 
<<New appendix to describe the C-
SSRS details>> 
18.12 Fatigue 
Severity Scale 
(FSS) 
119 
18.11 Fatigue Severity Scale 
(FSS) 
18.12 Fatigue Severity Scale (FSS) 
18.14 Schedule of 
Assessments 
121 
18.13 Schedule of Assessments 
18.14 Schedule of Assessments 


 
 
 
 
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18.14 Schedule of 
Assessments 
121 
<<Blank>> 
<<New column between Visit 2 and 
Visit 3 to precise the start of the 
GENEActive® start>> 
<<New row to describe the C-SSRS 
to be assessed both at screening and 
Visit 3 (week 6)>> 
<<Footnotes updated>> 
 
 
 
 


 
 
 
 
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2.0 
Summary 
 
Name of Sponsor(s): BenevolentAI Bio 
 
Compound: Bavisant (H3 receptor antagonist) 
Title of Protocol: Dose finding phase IIb study of Bavisant to evaluate its 
safety and effiCacy in treAtment of exceSsive daytime sleePiness (EDS) in 
PARkinson’s Disease (PD). CASPAR study. 
 
EudraCT No.: 
2017-000877-35 
Study Number: BB-2001-201b 
Phase: 2b 
 
Study design: Phase IIb, randomized, double blind, parallel group, placebo controlled, multicentre, 6-week 
dose-finding study. 
 
Primary objective: To assess the efficacy of Bavisant compared to placebo after a 6-week treatment period 
on excessive daytime sleepiness in Parkinson's disease. 
 
Secondary objectives: To assess the efficacy and safety assessment of Bavisant compared to placebo after 2 
weeks and 6 weeks of treatment. The efficacy assessment will include excessive daytime sleepiness, motor 
control and depression. 
 
Exploratory objectives: Exploratory objectives will include the assessment of free living activity on 
Bavisant compared to placebo after 6 weeks of treatment using a wrist-worn actigraphy device and 
pharmacogenomics analysis. 
 
Subject Population: 
 
Number of Subjects: 200 completed 
 
Number of sites: Appr. 48 sites globally 
Dose Levels: 0.5, 1 and 3 mg tablets and 
matching placebo. 
 
Route of Administration: Oral 
Duration of Treatment: Maximum 14 weeks per 
subject 
Period of Evaluation: 
Screening of 3 weeks 
Baseline assessment of 1 week 
Treatment of 6 weeks 
Safety follow-up of 4 weeks after treatment 
 
Main Criteria for Inclusion: 
(1) 
Signed informed consent (no study-related procedures may be performed before the subject has 
signed the consent form). 
(2) 
Subjects of either sex aged 50 to 80 years (both inclusive and relative to Day 1). 
(3) 
Subjects with previous diagnosis of Parkinson's disease (following the UK Parkinson’s disease 
society brain bank clinical diagnostic criteria)* of minimum 3 months before informed consent 
date. 
(4) 
Subjects capable of understanding and complying with protocol requirements. 
(5) 
Subjects with medical history of excessive daytime sleepiness. 
(6) 
Subjects with moderate or severe excessive daytime sleepiness indicated by an Epworth Sleepiness 
Score (ESS) > 12 at screening . 
(7) 
Subjects with stable nocturnal sleep hygiene practices (e.g. temperature, darkness, quiet, place to lie 
down and stretch out) as per investigator's judgement. 


 
 
 
 
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(8) 
Male subjects who are nonsterilized and sexually active with a female partner of childbearing 
potential agree to use adequate contraception from signing of informed consent throughout the 
duration of the study and for 4 weeks after last dose**. 
(9) 
Female subjects of childbearing potential who are sexually active with a nonsterilized male partner 
agree to use adequate contraception from signing of informed consent throughout the duration of 
the study and for 4 weeks after last dose**. 
(10) Subjects on stable permitted concomitant medication for at least 4 weeks before screening. 
 
* Additional details on the UK Parkinson's disease society brain bank clinical 
diagnostic criteria are included in Appendix 18.2. 
** Definitions and acceptable methods of contraception, and Contraception and 
Pregnancy Avoidance Procedure and reporting responsibilities are defined in Section 
8.4.1.8. 
 
 
Main Criteria for Exclusion: 
(1) 
Subjects with excessive daytime sleepiness due to conditions other than Parkinson's disease 
(including narcolepsy) 
(2) 
Subjects with significant eye disease which may substantially impact the subject's mobility and 
ability to have eye examination conducted as per investigator's judgement. 
(3) 
Subjects with a  recent history of suicide attempt (defined as an active, interrupted or aborted 
attempt within the past 1 year), or reports suicidal ideation in the past 3 months as indicated by a 
positive response on the C-SSRS at screening visit (an answer of ‘yes’ to any of the 6 questions)   
(4) 
Subjects with clinical evidence of depression with significant psychiatric comorbidities (Hamilton 
Rating Scale for Depression - HAM-D score ≥ 17; with or without treatment) 
(5) 
Subjects with evidence of significant Cognitive Impairment (Montreal Cognitive Assessment - 
MoCA score ≤ 22 at screening) 
(6) 
Subjects with evidence of significant fatigue (Fatigue Severity Scale - FSS ≥ 36) 
(7) 
Subjects with high risk of sleep apnoea (Berlin questionnaire with ≥ 2 categories where the score is 
positive) 
(8) 
Subjects taking any of the following prohibited medications at screening: 
 
Alerting agents, including r-modafinil, modafinil or methylphenidate 
 
Benzodiazepines 
 
Histamine active agents 
 
Hypnotics 
 
Cholinergics 
 
Skeletal muscle relaxants 
 
Clozapine 
 
Atomoxetine 
 
Amitriptyline 
 
Any other daytime medications which affect sleep 
(9) 
Subjects with chronic oral and / or ophthalmic steroidal use 
(10) Subjects with either renal or hepatic impairment defined by laboratory parameters >1.5x age-
adjusted limits of normal range 
 
Hepatic damage: Alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
alkaline phosphatase, or total bilirubin 
 
Renal damage: Blood creatinine, blood urea nitrogen [BUN], or estimated glomerular 
filtration rate [eGFR] < 60 mL/min/1.73m2 


 
 
 
 
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(11) Subjects with abnormal ECG time intervals at baseline including QTc (> 450 for males and > 470 
for females) 
(12) Subjects with known history of lung malignancy. 
(13) Subjects with known history of abuse of alcohol or other addictive substances in the 6 months prior 
to inclusion.  
(14) Subjects with known allergies or hypersensitivity to Bavisant or any of its excipients. 
(15) Subjects who are pregnant or lactating. 
(16) Subjects who do not wish to or cannot comply with study procedures.  
(17) Subjects currently receiving, or having received within 3 months prior to enrolment into this clinical 
study, any investigational drug. 
(18) Subjects who are study-site employees, or are immediate family members (i.e., spouse, parent, 
child, sibling) of a study site employee involved in conduct of this study. 
 
Main Criteria for Evaluation and Analysis: 
Primary variable: 
ESS mean absolute change from baseline to the end of the 6-week treatment period will be analysed with an 
ANCOVA model, with the baseline ESS as a covariate, region and treatment as a factor. Missing data in the 
6-week ESS evaluation will be considered as a treatment failure , that is imputing the missing ESS reduction 
as 0. Least-squared (LS) absolute mean changes will be presented by treatment group together with their 
corresponding 95% confidence interval. Paired-comparisons will be performed without any multiplicity 
adjustment.   
As sensitivity analyses: 
a) A mixed-effect model with repeated measures (MMRM) approach will be used, under the missing at 
random framework carried out using an adequate contrast at Week 2 or Week 6, accordingly. The 
model will include fixed categorical effects of treatment group, region, visit and treatment-by-visit 
interaction as well as the continuous fixed covariates of mean baseline ESS. This MMRM model will 
be run with an unstructured correlation matrix to model the within-subject errors. 
b) MCP-Mod approach will be applied to identify the most suitable dose-response curve. Further details 
about the curve selection and validation procedures being used will be stated in the Statistical Analysis 
Plan. 
c) Similar to the primary analysis a Rank ANCOVA will be modelled in order to provide evidence of the 
treatment effect in case of violation of normality assumption. 
d) Primary Analysis, and sensitivity analysis as described above will be performed in the Per Protocol 
Population. 
Secondary variables: 
All secondary variables assessing a mean absolute or a mean relative change will follow a similar 
methodology as for the primary variable; i.e., mean changes of ESS (up to 2-week treatment period), 
SCOPA-Sleep (up to 2-week and 6-week treatment period), PDSS-2 (2-week and 6-week), MWT (6-week), 
polysomnography (6-week), UPDRS Part III (2-week and 6-week), motor function assessed by the wearable 
tool (6-week), HAM-D (2-week and 6-week), MoCA (6-week), and FSS (6-week). 
Percentage of subjects who showed ESS clinical response (defined as an ESS decrease from baseline of at 
least 3.0 points and/or final ESS score ≤10) after 2 and 6 weeks of treatment will be described and compared 
between groups by means of a Chi-square test (or Fisher's exact test according to corresponding 
applicability). Percentages and difference between treatments will be expressed with their 95% confidence 
interval calculated with a binomial exact method.  
Adverse events (AEs), adverse events of special interest (AESIs), serious adverse events (SAEs), serious and 
related adverse events will be coded using the latest available MedDRA version and their corresponding 
incidences will be summarised as overall events, related events, and events by intensity. AEs will be 
summarised by MedDRA preferred term and system organ class (primary SOC). Summaries of AEs by 
preferred term and decreasing frequency and by maximum severity will also be prepared. 
Physical examination changes, vital signs changes, laboratory tests changes, cardiovascular changes, ocular 
changes, suicidal ideation (C-SSRS) findings, and positive psychotic symptoms (BPRS+) findings will be 


 
 
 
 
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described for the different treatment groups and assessed as either clinically or non-clinically significant 
findings. 
Exploratory variables: 
The effect of Bavisant compared to placebo after the 6-week treatment period of free living activity will be 
assessed by means of wrist-worn actigraphy. For each set of continuous tri-axial accelerometry 
measurement, descriptive statistics of values at baseline, endpoint and change from baseline will be provided 
by treatment group. 
Pharmacogenomic information will be assessed in order to identify genetic reasons why certain people 
respond differently to Bavisant, to find out more information about how Bavisant works, and to generate 
information needed for research, development, and regulatory approval of tests to predict response to 
Bavisant, and to identify variations in genes related to the biological target of Bavisant. 
 
Sample size Justification: A total of approximately 200 completed subjects will be evaluated for the study 
(50 completed subjects per treatment group, with expected early withdrawal rate of around 15%). This 
sample size will be enough to confirm a statistically significant difference of at least 3.0 points in ESS 
between Bavisant and placebo (between treatment =3.0; SD=5.0; two-side =0.05; =0.20; power=80%; 
two-sample equal-variance t-test). 
Polysomnography and Maintenance of Wakefulness Test (MWT) will be performed in a minimum of 20 
subjects per group (80 overall) in order to show statistically significant differences if the expected MWT 
absolute change from baseline differs at least in one standard deviation (effect size = 1.0). 
 
 
 


 
 
 
 
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3.0 
Table of contents 
 
 
 
Page 
 
1.0 
TITLE PAGE ................................................................................................................................... 1 
2.0 
SUMMARY .................................................................................................................................... 21 
3.0 
TABLE OF CONTENTS .............................................................................................................. 25 
4.0 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................... 30 
5.0 
INTRODUCTION ......................................................................................................................... 33 
5.1. 
Background .......................................................................................................................... 33 
5.2. 
Study Rationale .................................................................................................................... 35 
6.0 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................ 36 
6.1. 
Objectives ............................................................................................................................. 36 
6.1.1 
Primary Objective ................................................................................................ 36 
6.1.2 
Secondary Objective(s) ....................................................................................... 36 
6.1.3 
Exploratory Objective(s) ..................................................................................... 36 
6.2. 
Endpoints.............................................................................................................................. 36 
6.2.1 
Primary Endpoint ................................................................................................ 36 
6.2.2 
Secondary Endpoint(s) ........................................................................................ 36 
6.2.3 
Exploratory Endpoint(s) ...................................................................................... 37 
7.0 
INVESTIGATIONAL PLAN ....................................................................................................... 38 
7.1. 
Overall Study Design and Plan: Description ........................................................................ 38 
7.2. 
Discussion of Study Design, including the Choice of Control Groups ................................ 39 
8.0 
SELECTION OF STUDY POPULATION ................................................................................. 43 
8.1. 
Inclusion Criteria .................................................................................................................. 43 
8.2. 
Exclusion Criteria ................................................................................................................. 44 
8.3. 
Prior and Concomitant Therapy ........................................................................................... 45 
8.4. 
Efficacy and Safety Assessments / Variables ....................................................................... 46 
8.4.1 
Description of study procedures .......................................................................... 46 
8.4.1.1 
Informed Consent ..................................................................................... 46 
8.4.1.2 
Pharmacogenomic Informed Consent ...................................................... 47 
8.4.1.3 
Demographics .......................................................................................... 47 
8.4.1.4 
Medical history and previous medication ................................................ 47 
8.4.1.5 
Concurrent Medical Condition ................................................................. 47 


 
 
 
 
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8.4.1.6 
Physical examination ............................................................................... 47 
8.4.1.7 
Vital signs ................................................................................................ 47 
8.4.1.8 
Contraception and Pregnancy Avoidance ................................................ 48 
8.4.1.9 
Pregnancy ................................................................................................. 49 
8.4.1.10 Procedure for Clinical Laboratory Samples ............................................. 49 
8.4.1.11 Pharmacogenomic blood sample .............................................................. 50 
8.4.1.12 Electrocardiogram, heart rate, blood pressure .......................................... 51 
8.4.1.13 Eye Examination ...................................................................................... 51 
8.4.1.14 Patient-Reported Outcome Instruments (PRO) ........................................ 51 
8.4.1.14.1 Epworth Sleepiness Scale (ESS) .......................................... 52 
8.4.1.14.2 Scales for Outcome in Parkinson's Disease Sleep (SCOPA-
Sleep) .................................................................................... 52 
8.4.1.14.3 Parkinson's Disease Sleep Scale (PDSS-2)........................... 53 
8.4.1.14.4 Fatigue Severity Scale (FSS) ................................................ 53 
8.4.1.14.5 Berlin Questionnaire (BQ) ................................................... 53 
8.4.1.15 Clinician-Reported Outcome Instruments ................................................ 53 
8.4.1.15.1 Unified Parkinson's Disease Rating Scale (UPDRS Part 
III)......................................................................................... 54 
8.4.1.15.2 Cognitive Impairment (Montreal Cognitive Assessment – 
MoCA) ................................................................................. 54 
8.4.1.15.3 Hamilton Rating Scale for Depression (HAM-D) ................ 55 
8.4.1.15.4 Columbia-Suicide Severity Rating Scale (C-SSRS) ............. 55 
8.4.1.15.5 Brief Psychiatric Rating Scale Positive Subscale (BPRS+) . 56 
8.4.1.15.6 Rater Qualification and Certification ................................... 57 
8.4.1.15.7 Maintenance of Wakefulness Test (MWT) .......................... 57 
8.4.1.15.8 Polysomnography ................................................................. 58 
8.4.1.15.9 Free Living Activity ............................................................. 58 
8.4.2 
Study Procedures ................................................................................................. 58 
8.4.3 
Efficacy Variables ............................................................................................... 62 
8.4.4 
Primary Variables ................................................................................................ 62 
8.4.5 
Secondary Variables ............................................................................................ 62 
8.4.6 
Exploratory Variables .......................................................................................... 63 
8.4.7 
Safety Variables .................................................................................................. 63 
8.5. 
Removal of Subjects from Therapy or Assessment .............................................................. 64 
8.5.1 
Screening failures ................................................................................................ 64 


 
 
 
 
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8.5.2 
Discontinuation or Withdrawal of Individual Subjects ....................................... 64 
8.6. 
Treatments ............................................................................................................................ 65 
8.6.1 
Treatments Administered .................................................................................... 65 
8.6.2 
Identity of Investigational Product(s) .................................................................. 65 
8.6.3 
Dosages and Regimen ......................................................................................... 66 
8.6.4 
Packaging and Labelling ..................................................................................... 66 
8.6.5 
Storage and Disposition of Study Drug ............................................................... 67 
8.6.6 
Method of Assigning Subjects to Treatment Groups........................................... 67 
8.6.7 
Blinding ............................................................................................................... 68 
8.6.8 
Treatment Adherence .......................................................................................... 68 
8.6.9 
Overdose .............................................................................................................. 69 
8.6.10 
Drug Accountability ............................................................................................ 69 
9.0 
PRETREATMENT EVENTS (PTES) AND ADVERSE EVENTS (AES) ............................... 71 
9.1. 
Definitions ............................................................................................................................ 71 
9.1.1 
Adverse Event ..................................................................................................... 71 
9.1.2 
Additional Points to Consider for PTEs and AEs ................................................ 71 
9.1.3 
Serious Adverse Event ........................................................................................ 73 
9.1.4 
Unexpected Adverse Event ................................................................................. 74 
9.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .............................. 74 
9.2. 
Adverse Event Severity ........................................................................................................ 74 
9.3. 
Relationship to Study Drug .................................................................................................. 74 
9.4. 
Action Concerning Study Medication .................................................................................. 75 
9.5. 
Outcome ............................................................................................................................... 75 
9.6. 
Adverse Event Collection Period ......................................................................................... 76 
9.7. 
Adverse Event Reporting ..................................................................................................... 76 
9.7.1 
Serious Adverse Events ....................................................................................... 76 
9.7.2 
Non Serious Adverse Events ............................................................................... 77 
9.7.3 
Data Monitoring Committee ................................................................................ 77 
10.0 
PROTOCOL DEVIATIONS ........................................................................................................ 78 
10.1. Protocol Deviations .............................................................................................................. 78 
10.2. Procedure for protocol amendments ..................................................................................... 78 
11.0 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ......................... 79 
11.1. Statistical and analytical plans ............................................................................................. 79 
11.1.1 
Data Sets Analysed .............................................................................................. 79 


 
 
 
 
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11.1.2 
Demographic and Other Baseline Characteristics ............................................... 79 
11.1.3 
Efficacy Analyses ................................................................................................ 80 
11.1.4 
Primary Efficacy Analyses .................................................................................. 80 
11.1.5 
Secondary Efficacy Analyses .............................................................................. 80 
11.1.6 
Exploratory Analyses .......................................................................................... 80 
11.1.7 
Safety Analyses ................................................................................................... 81 
11.1.8 
Other Analyses .................................................................................................... 81 
11.2. Determination of sample size ............................................................................................... 81 
11.3. Randomisation Methods ....................................................................................................... 82 
11.4. Interim Analysis ................................................................................................................... 82 
11.5. Handling of dropouts or missing data .................................................................................. 82 
11.6. Multiple Comparisons/ Multiplicity ..................................................................................... 82 
11.7. Examination of subgroups .................................................................................................... 83 
12.0 
ETHICS .......................................................................................................................................... 84 
12.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ........................ 84 
12.2. Ethical Conduct of the Study................................................................................................ 84 
12.3. Subject Information and Consent ......................................................................................... 84 
12.4. Confidentiality ...................................................................................................................... 85 
12.5. Insurance Policy ................................................................................................................... 86 
13.0 
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION ............................. 87 
13.1. Source Documents................................................................................................................ 87 
13.2. Case Report Forms ............................................................................................................... 87 
13.3. Monitoring............................................................................................................................ 88 
14.0 
DATA QUALITY ASSURANCE ................................................................................................. 89 
15.0 
PRACTICAL ISSUES ................................................................................................................... 90 
15.1. Early Termination of the Study ............................................................................................ 90 
15.2. Publication Policy ................................................................................................................ 90 
15.2.1 
Clinical Trial Registration ................................................................................... 91 
15.2.2 
Clinical Trial Results Disclosure ......................................................................... 91 
16.0 
DATA MANAGEMENT PROCEDURES .................................................................................. 92 
16.1. Review and Confirmation of Case Report Forms ................................................................ 92 
16.2. Database production and verification ................................................................................... 92 
16.2.1 
Data Management Plan........................................................................................ 92 
16.2.2 
Database .............................................................................................................. 92 


 
 
 
 
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16.2.3 
Database access ................................................................................................... 92 
16.2.4 
Quality and consistency controls ......................................................................... 92 
16.2.5 
Data queries ......................................................................................................... 92 
16.2.6 
Clean File ............................................................................................................ 93 
16.2.7 
Data coding ......................................................................................................... 93 
17.0 
REFERENCE LIST ...................................................................................................................... 94 
18.0 
APPENDICES................................................................................................................................ 98 
18.1. Administrative Information - Contacts ................................................................................. 98 
18.2. UK PDS Brain Bank Diagnostic Criteria for Parkinson's Disease ..................................... 100 
18.3. Epworth Sleepiness Scale (ESS) ........................................................................................ 101 
18.4. Maintenance of Wakefulness Test (MWT) ........................................................................ 102 
18.5. Polysomnography (PSG) .................................................................................................... 104 
18.6. Parkinson's Disease Sleep Scale (PDSS-2) ........................................................................ 110 
18.7. Scales for Outcome in Parkinson's Disease Sleep (SCOPA-Sleep) ................................... 111 
18.8. Unified Parkinson's Disease Rating Scale Part III (UPDRS Part III) ................................. 112 
18.9. Hamilton Rating Scale for Depression (HAM-D) .............................................................. 118 
18.10. Brief Psychiatric Rating Scale Positive Subscale (BPRS+) ............................................... 122 
18.11. Montreal Cognitive Assessment (MoCA) .......................................................................... 125 
18.12. Columbia-Suicide Severity Rating Scale (C-SSRS)........................................................... 130 
18.13. Fatigue Severity Scale (FSS) .............................................................................................. 140 
18.14. Berlin Questionnaire (BQ) ................................................................................................. 141 
18.15. Schedule of Assessments ................................................................................................... 142 
 


 
 
 
 
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4.0 
List of abbreviations and definition of terms 
 
Abbreviation 
Description 
5-HT 
Serotonin 
AASM 
American Association of Sleep Medicine 
ASST 
American Association of Sleep Technologists 
ACh 
Acetylcholine 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ASP 
Average Sleep Propensity 
AST 
Aspartate Aminotransferase 
BPRS 
Brief Psychiatric Rating Scale 
BPRS+ 
Brief Psychiatric Rating Scale Positive Subscale 
BUN 
Blood Urea Nitrogen 
CM 
Concomitant Medication 
CNS 
Central Nervous System 
COMT 
Catechol-O-methyl transferase 
CRF/eCRF 
Case Report Form / electronic CRF 
CRO 
Clinical Research Organisation 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DHM 
Data Handling Manual 
DMC 
Data Monitoring Committee 
DS 
Daytime Sleepiness 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EDS 
Excessive Daytime Sleepiness 
EEG 
Electroencephalogram 
eGFR 
Estimated Glomerular Filtration Rate 
EMG 
Electromyogram 
EOG 
Electro-oculogram 


 
 
 
 
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Abbreviation 
Description 
EoS 
End of Study Visit 
EMA 
European Medicines Agency 
ESS 
Epworth Sleepiness Scale 
EU 
European Union 
FAS 
Full Analysis Set 
FSS 
Fatigue Severity Scale 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transpeptidase 
GOT 
Glutamate Oxaloacetic Transaminase 
GPT 
Glutamate Pyruvic Transaminase 
HAM-D 
Hamilton rating scale for depression 
HIPPA 
Health Insurance Portability and Accountability Act 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
INN 
International Non-proprietary Name 
IRB 
Institutional Review Board 
ISF 
Investigator’s Study File 
ITT 
Intention-to-Treat 
IV 
Intravenous 
LOCF 
Last Observation Carried Forward 
LOCS III 
Lens Opacities Classification System III 
MAOI 
Monoamine Oxidase Inhibitors 
MDD 
Major Depressive Disorder 
UPDRS Part III 
Unified Parkinson's Disease Rating Scale Part III 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed models for repeated measures 
MoCA 
Montreal Cognitive Assessment 
MWT 
Maintenance of Wakefulness Test 
NA 
Noradrenaline 
NS 
Night time Sleep 
PD 
Parkinson's Disease 


 
 
 
 
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Abbreviation 
Description 
PDSS-2 
Parkinson's Disease Sleep Scale 2 
PP 
Per-Protocol 
PTE 
Pre treatment event 
QT 
Electrocardiogram QT interval 
QTc 
Electrocardiogram QT interval corrected 
QTcB 
Electrocardiogram QT interval corrected Bazzett's method 
QTcF 
Electrocardiogram QT interval corrected Fridericia's method 
RR 
Electrocardiogram RR interval 
RSI 
Reference Safety Information 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
s.c. 
Subcutaneous 
SCOPA-Sleep 
Scales for Outcome in Parkinson's Disease Sleep 
SD 
Standard Deviation 
SL 
Sleep Latency 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TMN 
Tuberomammillary Nucleus 
VAS 
Visual Analogue Scale 
WHO 
World Health Organisation 
 


 
 
 
 
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5.0 
Introduction  
5.1. Background 
Parkinson’s Disease (PD) is the second most common neurological disease after Alzheimer’s 
disease. PD affects between 150 and 200 people in every 100,000 population. Thus, some 800,000 
people in Europe are estimated to have Parkinson’s disease and about 75,000 new cases are 
diagnosed annually(4). In the United States around 1 million people are living with PD with about 
60,000 new cases per year(5). 
In the DSM 5 classification of neurodegenerative conditions, diseases such as Parkinson’s disease 
(PD), are associated with hypersomnolence. Excessive daytime sleepiness (EDS) , with or without 
SOREMs is recognised as a core part of the Parkinson Disease phenotype(6). 
In the Honolulu Ageing Study, EDS was assessed in 3078 men without PD aged 71 to 93 years 
from 1991 to 2001. During follow-up, neurological assessment indicated that 43 men developed 
PD (19.9/10,000 person-years),and the authors concluded that EDS is part of the non motor 
spectrum of PD clinical expression and can pre date motor symptoms(7). Excessive daytime 
sleepiness (EDS) is described as inappropriate and undesirable sleepiness during waking hours 
and is a common non-motor symptom in Parkinson's disease, affecting up to 50% of patients, 
being more prominent as the disease advances. EDS has a large impact on the quality of life of 
Parkinson's disease patients as well as of their caregivers, in some cases even more than the motor 
symptoms of the disease(8). Daytime sleepiness may arise in patients with Parkinson's disease for 
many reasons, including poor night's sleep and drug-induced EDS, which is particularly shown 
as an adverse event of many dopamine agonists used for the treatment of Parkinson's disease. 
Dopaminergic treatment may also render a subset of Parkinson's disease patients at risk for 
sudden-onset sleep attacks that occur without warning and can be particularly hazardous. Leading 
neurologists attribute significant morbidity from EDS: 
‘In a well-managed patient with PD, the most common residual complaints are fatigue, lack of 
energy and sleepiness’ (W.Ondo, US Neurologist) 
‘Of all my symptoms EDS is the one that gives me the most trouble in the real world’ (Marshall 
Davidson MD – physician with PD – see http://www.dopadoc.com) 
EDS can occur in patients that are untreated and may precede the onset of movement 
dysfunction(9).  
Non-pharmacological approaches are the mainstay of treatment for mild to moderate EDS as 
pharmacological approaches have yet to provide consistent and reliable results and have 
significant adverse effects e.g. modafinil (Provigil) has not been shown to be consistently 
effective in placebo controlled double blind trials. Other agents that have been used are bupropion 
and psychostimulants, such as amphetamine, but there are significant side effects associated with 
both approaches to therapy. Therefore, there is a real unmet need for an effective, safe agent to 
treat EDS in PD. 
The pathophysiology of EDS in PD is thought to relate to dysfunctional sleep-wake 
control/vigilance mechanisms due to the underlying disease pathology that involves different 
neuroanatomical substrates beyond the classical substrates associated with motor symptoms – the 
nigro-striatal pathway.  


 
 
 
 
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The cellular aetiology of non motor symptoms including sleep disorder is less well defined. Loss 
of dopamine action on neural excitability in several regions outside the striatum may be a factor, 
but neurons producing hypocretin (orexin) - a hypothalamic protein involved in sleep-wake 
regulation, food intake and reward mechanism have been shown to be reduced in PD 
Fronczek et al showed a significant decrease between PD patients and controls in the number of 
hypocretin neurons, the hypocretin-1 concentration in post-mortem ventricular CSF and the 
hypocretin-1 concentrations in prefrontal cortex. The hypocretin-1 concentration in the prefrontal 
cortex was almost 40% lower in PD patients, while ventricular CSF levels were almost 25% 
reduced. The total number of hypocretin neurons was almost half compared to controls(10). 
In a study by Thannikal et al of the hypothalamus of 11 PD (mean age 79 +/- 4) and 5 normal 
(mean age 77 +/- 3) brains, Hcrt (Hypocretin) cells were lost throughout the anterior to posterior 
extent of their hypothalamic distributions. The percentage loss of Hcrt cells was minimal in stage 
I disease (23%) and was maximal in stage V disease (62%). PD was characterized by a massive 
loss of Hcrt neurons, which significantly correlated with the clinical stage of PD, and authors 
commented that the loss of Hcrt cells may be a cause of disordered sleep symptoms of PD(11). 
Extensive neuropathological studies have shown that PD affects areas of the brain that have been 
shown to be key in promoting wakefulness e.g. locus coeruleus, dorsal raphe, and 
pedunculopontine tegmental nucleus(12, 13). The decreases in neurotransmitter function that this 
damage causes may underlay the EDS seen in PD with decreases in levels of acetylcholine (ACh), 
noradrenaline (NA), and serotonin (5-HT), all neurotransmitters important for wakefulness. 
The histamine system has been a rich source of biologically important medicines such as the anti-
allergic H1 antagonists and the anti-ulcer H2 antagonist medicines Tagamet and Zantac. Unlike 
the H1 and H2 receptors, the Histamine H3 receptor is restricted to the CNS and therefore any 
on-target actions against the H3 receptor in the periphery are expected to be minimal. 
Histaminergic neurons arise solely from the tuberomammillary nucleus (TMN) of the posterior 
hypothalamus and project into widespread regions of the mammalian brain and histamine has 
been shown to play a key role in a wide range of higher brain functions such as the sleep-wake 
cycle, appetite, nociception, cognition and emotion. On histaminergic neurons, the histamine H3 
receptor is an auto-receptor which controls neuronal secretion of histamine, with agonists 
(including histamine itself) decreasing synaptic histamine and antagonist or inverse-agonist 
increasing synaptic levels of histamine. Histamine signals wakefulness via H1 receptors, stress 
responses via H1 and H2 receptors and immune regulation via H4 receptors. Additionally, on 
non-histaminergic neurones, the histamine H3 receptor is a heteroreceptor, where histamine acts 
to decrease the release of other neurotransmitters such as acetylcholine, dopamine, serotonin and 
GABA. H3 receptor antagonists and inverse-agonists act at these heteroreceptors to increase the 
release of these neurotransmitters(14, 15). 
The histaminergic system fulfils a major role in the maintenance of waking. Histaminergic 
neurons are located exclusively in the posterior hypothalamus from where they project to most 
areas of the central nervous system. The histamine H3 receptors are autoreceptors damping 
histamine synthesis, the firing frequency of histamine neurons, and the release of histamine from 
axonal varicosities. It is noteworthy that this action also extends to heteroreceptors on the axons 
of most other neurotransmitter systems, allowing a powerful control over multiple homeostatic 


 
 
 
 
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functions. The particular properties and locations of histamine H3 receptors provide quite 
favourable attributes to make this a most promising target for pharmacological interventions of 
sleep and waking disorders associated with narcolepsy, Parkinson's disease, and other 
neuropsychiatric indications(16).  
Preclinically H3 agonists cause sedation whilst H3 antagonists or inverse agonists have the 
opposite effect, increasing wakefulness(16). They have also been shown to increase cognitive 
performance in preclinical species. A number of H3 antagonists have been taken to clinical proof 
of concept studies for a range of CNS disorders including those relating to excessive sleepiness 
such as narcolepsy and one compound, pitolisant has been studied in EDS in PD. Whilst many of 
the studies were negative, studies with pitolisant did produce positive results in narcolepsy, day 
time sleepiness associated with sleep apnoea and EDS in PD. Pitolisant has been approved by the 
EMA for narcolepsy with and without catalepsy and has been launched in the European Union 
(EU) in 2016 under the trade name Wakix. 
 
5.2. Study Rationale 
This Phase 2b study will be conducted with the aim of investigating the efficacy and safety of 
three fixed doses of Bavisant (0.5, 1 and 3 mg/d) compared to placebo for the treatment of 
excessive daytime sleepiness (EDS) in subjects with Parkinson's disease.  
Pathological sleepiness is present in 20-50% of PD (as assessed by an objective measure of 
sleepiness like the multiple sleep latency test [MSLT], with a narcolepsy-like phenotype in 15-
50% of these patients. With a subjective measure widely used to screen for EDS in PD (the 
Epworth Sleepiness score [ESS]), it has been shown that EDS in PD is not reflective of inadequate 
sleep at night but is intrinsic to the disease process and can be exacerbated by therapies given to 
treat the motor symptoms of the disease. Dopaminergic agonist treatment may also render 
Parkinson's disease patients at risk for sudden-onset sleep attacks that occur without warning and 
can be particularly hazardous if the patient is driving. In fact, 11-22% of PD patients experience 
sleepiness while driving and this correlates with higher ESS scores(17, 18). These findings reinforce 
the need for early recognition and management of EDS not only to increase health-related quality 
of life but also to ensure patient safety. 
Bavisant is a potent H3 receptor antagonist with considerable affinity for the human H3 receptor 
and minimal affinity for other neurotransmitters at concentrations up to 1000 times higher than 
its human H3 receptor affinity. In animals, Bavisant has been shown to promote wakefulness and 
attention, reduce sleepiness, and increase cognitive performance. There is therefore strong reason 
to believe that Bavisant will be effective in EDS in PD if administered at the appropriate dose(s). 
Bavisant has been investigated in Phase 2 for the treatment of ADHD (attention deficit 
hyperactivity disorder) and its efficacy was demonstrated at doses up to 30 mg/day; but this was 
not considered adequate to offer advantages over active comparator therapies. From a safety 
perspective, Bavisant was generally well tolerated with common adverse events including 
insomnia, abnormal dreams, headache and nausea, which were dose related. 
Based on preclinical and clinical properties shown, Bavisant has been selected for testing in EDS 
in Parkinson's disease. 


 
 
 
 
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6.0 
Study Objectives and Endpoints 
6.1. Objectives 
6.1.1 
Primary Objective 
To assess the efficacy of Bavisant compared to placebo after a 6-week treatment period on the 
excessive daytime sleepiness in Parkinson's disease. 
 
6.1.2 
Secondary Objective(s) 
To assess the efficacy and safety assessment of Bavisant compared to placebo after 2 weeks and 
6 weeks of treatment. The efficacy assessment will include excessive daytime sleepiness, motor 
control, and depression. 
 
6.1.3 
Exploratory Objective(s) 
Exploratory objectives will include the assessment of free living activity in subjects on Bavisant 
compared to placebo after 6 weeks of treatment using a wrist-worn actigraphy device and 
pharmacogenomics analysis.  
 
6.2. Endpoints 
6.2.1 
Primary Endpoint 
The primary endpoint will be the mean absolute change of Bavisant treatment groups in the 
Epworth Sleepiness Scale (ESS) from baseline to the end of the 6-week treatment period, assessed 
as both the intragroup change compared to baseline and intergroup change compared to placebo.  
 
6.2.2 
Secondary Endpoint(s) 
Efficacy in Excessive Daytime Sleepiness (EDS): 
 
Mean absolute change in the Epworth Sleepiness Scale (ESS) from baseline to the end of 
the 2-week treatment period. 
 
ESS clinical response, defined as ESS absolute decrease from baseline of at least 3.0 
points, after 2 and 6 weeks of treatment. 
 
ESS clinical response, defined as ESS ≤ 10 after 2 and 6 weeks of treatment. 
 
ESS clinical response, defined as either ESS ≤ 10 after 2 and 6 weeks of treatment or ESS 
absolute decrease from baseline of at least 3.0 points after 2 and 6 weeks of treatment.  
 
Mean relative change in the Epworth Sleepiness Scale (ESS) from baseline to the end of 
the 2-week and 6-week treatment periods (percentage of absolute decrease compared to 
baseline ESS). 
 
Mean absolute change in the Scales for Outcome in Parkinson’s Disease Sleep (SCOPA- 
Sleep) from baseline to the end of the 2-week and 6-week treatment period. 


 
 
 
 
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 
Mean absolute change in the Parkinson's Disease Sleep Scale (PDSS-2) from baseline to 
the end of the 2-week and 6-week treatment period. 
 
Mean absolute change in the Maintenance of Wakefulness Test (MWT) from baseline to 
the end of the 6-week treatment period. 
 
Mean absolute change in the polysomnography from baseline to the end of the 6-week 
treatment period. 
Efficacy in Parkinson's disease (PD): 
 
Mean absolute change in the UDPRS scale Part III (motor control) from baseline to the 
end of the 2-week and 6-week treatment period. 
 
Mean absolute change in the depression HAM-D score from screening/baseline to the 
end of the the 2-week and 6-week treatment period and safety follow-up. 
 
Mean absolute change in the Montreal Cognitive Assessment – MoCA score from 
screening/baseline to the end of the 6-week treatment period. 
 
Mean absolute change in the Fatigue Severity Scale – FSS score from screening/baseline 
to the end of the 6-week treatment period. 
The safety of Bavisant compared to placebo will be assessed by the evaluation of the following: 
 
Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events 
of Special Interest (AESIs) such as headache, nausea and insomnia 
 
Incidence of suicidal ideation (C-SSRS) findings from screening/baseline to the end of 
the 2-week and the 6-week treatment period and safety follow-up 
 
Incidence of positive psychotic symptoms (BPRS+) findings from screening/baseline to 
the end of the 2-week and the 6-week treatment period and safety follow-up 
 
Incidence of physical examination, vital signs and laboratory tests findings (haematology 
and biochemistry) 
 
Incidence of cardiovascular safety findings (blood pressure, heart rate, ECG including 
QT/QTc) 
 
Incidence of eye exam findings 
 
6.2.3 
Exploratory Endpoint(s) 
The efficacy of Bavisant compared to placebo after the 6-week treatment period of free living 
activity will be assessed by means of wrist-worn actigraphy. For each set of continuous tri-axial 
accelerometry measurement, descriptive statistics of values at baseline, endpoint and change from 
baseline will be provided by treatment group. 
A pharmacogenomic analysis will be used to identify genetic reasons why certain people respond 
differently to Bavisant, to find out more information about how Bavisant works, and to generate 
information needed for research, development, and regulatory approval of tests to predict 
response to Bavisant, and to identify variations in genes related to the biological target of 
Bavisant. 


 
 
 
 
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7.0 
Investigational Plan 
7.1. Overall Study Design and Plan: Description 
This phase 2b study is designed as multicentre, multinational, randomized, double blind, parallel 
group and placebo controlled with three doses of Bavisant (0.5, 1, and 3 mg/d) in subjects with 
excessive daytime sleepiness with Parkinson's disease. This study will involve approximately 230 
subjects from around 48 sites globally. 
Eligible subjects will be randomly allocated at a ratio of 1:1:1:1 to either Bavisant (at doses of 
0.5, 1, and 3 mg/d) or placebo.  
After signing the study informed consent, subjects meeting the UK PDS Brain Banks Diagnostic 
Criteria for Parkinson's disease(19) (see details in Appendix 18.2) will enter a screening period 
(lasting up to 3 weeks) followed by a baseline period (lasting up to 1 week). Key inclusion / 
exclusion criteria will be verified to determine subject eligibility at the screening, baseline periods 
and prior to randomisation, including the suicide risk assessment following the FDA Guidance 
for Industry on Suicidal Ideation and Behavior(1). 
There is a 6 weeks treatment period, starting on Day 1, followed by a safety follow-up at least 4 
weeks after completion of the treatment period. Additional unscheduled visits may be required 
based on the investigators' judgement at the end of study visit or at the safety follow-up. For early 
termination, all the assessments of the treatment week 6 visit should be performed, if possible, 
including the safety follow-up 4 weeks after the last IMP administration. 
A schematic of the study design is included in Figure 1 and the schedule of assessments is listed 
in Appendix 18.15. 
 


 
 
 
 
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Figure 1. Study figure 
 
 
7.2. Discussion of Study Design, including the Choice of Control Groups 
This trial is designed as a phase 2b, randomized, double blind, parallel group, placebo controlled, 
multicentre, 6-week dose-finding study to assess the efficacy and safety of Bavisant for the 
treatment of excessive daytime sleepiness in subjects with Parkinson's disease. 
There is no regulatory approved pharmacological agent for the treatment of excessive daytime 
sleepiness and despite the use of agents such as modafinil (Provigil), which have not shown 
consistent and reliable effectiveness, there is still a real unmet need in the subject population. 
Bavisant has a unique mechanism of action and may be able to address this need. 
The intention of the proposed selection criteria is to limit participation to PD subjects with 
moderate sleepiness and ability to complete the study assessments without any major impairment 
that may impact the collection of either the efficacy endpoints (should have moderate sleepiness 
due to PD only and no other conditions, be on stable medication without interference of 
concomitant medication as assessed before study participation, have no clinical evidence of 
suicidal ideation, depression, cognitive impairment, or fatigue) or the safety endpoints (hepatic, 
renal, cardiac, ophthalmological). The inclusion criteria of the planned clinical study are intended 
to select adult subjects (50-80 years old, both inclusive), with a previous diagnosis of Parkinson's 
disease (PD), and an objective assessment of at least moderate excessive daytime sleepiness 


 
 
 
 
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(EDS) (Epworth Sleepiness Score [ESS] > 12 at screening). Stable medication for at least 4 weeks 
before screening is mandatory regarding medication which may affect sleep (for example, 
dopaminergics, L-dopa, monoamine oxidase inhibitors, antipsychotics, or hypnotics). The 
exclusion criteria will exclude subjects with EDS due to conditions other than Parkinson's disease 
(including narcolepsy and sleep apnoea), any significant eye disease which may have an impact 
on a subject's mobility (which could hamper the study assessments), clinical evidence of 
depression (HAM-D score ≥ 17, as a certain degree of depression is shown by most of the PD 
subjects), positive response on the C-SSRS (an answer of ‘yes’ to any of the 6 questions), clinical 
evidence of cognitive impairment (MoCA score ≤ 22, as it could interfere with the study 
assessments), clinical evidence of fatigue (FSS ≥ 36, for similar reasons), any alerting medication 
(including r-modafinil, modafinil or methylphenidate), benzodiazepines, histamine active agents, 
clozapine, atomoxetine, skeletal muscle relaxants, or any other daytime medications which affect 
sleep (in order to avoid any selection bias). Subjects with hepatic, renal, cardiac (ECG, including 
QTc), or ophthalmological impairment will not be entered into the study. The suicide risk will be 
assessed (C-SSRS) before and after treatment administration at all study visits including follow-
up following the the FDA Guidance for Industry on Suicidal Ideation and Behavior(1). BPRS+ 
(Brief Psychiatric Rating Scale) positive subscale to monitor psychotic symptoms and HAM-D 
to monitor depression will be assessed at all study visits (including follow-up). These assessments 
are included because patients with Parkinson’s disease are known to be at higher risk of psychosis 
and depression than the general population. Follow-up procedures for a positive finding on the C-
SSRS, or an elevated HAM-D or psychosis scale score will be managed as per the standard of 
care at the site, including an assessment by the investigator of the need for further mental health 
evaluation. Vital signs (including blood pressure and heart rate) will be assessed at all study visits 
(including follow-up) as patients with Parkinson’s disease are known to commonly exhibit 
orthostatis and other cardiovascular changes. 
The Bavisant doses for this study have been selected based on data from previous preclinical and 
clinical research and are lower than the previously anticipated maximum clinical dose of 10 mg/d 
(for more details, please refer to the Investigator Brochure Ed. 9, 2017). Bavisant has been 
evaluated at dosages of 10 mg/d or lower in a total of 9 clinical trials and 481 subjects: 4 phase 1 
studies in healthy adult subjects, 1 study in healthy elderly subjects, a phase 1 study in Japanese 
healthy adult male subjects, 2 phase 1 studies in children with ADHD, and a phase 2b study in 
adult subjects with ADHD. Bavisant has also been used at dosages higher than 10 mg/d in 5 
clinical trials and 198 subjects: 4 phase 1 studies in healthy adult subjects and a phase 2a study in 
men with ADHD. No relevant safety issues are expected since the most common treatment 
emergent adverse events reported (at least 5%) in the Bavisant 10 mg/d group compared to 
placebo were: middle insomnia (27.4% vs 0%), initial insomnia (24.7% vs 6.8%), nausea (19.2% 
vs 1.4%), abnormal dreams (17.8% vs 0%), insomnia (15.1% vs 4.1%), dizziness (12.3% vs 0%), 
and dysgeusia (12.3% vs 0%). Levels of these events at 1 and 3 mg were lower than at 10mg/d. 
The Epworth Sleepiness Scale (ESS) has been selected for the evaluation of the study primary 
endpoint because this is a well-established validated tool for assessing EDS. Normal range is 
between 0 and 10 (2.5 and 97.5 percentiles) which corresponds to "lower normal" (0-5) and 
"higher normal" (6-10). Other ranges can be interpreted as "mild excessive" (11-12), "moderate 
excessive" (13-15) and "severe excessive" (16-24); so in order to control the variability of the 


 
 
 
 
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ESS, the current study requests the categories of either "moderate excessive" or "severe 
excessive" ESS for the study (>12). As the ESS questionnaire is not suitable for use among people 
with serious cognitive impairment, correspondingly subjects with evidence of significant 
cognitive impairment will be excluded from the study (MoCA score ≤ 22).  
The ESS, together with the Multiple Sleep Latency Test (MSLT) and the Maintenance of 
Wakefulness Test (MWT), are three of the most widely used tests of daytime sleepiness. Although 
all these three tests give results that are significantly correlated statistically, the ESS has been 
selected as the primary endpoint for the study as it is considered to be the most discriminating test 
of average of sleep propensity and sleepiness in daily life than either the MSLT or the MWT(20). 
The observation of the US modafinil study group on the effects of modafinil in reducing the EDS 
of narcoleptics was shown more clearly in ESS than the MWT, and least by the MSLT(21). The 
ESS, which is based on retrospective subjective reports, has been shown to produce more accurate 
results than the objective measurement made of the mean sleep latency (SL) in the MSLT or 
MWT. One reason is that the MSLT and MWT can each measure only one situational sleep 
propensity, each of which is correlated in an uncertain way with what is intended to be measured 
–the average of many different situational sleep propensities that reflect the activities of daily life. 
The ESS provides an estimate of the latter, the average sleep propensity in eight specified 
situations(20, 22-25). Whatever cut-off point is used with the mean MSLT-SL it will tend either to 
misdiagnose a significant number of normal subjects as having EDS (false positives) or will fail 
to diagnose some narcoleptics or subjects with other sleep disorders as having EDS (false 
negatives). To do a MSLT or MWT on all subjects suspected of having EDS is difficult to justify 
when the ESS is a more discriminating test, is far cheaper and easier to administer with less burden 
on the patient. On the other hand, the ESS has a clear external validity, and this is the reason why 
the ESS has been already used to confirm the treatment effect (modafinil) on excessive daytime 
sleepiness (although not in Parkinson's disease). 
The polysomnography and MWT will be performed locally by sites that have the practice 
parameters to develop the MWT assessment in accordance with the recommendations developed 
by the Standards of Practice Committee and reviewed and approved by the Board of Directors of 
the American Academy of Sleep Medicine (26). This is key to standardise the procedure at all 
participating sites. 
The study sample size is based on the expected Epworth Sleepiness score (ESS) change from 
baseline after 6 weeks of treatment. The endpoint of 6 weeks has been selected as this is a valid 
time frame for the ESS scale ('Respondents to the ESS rate their chances of having dozed off or 
fallen asleep in particular situations in "recent times". […] intended to mean a few weeks to a 
few months, not a few hours or days.', Johns, http://epworthsleepinessscale.com/about-the-ess/). 
We consider the effect of Bavisant in sleepiness can be observed within 6 weeks which is a valid 
recall period for the ESS, and also there are results already published from clinical trials after 
even lower periods (2 weeks with modafinil in a crossover design in another indication(27, 28), 3 
weeks with caffeine [ClinicalTrials.gov NCT00459420]). The parallel design is preferred over a 
crossover design which can always present a carryover effect which could bias the second 
period(27).  
Although there is not any published agreement on the minimal clinically important difference 
(MCID) for the ESS, the distribution-based method of the standard error of measurement has been 


 
 
 
 
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previously used(22, 29-32), and that is the method chosen for this study. As there is no previous 
reported experience in parallel designs of the standard error of the ESS in Parkinson's disease, the 
assessment report of pitolisant has been used as a reference (EMA/828546/2015)(33). The sample 
size of the corresponding studies, although in another indication, was calculated under the 
hypothesis derived from historical trials with a MCID of 3.0 and a standard deviation of 5.0(34). 
This study will give the assumptions for further research which may use the distribution-based 
method of the standard error once there is experience with Bavisant used in EDS in PD.  
As there is no previous data published on ESS which demonstrate a positive effect of ESS in 
excessive daytime sleepiness in Parkinson's disease, the assumptions used for the sample size 
calculation are based on the pitolisant EPAR with (a) a mean absolute change in the Epworth 
Sleepiness Scale (ESS) from baseline to the end of 6-week treatment period of at least 3.0 points 
and (b) a standard deviation of 5.0(34) which showed an ESS decrease between 2.5 and 2.7 at 
baseline.  
The effect size of Bavisant in EDS is unknown. Smaller changes in ESS may be detected that may 
be clinically useful. In addition, although higher variability is expected in this multicentre study, 
variability may be lower as the selection criteria restricts a baseline ESS > 12.0 points (compared 
to 10.0 by other studies). Therefore, in order to confirm both the intragroup statistical decrease in 
daytime sleepiness together with the intergroup statistical comparison vs. placebo, a total sample 
size of 200 completed subjects (50 per treatment group + expected 15% of early withdrawal rate) 
is proposed in this planned first study. The study will be powered to detect a minimum 3.0 point 
difference in the ESS change from baseline compared to placebo assuming an SD range from 4.0 
to 5.3 (=0.05; =0.20; power=80%; =3.0; SD=5.0).  
Finally, a placebo control group has been considered relevant for the study among other reasons 
because the primary endpoint is a self-reported assessment, subjective by nature. This subjectivity 
is controlled by intra-subject comparisons compared to baseline score, and by statistical methods 
(ANCOVA and MMRM models); but an additional control group with placebo could be 
considered as the natural progression of the EDS within a clinical trial environment. In any case, 
the subjects will be informed about the possibility of receiving placebo, the possible consequences 
and their right to withdraw from the study at any time. 
 
 


 
 
 
 
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8.0 
Selection of study Population 
The subject population will comprise male and female subjects of any race, aged between 50 and 
80 years at Day 1, with a previous diagnosis of Parkinson's disease and a medical history of 
excessive daytime sleepiness confirmed with an Epworth Sleepiness Scale (ESS) > 12 at 
screening which correlates to at least moderate sleepiness ("moderate excessive" [13-15] and 
"severe excessive" [16-24]). Prior to any and all study-specific examinations, subjects will be 
informed as to the extent and nature of their study participation and will be given the opportunity 
to provide their written informed consent. 
Approximately 48 active study sites globally will randomize a total of 230 subjects in order to 
have at least 200 completed subjects (50 completed subjects per treatment group, assuming an 
early withdrawal rate of around 15%). Recruitment will be competitive throughout all counties 
and sites. 
Both inclusion and exclusion criteria will be assessed during the screening period and reconfirmed 
during the baseline period (see Section 8.1 and Section 8.2, respectively). Corresponding 
information should be provided in the eCRF. 
 
8.1. Inclusion Criteria 
Subjects will be eligible for inclusion into the study only if all of the following criteria are met: 
(1) 
Signed informed consent (no study-related procedures may be performed before the 
subject has signed the consent form). 
(2) 
Subjects of either sex aged 50 to 80 years (both inclusive and relative to Day 1) 
(3) 
Subjects with previous diagnosis of Parkinson's disease (following the UK 
Parkinson’s disease society brain bank clinical diagnostic criteria)* of minimum 3 
months before informed consent date.  
(4) 
Subjects capable of understanding and complying with protocol requirements 
(5) 
Subjects with medical history of excessive daytime sleepiness 
(6) 
Subjects with moderate or severe excessive daytime sleepiness indicated by an 
Epworth Sleepiness Score (ESS) > 12 at screening  
(7) 
Subjects with stable nocturnal sleep hygiene practices (e.g. temperature, darkness, 
quiet, place to lie down and stretch out) as per investigator's judgement 
(8) 
Male subjects who are nonsterilized and sexually active with a female partner of 
childbearing potential agree to use adequate contraception from signing of informed 
consent throughout the duration of the study and for 4 weeks after last dose** 
(9) 
Female subjects of childbearing potential who are sexually active with a nonsterilized 
male partner agree to use adequate contraception from signing of informed consent 
throughout the duration of the study and for 4 weeks after last dose** 
(10) Subjects on stable permitted concomitant medication for at least 4 weeks before 
screening.  


 
 
 
 
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* Additional details on the UK Parkinson's disease society brain bank clinical diagnostic 
criteria are included in Appendix 18.2. 
** Definitions and acceptable methods of contraception, and Contraception and Pregnancy 
Avoidance Procedure and reporting responsibilities are defined in Section 8.4.1.8. 
 
8.2. Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria are met: 
(1) 
Subjects with excessive daytime sleepiness due to conditions other than Parkinson's 
disease (including narcolepsy) 
(2) 
Subjects with significant eye disease which may substantially impact the subject's 
mobility and ability to have eye examination conducted as per investigator's 
judgement. 
(3) 
Subjects with a  recent history of suicide attempt (defined as an active, interrupted or 
aborted attempt within the past 1 year), or reports suicidal ideation in the past 3 months 
as indicated by a positive response on the C-SSRS at screening visit ( an answer of 
‘yes’ to any of the 6 questions)   
(4) 
Subjects with clinical evidence of depression with significant psychiatric 
comorbidities (Hamilton Rating Scale for Depression – HAM-D score ≥ 17; with or 
without treatment) 
(5) 
Subjects with evidence of significant Cognitive Impairment (Montreal Cognitive 
Assessment - MoCA score ≤ 22 at screening) 
(6) 
Subjects with evidence of significant fatigue (Fatigue Severity Scale - FSS ≥ 36) 
(7) 
Subjects with high risk of sleep apnoea (Berlin questionnaire with ≥ 2 categories 
where the score is positive) 
(8) 
Subjects taking any of the following prohibited medications at screening: 
 
Alerting agents, including r-modafinil, modafinil or methylphenidate 
 
Benzodiazepines 
 
Histamine active agents 
 
Hypnotics 
 
Cholinergics 
 
Skeletal muscle relaxants 
 
Clozapine 
 
Atomoxetine 
 
Amitriptyline 
 
Any other daytime medications which affect sleep 
(9) 
Subjects with chronic oral and / or ophthalmic steroidal use 
(10) Subjects with either renal or hepatic impairment defined by laboratory parameters 
>1.5x age-adjusted limits of normal range 


 
 
 
 
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 
Hepatic damage: Alanine aminotransferase [ALT], aspartate aminotransferase 
[AST], alkaline phosphatase, or total bilirubin 
 
Renal damage: Blood creatinine, blood urea nitrogen [BUN], or estimated 
glomerular filtration rate [eGFR] < 60 mL/min/1.73m2 
(11) Subjects with abnormal ECG time intervals at baseline including QTc (> 450 for males 
and > 470 for females) 
(12) Subjects with known history of lung malignancy. 
(13) Subjects with known history of abuse of alcohol or other addictive substances in the 6 
months prior to inclusion.  
(14) Subjects with known allergies or hypersensitivity to Bavisant or any of its excipients. 
(15) Subjects who are pregnant or lactating. 
(16) Subjects who do not wish to or cannot comply with study procedures.  
(17) Subjects currently receiving, or having received within 3 months prior to enrolment 
into this clinical study, any investigational drug. 
(18) Subjects who are study-site employees, or are immediate family members (i.e., spouse, 
parent, child, sibling) of a study site employee involved in conduct of this study. 
 
8.3. Prior and Concomitant Therapy 
Any medication or therapy given in addition to the study medication is defined as concomitant 
medication/therapy (CM) and is to be thoroughly documented in the eCRF together with any 
previous medication administered within 4 weeks prior to the date of the informed consent 
signature. These may be prescribed by a physician or obtained by the subject over the counter. 
Concomitant medication is not provided by Sponsor. 
At each study visit, subjects will be asked whether they have taken any medication other than the 
study medication (used from signing of informed consent through the end of the study), and all 
medication including vitamin supplements, over-the-counter medications, and oral herbal 
preparations, must be recorded in the eCRF. 
To the extent possible, the dose of any CM required for chronic diseases should be kept as constant 
as possible throughout the study. Any changes in administration of any CM must be recorded by 
the investigator in the relevant eCRF page. 
The following primary PD medications will be permitted at any time during the study if taken as 
stable medication for at least 4 weeks before screening. Any treatment / dose not described in this 
list should be checked with the medical monitor before deciding the subject randomisation: 
 
Dopaminergics 
 
L-dopa 
 
Monoamine oxidase inhibitors (MAOI) 
 
Short-acting antipsychotics if taken in the evening 
 
Catechol-O-methyl transferase (COMT) inhibitors 
 
Amantadine if not used as an alerting agent 


 
 
 
 
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At a minimum, the following medications will be prohibited at any time during the study (see 
exclusion criterion #8): 
 
Alerting agents, including r-modafinil, modafinil or methylphenidate 
 
Benzodiazepines 
 
Histamine active agents 
 
Hypnotics 
 
Cholinergics 
 
Skeletal muscle relaxants 
 
Clozapine 
 
Atomoxetine 
 
Amitriptyline 
 
Any other daytime medications which affect sleep 
Subjects must be instructed not to take any other medication, including over-the-counter products, 
without consulting with the investigator first; who should contact the medical monitor for 
questions regarding episodic use. 
 
8.4. Efficacy and Safety Assessments / Variables 
The schedule of assessments is described in the Appendix 18.15. 
Subject recruitment for the study is competitive through all sites and countries. Subject data must 
be entered –after written informed consent is obtained– into the eCRF system as soon as possible, 
including demographic data. Data/results from screening and baseline should be added 
immediately upon availability. 
Subjects not entered in the eCRF are not considered as enrolled in the study. 
Study visits are categorized according to the following schedule: pre-treatment screening visit, 
pre-treatment baseline visits, randomisation visit 1 (day-1), treatment visit 2 (day 14 / week 2) 
and visit 3 (day 42 / week 6), and follow-up safety visit 4 weeks after the last IMP administration 
(+28 days). The activities planned for all study visits are described in this section.  
 
8.4.1 
Description of study procedures 
8.4.1.1 
Informed Consent 
Subject Information Sheet and Informed Consent should be obtained prior to the subject entering 
into the study and before any study specific assessment and/or procedures are performed (see 
Section 12.3).  
A unique subject identification number (subject number) will be assigned to each subject at the 
time of screening; this subject number will be used throughout the study. 
 


 
 
 
 
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8.4.1.2 
Pharmacogenomic Informed Consent 
A separate informed consent form pertaining to storage of the sample must be obtained prior to 
collecting blood samples for pharmacogenomic research for this study (see Section 12.3). The 
provision of consent to collect and analyse the pharmacogenomic samples is optional and 
independent of consent to the other aspects of the study. 
 
8.4.1.3 
Demographics 
Demographic information will be collected at screening, including age, gender, race and smoking 
status. 
 
8.4.1.4 
Medical history and previous medication 
Medical history including EDS and PD will be checked and recorded during both the screening 
and the baseline periods. Medical history to be obtained will include determining whether the 
subject has any significant conditions or diseases that stopped at or prior to Screening (time of 
informed consent). Ongoing conditions are considered concurrent medical conditions. 
All relevant previous medication, including all ongoing medication and medication of the last 4 
weeks before screening, should be recorded in the eCRF too. 
 
8.4.1.5 
Concurrent Medical Condition 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at Screening (at time of informed consent). This includes clinically significant laboratory, 
ECG, or physical examination abnormalities. The condition (i.e., diagnosis) should be described, 
and the date that the condition began should be documented 
 
8.4.1.6 
Physical examination 
Complete physical examination will be performed at screening and visit 3 (day 42) or early 
termination. Physical examinations will consist of the following body systems: (1) general 
appearance; (2) extremities; (3) skin; (4) head and neck; (5) eyes, ears, nose and throat; (6) lungs 
and chest; (7) heart/ cardiovascular; (8) neurological; (9) abdomen / gastrointestinal; (10) liver; 
(11) musculoskeletal; and (12) other. Each system should be assessed as normal or abnormal and 
in this last case if that is clinically relevant or not. 
 
8.4.1.7 
Vital signs 
Vital signs (respiratory rate, height, weight and BMI) will be assessed at all study visits 
(screening, visit 2 (day 14), visit 3 (day 42) or early termination, and follow-up. Blood pressure 
(both systolic and diastolic and heart rate) will be assessed at the same visits but this is considered 
for this protocol as specific cardiovascular assessment (see later). 
 


 
 
 
 
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8.4.1.8 
Contraception and Pregnancy Avoidance 
From signing of informed consent, throughout the duration of the study, and for 4 weeks after last 
dose of study medication, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (e.g., condom with spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period. 
From signing of informed consent, throughout the duration of the study, and for 4 weeks after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with 
a nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period. 
*Females NOT of childbearing potential are defined as those who have been surgically 
sterilized (hysterectomy, bilateral oophorectomy or tubal ligation) or who are 
postmenopausal (e.g., defined as at least 1 year since last regular menses with an FSH 
>40 IU/L or at least 5 years since last regular menses, confirmed before any study 
medication is implemented). 
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate. 
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, the only acceptable methods of contraception are: 
Table 1. Acceptable methods of contraception 
(A)Barrier methods (each time the 
subject has intercourse): 
(B) Intrauterine devices 
(IUDs): 
(C)Hormonal 
contraceptives: 
1. Male 
condom 
PLUS 
spermicide. 
2. Cap (plus spermicidal cream 
or jelly) PLUS male condom 
and spermicide. 
3. Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide. 
1. Copper 
T PLUS 
condom 
or 
spermicide. 
2. Progesterone 
T 
PLUS condom or 
spermicide. 
1. Implants. 
2. Hormone 
shot/injection. 
3. Combined pill. 
4. Minipill. 
5. Patch. 
6. Vaginal ring PLUS 
male condom and 
spermicide. 
 
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study. 
All potential participate in this clinical trial that are of child bearing potential MUST use adequate 
contraception methods; this should be one highly reliable method (such as intrauterine device, 
sterilisation of one of the partners, hormonal birth control methods) plus one supplementary 
barrier method (such as condom, diaphragm) with a spermicide. 
During the course of the study, subjects will receive continued guidance with respect to the 
avoidance of pregnancy as part of the study procedures. 
 


 
 
 
 
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8.4.1.9 
Pregnancy  
Blood pregnancy sampling for central assessment will be obtained together with the laboratory 
samples at screening and at visit 3 (day 42) or early termination. A Dipstick pregnancy test to be 
completed before randomisation on day -1. 
If any subject is found to be pregnant during the study she should be withdrawn and any sponsor-
supplied drug should be immediately discontinued and returned to the study site. In addition, any 
pregnancies in the partner of a male subject during the study or for 4 weeks after the last dose, 
should also be recorded following authorisation from the subject’s partner. 
If the pregnancy occurs during administration of active study medication or within 4 weeks of the 
last dose of active study medication, the pregnancy should be reported immediately, using a 
pregnancy notification form. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed. 
If the female subject, or female partner of a male subject, agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject was 
participating in a clinical study at the time the subject/female partner of the subject became 
pregnant and provide details of treatment the subject received. 
All pregnancies from female subjects, or female partner of a male subjects on active study drug 
will be followed up to final outcome, using the pregnancy form. The outcome, including any 
premature termination, must be reported to the sponsor. An evaluation after the birth of the child 
will also be conducted. 
 
8.4.1.10 
Procedure for Clinical Laboratory Samples 
Blood sampling for central assessment will be obtained at screening, baseline (if there is more 
than 14 days between screening and baseline) and finally at visit 3 (day 42) or early termination. 
All samples will be collected in accordance with acceptable laboratory procedures. Details of 
these procedures and required safety monitoring will be given in the laboratory manual provided 
to the site. 
All laboratory values outside the normal range must be evaluated and assessed by the investigator 
for clinical relevance and in this case, they should be recorded in the eCRF as adverse events.  
The clinical analyses will be performed in a central laboratory with blood volumes of around 7 
mL per sampling visit (including haematology, biochemistry and pregnancy testing). Total of 
around 14 mL of blood will be obtained during the whole study for the central laboratory 
examination. 
All material for blood sampling and postage to the central laboratory will be provided by the 
central laboratory. All samples will be labelled with the subject number, visit number, and study 
number. Information on site number, date of sampling, and age will be provided on an 
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The following parameters will be assessed: 
 
Haematology: White Blood Cells (WBC), neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, Red Blood Cells (RBC), Haemoglobin, Haematocrit, Platelet 
Count. 
 
Biochemistry: Total protein, albumin, globulin, glucose, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, urea nitrogen 
(BUN), creatinine, cholesterol, triglycerides, calcium, phosphorus, sodium, potassium, 
chloride. The estimated glomerular filtration rate (eGFR) will be calculated following the 
CKD-EPI Creatinine Equation (2009)(35, 36). 
 
8.4.1.11 
Pharmacogenomic blood sample 
An additional blood sample of 11 mL will be obtained from subjects at screening (separate written 
informed consent) for further pharmacogenomics analysis. 
All material for the pharmacogenomics blood sampling and postage to the central laboratory will 
be provided by the central laboratory. 
When sampling of whole blood for pharmacogenomic analysis occurs, every subject must sign 
the pharmacogenomics informed consent/be consented in order to participate. 
Two whole blood samples (3 mL per sample) for deoxyribonucleic acid (DNA) isolation will be 
collected during the screening period from each subject in the study.  
Two whole blood ribonucleic acid (RNA) samples (2.5 mL per sample) will be collected into 
PAXgeneTM tubes during the screening period. 
 
DNA forms the basis for the genes that make the body produce proteins such as enzymes, 
drug transporters or drug targets. RNA has multiple vital roles in the coding, decoding, 
regulation, expression of genes, and sensing and communicating responses to cellular 
signals. Both DNA and RNA samples may be evaluated for the genetic and expressional 
contribution to how the drug is broken down, or how the drug affects the body. This is 
called a “Pharmacogenomics research study.”  
Specific purposes of this study include: 
 
Identifying genetic reasons why certain people respond differently to Bavisant. 
 
Finding out more information about how Bavisant works. 
 
Generating information needed for research, development, and regulatory approval of 
tests to predict response to Bavisant. 
 
Identifying variations in genes related to the biological target of Bavisant. 
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of Bavisant and other study medications, and for improving the efficiency, design and 
study methods of future research studies.  
If necessary and feasible, a second aliquot of blood may be taken if isolation of DNA from the 
first sample was not successful or possible. Please refer to the Study Manual for information on 
sample collection and preparation. 


 
 
 
 
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The samples will be stored for no longer than 15 years after completion of the study. No samples 
will be stored for longer than permitted by the applicable law and samples will be destroyed upon 
notification from BenevolentAI Bio. “Stored samples” are defined as pseudo anonymised 
samples. Pseudonymisation is a procedure by means of which identifying data with a particular 
algorithm are replaced by encrypted data (the pseudonym). The algorithm can always calculate 
the same pseudonym for a person, by means of which information about the person, also from 
various sources, can be combined. Pseudonymisation distinguishes itself in this way from 
anonymisation, because linking information to a person, from various sources, is not possible 
with anonymisation. With this pseudonymisation the samples are stripped of all personal 
identifying information but the specifications listed below will link the samples to the clinical 
data collected from the sample donor, which is a usual process used in the analysis of 
investigational drug or related drugs:  
 
Study number 
 
Subject number 
 
Sampling date 
Future analysis of the stored pharmacogenomics samples may be conducted as appropriate.  
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual. 
 
8.4.1.12 
Electrocardiogram, heart rate, blood pressure 
A 12-lead ECG will be performed locally at screening and visit 3 (day 42) or early termination. 
Additional ECGs may be performed at the discretion of the investigator during follow-up. The 
findings and any abnormality will be recorded in the eCRF as either medical history (findings at 
screening) or adverse events (any further finding or change from screening). Standard ECG 
parameters will be recorded in the eCRF (heart rate, RR, QT, QTc following both Bazzett's and 
Fridericia's methods).  
 
8.4.1.13 
Eye Examination 
An eye examination will be performed at screening and after study treatment completion or early 
termination. This will include a full ocular check (lids, conjunctiva, sclera, cornea, anterior 
chamber, pupil, iris, and lens) and any abnormalities will be noted. Additional eye examinations 
may be performed at the discretion of the investigator during follow-up. An ophthalmologist will 
evaluate the findings and any abnormality will be recorded in the subject clinical notes as either 
medical history (findings at screening) or any further finding or change from screening after 
completion of study treatment. A specific eye exam procedure guidance document will be 
prepared for the study in order to harmonize the examination..  
 
8.4.1.14 
Patient-Reported Outcome Instruments (PRO) 
Subjects will complete the Epworth Sleep Scale (ESS), Scales for Outcome in Parkinson’s 
Disease Sleep (SCOPA-Sleep), Parkinson’s Disease Sleep Scale 2 (PDSS-2), Fatigue Severity 


 
 
 
 
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Scale (FSS) and the Berlin questionnaire (BQ) at the time points specified in the schedule of 
events (see Appendix 18.15). 
 
8.4.1.14.1 Epworth Sleepiness Scale (ESS) 
The Epworth Sleepiness Scale (ESS)(22-25) is the primary efficacy endpoint and will be assessed 
at all study visits: screening, baseline (day -1), visit 2 (day 14), and visit 3 (day 42) or early 
termination. 
The ESS is a self-administered questionnaire with 8 questions rated on a 4-point scale (0-3) for 
the assessment of the usual chances of dozing off or falling asleep while engaged in eight different 
activities. Most people engage in those activities at least occasionally, although not necessarily 
every day. The ESS score (sum of 8 item scores) ranges from 0 to 24, where the higher score 
corresponds to the higher average sleep propensity (ASP) in daily life (higher daytime sleepiness). 
The questionnaire takes no more than 2 or 3 minutes to answer and although the original language 
was English for Australia, this is validated in many different languages. All those validations were 
performed by Mapi Research Trust (https://eprovide.mapi-trust.org/instruments/epworth-
sleepiness-scale#languages). 
More information on the appropriateness of the ESS as the primary study endpoint is included in 
Section 7.2. An ESS sample questionnaire has been included in Appendix 18.2. 
 
8.4.1.14.2 Scales for Outcome in Parkinson's Disease Sleep (SCOPA-Sleep) 
The Scales for Outcome in Parkinson's Disease (SCOPA-Sleep) is one of the secondary efficacy 
endpoints and will be assessed at baseline (day -1), visit 2 (day 14), and visit 3 (day 42) or early 
termination. 
The SCOPA-Sleep is a specific PD rating scale for assessing night-time sleep (NS) and daytime 
sleepiness (DS) in the past month(37). The NS subscale addresses NS problems in the past month 
and includes 5 items with 4 response options. Subjects have to indicate how much they were 
bothered by particular sleep problems, ranging from 0 (not at all) to 3 (a lot). The 5 items address 
sleep initiation, sleep fragmentation, sleep efficiency, sleep duration, and early wakening. The 
maximum score of this scale is 15, with higher scores reflecting more severe sleep problems. One 
additional question evaluates overall sleep quality on a 7-point scale (ranging from slept very well 
to slept very badly). The score on this item is not included in the score of the NS scale but is used 
separately as a global measure of sleep quality. The DS subscale evaluates DS in the past month 
and includes 6 items with 4 response options, ranging from 0 (never) to 3 (often). Subjects indicate 
how often they fell asleep unexpectedly, fell asleep in particular situations (while sitting 
peacefully, while watching TV or reading, or while talking to someone), how often they had 
difficulty staying awake, and whether falling asleep in the daytime was considered a problem. 
The maximum score is 18, with higher scores reflecting more severe sleepiness. A SCOPA-Sleep 
sample questionnaire has been included in Appendix 18.7. 
 


 
 
 
 
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8.4.1.14.3 Parkinson's Disease Sleep Scale (PDSS-2) 
The Parkinson's Disease Sleep Scale revised version 2 (PDSS-2) is one of the secondary efficacy 
endpoints and will be assessed at baseline (day -1), visit 2 (day 14), and visit 3 (day 42) or early 
termination. 
The Parkinson's Disease Sleep Scale (PDSS) is a scale for the assessment of sleep disorders in 
PD in the past week(6). The scale has 15 items and subjects mark their response to each item on a 
10-cm visual analogue scale (VAS). All PDSS items are focussed on nocturnal sleep, except item 
15 which addresses DS. The total score is the sum of the item scores and the maximum is 150.  
The Revised Version PDSS-2 was developed in order to extend the spectrum of PDSS regarding 
nocturnal disabilities and for an easier use for subjects as the answers are rated in 5 categories 
(from 0 [never] to 4 [very frequent])(38). PDSS-2 total score ranges from 0 (no disturbance) to 60 
(maximum nocturnal disturbance). The scale was originally validated in both English and 
German, and further language validations were performed by Mapi Research Trust 
(https://eprovide.mapi-trust.org/instruments/parkinson-s-disease-sleep-scale-2#languages). 
A 
PDSS-2 sample questionnaire has been included in Appendix 18.5. 
 
8.4.1.14.4 Fatigue Severity Scale (FSS) 
The Fatigue Severity Scale (FSS) is used as one of the exclusion criteria, and will be assessed at 
screening and visit 3 (day 42) or early termination. 
The FSS is a self-administered questionnaire with 9 items investigating the severity of fatigue in 
different situations during the past week. It was developed in 1989 and it is the most commonly 
used fatigue specific questionnaire(39) with its 9 items ranging from 1 to 7, where 1 indicates strong 
disagreement and 7 strong agreement, and the final score represents the mean value of the 9 items. 
A FSS sample questionnaire has been included in Appendix 18.12. 
 
8.4.1.14.5 Berlin Questionnaire (BQ) 
The Berlin Questionnaire (BQ) is used as one of the exclusion criteria, and will be assessed at 
screening only. 
The BQ is a self-administered and validated questionnaire to be used as a screening tool  to 
identify persons in the community who are at high risk for sleep apnoea(40, 41). The questionnaire 
consists of 3 categories (questions 2 to 6 about snoring [category 1], questions 7 to 9 about 
daytime somnolence [category 2], and question 10 about hypertension and BMI [category 3]) and 
the risk is based on the responses to individual items and overall scores in the symptom categories 
(high risk is assessed with 2 or more categories where the score is positive). A BQ sample 
questionnaire has been included in Appendix 18.14. 
 
8.4.1.15 
Clinician-Reported Outcome Instruments 
The following assessments will be performed by qualified personnel (rater) as indicated in the 
schedule of procedures. Rater qualification, certification and training required for any rater and/or 
investigator who will be administering outcomes in this study will be provided 


 
 
 
 
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Qualified personnel (rater) will complete the Unified Parkinson's Disease Rating Scale (UPDRS 
Part III), Cognitive Impairment (Montreal Cognitive Assessment – MoCA), Columbia-Suicide 
Severity Rating Scale (C-SSRS), Brief Psychiatric Rating Scale Positive Subscale (BPRS+), and 
the Hamilton Rating Scale for Depression (HAM-D) at the time points specified in the schedule 
of events (see Appendix 18.15). 
 
8.4.1.15.1 Unified Parkinson's Disease Rating Scale (UPDRS Part III) 
The Unified Parkinson's Disease Rating Scale Part III (UPDRS Part III) is one of the secondary 
efficacy endpoints and will be assessed at baseline (day -1), visit 2 (day 14), and visit 3 (day 42) 
or early termination. Patients will be instructed to have already taken their normally scheduled  
dose of anti-parkinsonian medication and their IMP prior to arriving at the study site in order to 
have their UPDRS Part III evaluated in ON (within approximately 1 to 3 hours after taking their 
levodopa dose). UPDRS in OFF will not be evaluated. 
The UPDRS is the most widely used clinical rating scale for PD(42). The UPDRS was originally 
developed in 1987, and a new version was sponsored in 2001 by the Movement Disorder Society 
in order to retain the strengths of the original scale, but resolving identified problems and 
especially incorporating a number of clinically pertinent PD-related problems poorly captured in 
the original version. The original four component (Parts I-IV) design was retained, but the focus 
of each part was changed. Part I concerns "non-motor experiences of daily living", Part II 
concerns "motor experiences of daily living", Part III is retained as the "motor examination", and 
Part IV concerns "motor complications". Rater involvement time for administering the UPDRS 
is estimated to require less than 15 minutes for Part III. Each question is anchored with five 
responses that are linked to commonly accepted clinical terms of 0 (normal), 1 (slight), 2 (mild), 
3 (moderate), and 4 (severe). Part III contains 33 scores based on 18 items, several with right, left 
or other body distribution scores. An UPDRS Part III sample questionnaire has been included in 
Appendix 18.8. 
 
8.4.1.15.2 Cognitive Impairment (Montreal Cognitive Assessment – MoCA) 
The Montreal Cognitive Assessment (MoCA) is used as one of the exclusion criteria, and will be 
assessed at screening and visit 3 (day 42) or early termination. 
The MoCA was developed as a tool to screen subjects who present with mild cognitive 
impairment(43). A total of 30 items are evaluated as follows: The short-term memory recall task 
(5 points) involves two learning trials of five nouns and delayed recall after approximately 5 
minutes. Visuospatial abilities are assessed using a clock-drawing task (3 points) and a three-
dimensional cube copy (1 point). Multiple aspects of executive functions are assessed using an 
alternation task adapted from the Trail Making B task (1 point), a phonemic fluency task (1 point), 
and a two-item verbal abstraction task (2 points). Attention, concentration, and working memory 
are evaluated using a sustained attention task (target detection using tapping; 1 point), a serial 
subtraction task (3 points), and digits forward and backward (1 point each). Language is assessed 
using a three-item confrontation naming task with low-familiarity animals (lion, camel, 
rhinoceros; 3 points), repetition of two syntactically complex sentences (2 points), and the 
aforementioned fluency task. Finally, orientation to time and place is evaluated (6 points). The 


 
 
 
 
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total possible score is 30 points; a score of 26 or above is considered normal. An MoCA sample 
questionnaire has been included in Appendix 18.10. 
 
8.4.1.15.3 Hamilton Rating Scale for Depression (HAM-D) 
The Hamilton Depression Rating Scale (HAM-D) is one of the secondary efficacy endpoints and 
will be assessed at screening, visit 2 (day 14), visit 3 (day 42) or early termination, and follow-up 
visit (28 days after the last IMP administration). 
The HAM-D was designed as a way of determining a patient's level of depression before, during, 
and after treatment(44). Although the HAM-D form lists 21 items, the scoring is based on the first 
17 (0-7 [normal], 8-13 [mild depression], 14-18 [moderate depression], 19-22 [severe 
depression], and ≥23 [very severe depression]). For the total sum, 8 items are scored on a 5-point 
scale, ranging from 0 (not present) to 4 (severe), and the remaining 9 are scored from 0 to 2. 
Subjects with a HAM-D score ≥ 17 at screening will be considered as excluded from the study. 
Patients with elevated HAM-D during the study will be managed as per the standard of care at 
the site, including an assessment by the investigator of the need for further mental health 
evaluation. 
 An HAM-D sample questionnaire has been included in Appendix 18.9. 
 
8.4.1.15.4 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be assessed at screening, visit 2 (day 
14), visit 3 (day 42) or early termination, and follow-up visit (28 days after the last IMP 
administration). 
The C-SSRS supports suicide risk assessment through a series of simple, plain-language questions 
that anyone can ask(2, 3). The answers help users identify whether someone is at risk for suicide, 
assess the severity and immediacy of that risk, and gauge the level of support that the person 
needs. Users of the C-SSRS tool ask people whether and when they have thought about suicide 
(ideation), what actions they have taken (and when) to prepare for suicide, and whether and when 
they attempted suicide or began a suicide attempt that was either interrupted by another person or 
stopped of their own volition.  
Columbia University, the University of Pennsylvania, and the University of Pittsburgh — 
supported by the National Institute of Mental Health (NIMH) — developed the screening tool for 
a 2007 NIMH study of treatments to decrease suicide risk among adolescents with depression. 
The C-SSRS, based on more than 20 years of scientific study, filled an urgent need for suicide 
research and prevention: a better way to uniformly and reliably identify people who are at risk. 
The C-SSRS achieved accurate and comparable results by using consistent, well-defined, and 
science-based terminology. Just as important as its ability to identify who might attempt suicide, 
it was the first scale to assess the full range of a person’s suicidal ideation and behavior, including 
intensity, frequency, and changes over time. 
In 2011, the Centers for Disease Control and Prevention adopted the scale’s definitions for 
suicidal behavior and recommended the use of the C-SSRS for data collection. In 2012, the Food 
and Drug Administration declared the C-SSRS the standard for measuring suicidal ideation and 


 
 
 
 
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behavior in clinical trials(1). Today, the C-SSRS is used in clinical trials, public settings, and 
everyday situations, such as in schools, faith communities, hospitals, and the military, to identify 
who needs help — saving lives in 45 nations on six continents. 
Subjects with a positive response on the C-SSRS (an answer of ‘yes’ to any of the 6 questions) 
will be considered as excluded from the study. Any positive finding on the C-SSRS during the 
study will be managed as per the standard of care at the site, including an assessment by the 
investigator of the need for further mental health evaluation. 
A C-SSRS sample questionnaire has been included in Appendix 18.12. 
 
8.4.1.15.5 Brief Psychiatric Rating Scale Positive Subscale (BPRS+) 
The Brief Psychiatric Rating Scale Positive Subscale (BPRS+) will be assessed at screening, visit 
2 (day 14), visit 3 (day 42) or early termination, and follow-up visit (28 days after the last IMP 
administration). 
The BPRS is an instrument originally developed to characterize psychopathology and to measure 
change in clinical psychopharmacology research(45). It permits the recording of severity of 18 
(originally 16) distinct signs and symptoms of psychopathology such as hostility, suspiciousness, 
hallucination, and grandiosity, based on clinical interview of a patient. It is particularly useful in 
gauging the efficacy of treatment in patients who have moderate to severe psychoses, and based 
on the clinician’s interview with the patient and observations of the patient’s behaviour over the 
previous 2-3 days. The patient’s family can also provide the behaviour report. The rater enters a 
number for each symptom construct that ranges from 1 (not present) to 7 (extremely severe). 
Psychiatric symptoms, associated with PD itself and specifically in patients with Parkinson’s 
psychosis, consist primarily of paranoid delusions, visual hallucinations and/or other sensory 
disturbances. Psychosis in PD most commonly manifests in visual hallucinations. Auditory 
hallucinations occur less commonly in PD psychosis (unlike hose seen in schizophrenia) and 
typically co-occur with visual hallucinations. Tactile, olfactory and gustatory hallucinations have 
also been reported in PD psychosis and also tend to co-occur with visual hallucinations, but less 
commonly than other forms of hallucinations. Delusions and is organized thinking are also seen 
in PD psychosis, although they are not as common as visual hallucinations. 
While it is assumed that in this study adverse events known to occur with Bavisant will be directly 
assessed along with any sleep related effects, the Brief Psychiatric Rating Scale Positive 
Symptoms Subscale (BPRS+) would be appropriate to observe for psychiatric symptoms 
occurring in this study, with this population. 
The BPRS+ has been used in studies of major depressive disorders(46-50) to observe for psychotic 
features occurring with drug treatment. It consist of 4 (Conceptual Disorganization, 
Suspiciousness, Hallucinatory Behaviour, and Unusual Thought Content) of the 18 domains of 
the full Brief Psychiatric Rating Scale and would cover those symptoms seen with Parkinson’s 
psychosis. It could readily be taught to neurologists to perform in a reasonable amount of time 
during a study visit without becoming an undue burden on either the rater or the subject. The full 
BPRS with its 18 items would require extended time to teach and to perform without offering any 
clear additional benefit over the BPRS+ here. 


 
 
 
 
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Alternatives, such as the Positive and Negative Syndrome Scales (PANSS) have been discarded 
as being primarily used in schizophrenia which has psychotic features which differ from those 
seen with Parkinson’s disease. 
A BPRS+ sample questionnaire has been included in Appendix Error! Reference source not 
found.. 
 
8.4.1.15.6 Rater Qualification and Certification 
In order to ensure satisfactory training of raters and quality execution with regards to data 
collection, raters assigned to this study will be required to adhere to certain requirements prior to 
participation in the trial. All raters will be required to successfully complete the full scope of rater 
training requirements prior to rating any subjects in this study. The rater training and certification 
process will consist of verifying rater qualification via completion of a Rater Experience Survey 
and completion of training or certification on key scales. Raters who successfully complete 
requirements will be approved for participation in the study. Raters who do not meet all the 
qualification and training requirements may be prohibited from participating as raters on this trial.  
 
8.4.1.15.7 Maintenance of Wakefulness Test (MWT) 
The Maintenance of Wakefulness Test (MWT) is one of the secondary efficacy endpoints and 
will be assessed at baseline (day -7 to day -2) and visit 3 (day 42) or early termination at specific 
sleep centres. 
The MWT is an evaluation used as a quantitative polysomnographic (PSG) measurement of 
daytime wakefulness/somnolence during soporific circumstances(51). The assessment of such 
disorders requires a polygraphic approach in which multiple physiologic parameters are recorded. 
This is usually performed during the day following a night sleep with some electrodes placed on 
the head, around the eyes and on the chin. The test isolates subjects from outside factors that can 
influence their ability to fall asleep (temperature, light, noise, activity). The test consists of four 
sleep trials timed at 2-hourly intervals, with the first trial performed 2 to 3 hours after the normal 
wake time and after having eaten a light breakfast at least one hour before the first trial. During 
each trial, subjects will sit quietly on the bed with both back and head supported by a pillow, and 
subjects will be asked to look directly ahead and try to stay awake as long as they can. If they fall 
asleep, they will be woken up after 90 seconds and the trial will end if the subjects do not fall 
asleep within 40 minutes. Start and stop times for each trial, sleep latency, total sleep time, stages 
of sleep achieved for each trial, and the mean sleep latency (the arithmetic mean in minutes of the 
four trials) will be recorded, considering sleep latency as the time from lights out until the first 
epoch of greater than 15 sec of cumulative sleep in a 30-sec epoch of either 3 consecutive epochs 
of stage 1 sleep, or one epoch of any other stage of sleep. In between trials subjects must stay 
awake and stay out of bed. From midnight of the day before the test, drinks containing caffeine 
(tea, coffee, cola drinks, energy drinks, etc.) need to be avoided. In order to harmonize the practice 
parameters of the MWT, a Task Force of content experts was appointed by the American 
Academy of Sleep Medicine and their recommendations were developed by the Standards of 
Practice Committee and reviewed and approved by the Board of Directors of the American 
Academy of Sleep Medicine(26). A copy of these recommendations is included in Appendix 18.4. 


 
 
 
 
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8.4.1.15.8 Polysomnography 
The Polysomnography (PSG) is one of the secondary efficacy endpoints and will be assessed at 
baseline (day -7 to day -2) and visit 3 (day 42) or early termination at specific sleep centres. 
The PSG is a sleep study which consists of a simultaneous recording of multiple physiologic 
parameters related to sleep and wakefulness and is used to evaluate abnormalities of sleep and/or 
wakefulness and other physiologic disorders that have an impact on or are related to sleep and/or 
wakefulness. For a standard test, the subject will have the electroencephalogram (EEG), the 
electro-oculogram (EOG), the electromyogram (EMG), and the electrocardiogram (ECG) 
performed. The American Association of Sleep Technologies developed the technical guideline 
of sleep technology for a standard polysomnography, updated July 2012(52). A copy of this 
guideline is included in Appendix 18.5. 
 
8.4.1.15.9 Free Living Activity  
Approximately half (50%) of subjects participating in the clinical study will be offered an 
opportunity to take part in the assessment of free living activity as an exploratoty assessment. A 
wrist-worn actigraphy device (GENEActiv®) will be provided to these subjects and they will be 
required to wear the actigraphy device on their non-dominant wrist for 7 consecutive days during 
the baseline period (day -7 to day -1) and 7 consecutive days before the last dose on visit 3 (day 
35 to day 42). 
The wrist-worn actigraphy device (GENEActiv®) is a tri-axial accelerometer which provides an 
objective measure of physical activity levels. A study manual with instructions will be provided 
to both the investigators and the subjects. 
 
8.4.2 
Study Procedures  
Screening assessments (Day -28 to Day -8)  
Subjects will be screened for enrolment within 3 weeks prior to the start of baseline assessments. 
Subjects will be screened in accordance with predefined entrance criteria as described in Sections 
8.1 and 8.2. See Section 8.5.1 for the procedure for documenting screen failures.  
Procedures to be completed at screening include: 
 
Subject information/Informed consent signed and dated.  
 
Assessment of inclusion / exclusion criteria. 
 
Demographics 
 
Medical history and previous medication (prohibited as of 4 weeks before D-28) 
 
Concurrent medical condition 
 
Physical examination 
 
Vital signs 


 
 
 
 
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 
For women of childbearing potential the method of contraception must be documented 
(as CM as applicable) 
 
Laboratory (haematology, biochemistry), serum pregnancy test (for women of 
childbearing potential) 
 
Pharmacogenomic blood sample 
 
Electrocardiogram, heart rate, blood pressure 
 
Eye examination 
 
Cognitive assessment (MoCA) 
 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Fatigue assessment (FSS) 
 
Assessment of sleepiness scales: ESS 
 
Other scales: HAM-D, BPRS+ and Berlin Questionnaire 
 
Determination of subject eligibility 
 
Recording of adverse events 
 
Baseline assessments (Day -7 to Day -2) 
Baseline assessment will be performed after subjects have passed all the screening assessments 
and up to 1 week prior to the day of the 1st treatment administration (Day 1). The following 
procedures will be performed and documented during the Baseline period: 
 
Re-assessment of inclusion / exclusion criteria. 
 
Medical history and previous medication  
 
Laboratory (haematology, biochemistry), serum pregnancy test (for women of 
childbearing potential) if there is more than 14 days between screening and baseline. 
 
Maintenance of Wakefulness Test (MWT) 
 
Polysomnography 
 
Wrist-worn actigraphy (GENEActiv®) assessment 7 days continuously before the first 
dose on Day 1 
 
Recording of adverse events 
 
Recording of concomitant medication 
 


 
 
 
 
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Randomisation Visit 1 (Day -1) 
 
Re-assessment of inclusion / exclusion criteria. 
 
Urine dipstick for pregnancy assessment. 
 
Assessment of sleepiness scales: ESS, SCOPA-Sleep, PDSS-2 
 
Other scales: UPDRS Part III 
 
Wrist-worn actigraphy (GENEActiv®) assessment 7 days continuously before the first 
dose on Day 1 
 
Vital signs (including heart rate and blood pressure) 
 
Confirmation of subject eligibility 
 
Subjects will be randomised to their treatment assignments 
 
Study drug dispensing  
 
Recording of adverse events 
 
Recording of concomitant medication 
 
Treatment Visit 2 (Day 14 ±2) 
This visit will be performed 2 weeks after the 1st treatment administration (Day 1). The following 
examinations/procedures will be performed: 
 
Vital signs (including heart rate and blood pressure) 
 
Assessment of sleepiness scales: ESS, SCOPA-Sleep, PDSS-2 
 
Other scales: UPDRS Part III, C-SSRS, HAM-D, BPRS+ 
 
Dispensing of double blind study medication  
 
Drug return and accountability 
 
Recording of adverse events 
 
Recording of concomitant medication 
 
Treatment Visit 3 (Day 42 ±3) 
This visit will be performed 6 weeks after the 1st treatment administration (Day 1). The following 
examinations/procedures will be performed: 
 
Physical examination 
 
Vital signs 
 
Laboratory (haematology, biochemistry), serum pregnancy test (for women of 
childbearing potential) 
 
Electrocardiogram, heart rate, blood pressure 
 
Assessment of sleepiness scales: ESS, SCOPA-Sleep, PDSS-2 
 
Maintenance of Wakefulness Test (MWT) 


 
 
 
 
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 
Polysomnography 
 
Cognitive assessment (MoCA) 
 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Fatigue assessment (FSS) 
 
Other scales: UPDRS Part III, HAM-D and BPRS+ 
 
Wrist-worn actigraphy assessment 7 days continuously  before last dose (day 35 to day 
42). 
 
Wrist-worn actigraphy device return 
 
Drug return and accountability 
 
Recording of adverse events 
 
Recording of concomitant medication 
 
Eye examination (should be performed after the last treatment on Day 42 and before the 
follow up safety call) 
 
Early Termination 
In case of an early termination after 1st IMP administration and before treatment at visit 3 (day 
42), the same procedures planned for the treatment at visit 3 (day 42) should be performed. 
 
Follow-up Period (+Day 28 ±2) 
During the following up period the eye examination post dose on Day 42 will be conducted and 
a follow-up safety visit will be performed 28 days after the last IMP administration where the 
vital signs (including heart rate and blood pressure), C-SSRS, HAM-D, and BPRS+ will be 
assessed. The eye examination should be performed before the follow up visit. Additional 
unscheduled visits may be arranged as needed for the management of eye examination findings 
and / or adverse event findings. 
 
Unscheduled Visit 
Unscheduled visits may be arranged following investigators' judgement for eye examination, or 
adverse event findings identified either at the end of study or during the follow-up period. The 
examinations/procedures may include: 
 
Physical examination 
 
Vital signs 
 
Laboratory (haematology, biochemistry), serum pregnancy test (for women of 
childbearing potential) 
 
Electrocardiogram, heart rate, blood pressure 
 
Other scales: C-SSRS, HAM-D and BPRS+ 
 
Recording of adverse events 


 
 
 
 
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 
Recording of concomitant medication 
 
Telephone Contacts 
Sites will maintain telephone contacts with subjects during the study as reminders for the study 
logistics, including the safety eye examination during follow-up.  
 
Post-Study Care 
The study medication will not be available upon completion of the subject’s participation in the 
study. The subject should be returned to the care of a physician and standard therapies as required. 
 
8.4.3 
Efficacy Variables 
8.4.4 
Primary Variables 
The primary variable will be the mean absolute change of Bavisant treatment groups in the 
Epworth Sleepiness Scale (ESS) from baseline to the end of the 6-week treatment period, assessed 
as both the intragroup change compared to baseline and intergroup change compared to placebo. 
 
8.4.5 
Secondary Variables 
Secondary variables will assess the efficacy on both the excessive daytime sleepiness and PD 
concomitant conditions: 
Efficacy in Excessive Daytime Sleepiness (EDS): 
 
Mean absolute change in the Epworth Sleepiness Scale (ESS) from baseline to the end of 
the 2-week treatment period. 
 
ESS clinical response, defined as ESS absolute decrease from baseline of at least 3.0 
points, after 2 and 6 weeks of treatment. 
 
ESS clinical response, defined as ESS ≤ 10 after 2 and 6 weeks of treatment. 
 
ESS clinical response, defined as either ESS ≤ 10 after 2 and 6 weeks of treatment or ESS 
absolute decrease from baseline of at least 3.0 points after 2 and 6 weeks of treatment.  
 
Mean relative change in the Epworth Sleepiness Scale (ESS) from baseline to the end of 
the 2-week and 6-week treatment periods (percentage of absolute decrease compared to 
baseline ESS). 
 
Mean absolute change in the Scales for Outcome in Parkinson’s Disease Sleep (SCOPA- 
Sleep) from screening/baseline to the end of the 2-week and 6-week treatment period. 
 
Mean absolute change in the Parkinson's Disease Sleep Scale (PDSS-2) from 
screening/baseline to the end of the 2-week and 6-week treatment period. 
 
Mean absolute change in the Maintenance of Wakefulness Test (MWT) from baseline to 
the end of the 6-week treatment period. 
 
Mean absolute change in the polysomnography from baseline to the end of the 6-week 
treatment period. 


 
 
 
 
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Efficacy in Parkinson's disease (PD): 
 
Mean absolute change in the MDS-UDPRS scale Part III (motor control) from 
screening/baseline to the end of the 2-week and 6-week treatment period. 
 
Mean absolute change in the depression HAM-D score from baseline to the end of the 2-
week and 6-week treatment period and safety follow-up. 
 
Mean absolute change in the Montreal Cognitive Assessment – MoCA score from 
screening/baseline to the end of the 6-week treatment period. 
 
Mean absolute change in the Fatigue Severity Scale – FSS score from screening/baseline 
to the end of the 6-week treatment period. 
 
8.4.6 
Exploratory Variables 
The effect of Bavisant compared to placebo after the 6-week treatment period of free living 
activity will be assessed by means of wrist-worn actigraphy. For each set of continuous tri-axial 
accelerometry measurement, descriptive statistics of values at baseline, endpoint and change from 
baseline will be provided by treatment group. 
Pharmacogenomic information will be assessed in order to identify genetic reasons why certain 
people respond differently to Bavisant, to find out more information about how Bavisant works, 
and to generate information needed for research, development, and regulatory approval of tests to 
predict response to Bavisant, and to identify variations in genes related to the biological target of 
Bavisant. 
 
8.4.7 
Safety Variables 
Safety variables will include: 
 
Incidence of Adverse Events (AEs) and Adverse Events of Special Interest (AESIs) like 
headache, nausea and insomnia 
 
Incidence of physical examination, vital signs and laboratory tests findings (haematology 
and biochemistry) 
 
Incidence of cardiovascular safety findings (blood pressure, heart rate, ECG including 
QT/QTc) 
 
Incidence of suicidal ideation (C-SSRS) findings from screening/baseline to the end of 
the 2-week and the 6-week treatment period and safety follow-up 
 
Incidence of positive psychotic symptoms (BPRS+) findings from screening/baseline to 
the end of the 2-week and the 6-week treatment period and safety follow-up 
 
Incidence of eye examination findings 
 


 
 
 
 
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8.5. Removal of Subjects from Therapy or Assessment 
8.5.1 
Screening failures 
Subjects who signed the informed consent form and performed screening and/or baseline 
activities (either completely or partially) but were not randomized to the study are considered 
screening failures. 
If the subject is found to be not eligible at this visit, the investigator should complete the eCRF.  
The primary reason for screen failure should be recorded in the eCRF using the following 
categories: 
 
PTE/AE. 
 
Did not meet inclusion criteria or did meet exclusion criteria.  
 
Significant protocol deviation. 
 
Lost to follow-up. 
 
Voluntary withdrawal, <specify reason>. 
 
Study termination. 
 
Other, <specify reason>. 
Subject numbers assigned to subjects who fail screening should not be reused. 
 
8.5.2 
Discontinuation or Withdrawal of Individual Subjects 
If a randomized subject terminates the study prematurely for any reason, all attempts should be 
made by the investigator to perform the procedures for the early termination visit (same as for the 
week 6 visit) and determine the primary reason for the termination and where possible the primary 
underlining reason, providing as much as detail as possible, and documenting the information on 
the eCRF. Randomized subjects will not be replaced. 
The primary reason for discontinuation or withdrawal of the subject from the study should be 
noted using the following categories: 
(1) Pretreatment event (PTE) or Adverse Event (AE). The subject has experienced an 
adverse event or pre-treatment event that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is 
unwilling to continue because of the adverse event or pre-treatment event.  
(2) Noncompliance with investigational medicinal product (IMP). This includes subjects 
who did not take the study drug for more than 6 consecutive days. 
(3) Major protocol deviation. The subject failed to meet protocol entry criteria or did not 
adhere to protocol requirements, and continued participation poses an unacceptable risk 
to the subject’s health, or a major protocol deviation occurred at the site such as the 
blind was broken.  
(4) Withdrawal of consent. The subject (or subject’s legally acceptable representative) 
wishes to withdraw from the study. The reason for withdrawal, if provided, should be 
recorded in the case report form (eCRF). Subjects may withdraw from the study at any 


 
 
 
 
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time at their own request without giving reasons and without any disadvantageous 
consequences for their subsequent medical care. 
(5) Lost to follow-up. The subject did not return to the clinic and attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented. 
(6) Subject does not fulfil randomisation criteria. 
(7) Other. 
 
In the case of study termination by the sponsor, institutional review board (IRB), independent 
ethics committee (IEC), or regulatory agency, reason for withdrawal should be captured as Other, 
Study Termination. 
If the subject is found to be pregnant during the study, the subject must be withdrawn 
immediately. The reason for withdrawal should be “major protocol deviation” unless there was a 
complication of the pregnancy which led to withdrawal, in which case the reason for withdrawal 
should be “adverse event(s)”. The procedure is described in Section 9.7. 
 
8.6. Treatments  
8.6.1 
Treatments Administered 
BenevolentAI Bio will supply the IMP consisting of: 
 
Bavisant 0.5 mg tablets 
 
Bavisant 1 mg tablets 
 
Bavisant 3 mg tablets  
 
Matching placebo tablets 
 
8.6.2 
Identity of Investigational Product(s) 
Experimental treatment: 
Product Name: 
 
Bavisant tablets 0.5/1/3 mg 
Drug substance: Bavisant dihydrochloride monohydrate 
Pharmaceutical Form: 
Tablets containing Bavisant dihydrochloride monohydrate equivalent 
to 0.5/1/3 mg of Bavisant 
Administration route: 
Oral use 
Dosage: 
Once daily administration 
Manufacturer: 
Nuvisan GmbH, Wegenerstr. 13, Neu-Ulm, Germany 
 
Control treatment: 
Control substance: 
Placebo 
Pharmaceutical Form: 
Tablets 


 
 
 
 
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Administration route: 
Oral use 
Dosage: 
Once daily administration 
Manufacturer: 
Nuvisan GmbH, Wegenerstr. 13, Neu-Ulm, Germany 
 
The IMP will be supplied in wallet cards. The IMP will be identifiable by a unique identification 
number. The wallet cards will contain a surplus of tablets to cover the treatment period and visit 
windows. The IMP should be stored at 25ºC; excursions permitted to 15ºC to 30ºC. 
Each card of investigational medication will be labelled with pertinent study information and 
country-specific regulatory caution statements in country-specific language(s). 
 
8.6.3 
Dosages and Regimen 
Each subject who qualifies for the study will receive wallet cards containing tablets of double-
blind study medication. Subjects will receive 1 wallet card of their assigned treatment at Visit 1 
(for 2 weeks treatment period) and 2 wallet cards at Visit 2 (for 4 weeks treatment period).  
Subjects will be instructed to take 1 tablet orally per day at the same time in the morning, with or 
without food. The first dose is to be taken the day after randomisation when study medication has 
been dispensed to the subject. 
The investigator or designee must instruct the subject to bring each of their study medication 
containers (wallet cards) to each clinic visit, regardless of whether the study medication cards are 
empty. 
 
8.6.4 
Packaging and Labelling 
IMP manufacture will be performed according to Good Manufacturing Practice (GMP) standards 
and according to the currently valid version of the respective national laws applicable at Nuvisan, 
Germany. Identity and stability of the substance for the duration of the study are ensured and 
documented through Certificates of Analyses. 
Products’ labelling will show at least the following information: 
 
Name and address and contact phone of Sponsor and CRO. 
 
Trial reference code and EudraCT Number. 
 
Pharmaceutical dosage form, route of administration and quantity of dosage units. 
 
The number of the IMP, batch number and expiry date. 
 
The statement “for clinical trial use only”. 
 
The statement “keep out of the reach of children”. 
 
The medication number and the Patient Number. 
 
Storage conditions. 
 
Name, principal investigator. 


 
 
 
 
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If applicable, local or country specific requirements regarding labelling of the blister wallets are 
also to be considered. 
 
8.6.5 
Storage and Disposition of Study Drug 
At each study site, the investigator is responsible for the correct storage and handling of the IMP. 
The IMP must be stored in a place with access limited to the investigator and/or especially 
authorized personnel of the local study team only, i.e. study nurse or study coordinator. 
The temperature of the storage area must be monitored and documented. The investigator is 
required to inform the responsible monitor immediately in cases of deviation of the storage 
temperature from the required range (+15°C - +25ºC). Furthermore adherence to the storage 
conditions will be checked routinely by the monitor during the on-site visits. 
 
8.6.6 
Method of Assigning Subjects to Treatment Groups 
A computer-generated randomisation scheme by region will be provided by Nuvisan according 
to Sponsor specification. 
Subjects will be randomized in order to have 200 completed subjects. At the end of the baseline 
period on day -1, all subjects fulfilling the inclusion and exclusion criteria will be randomly 
allocated to one of the 4 treatment groups at a ratio of 1:1:1:1. 
Treatment group 1: 
Bavisant 0.5 mg tablets 
Treatment group 2: 
Bavisant 1.0 mg tablets 
Treatment group 3: 
Bavisant 3.0 mg tablets 
Treatment group 4: 
Placebo tablets 
The randomisation will be stratified by region and by the polysomnography and the MWT 
assessment which will be performed to a subset of subjects (around 50%). The information on 
whether the subject will do the polysomnography and the MWT assessment will be collected first 
and the randomisation will be performed based on this information. A first block of medication 
according to the randomisation scheme created will be provided to each site. Upon completion of 
the first block of medication, the site should request a new supply of medication. In this case, if 
the subject will perform both the polysomnography and the MWT assessment, the randomisation 
number being provided will be selected as the first available from the bottom of the randomisation 
list; otherwise the subject will receive the maximum available subject number. With this method 
(also 
known 
as 
down-up 
/ 
up-down) 
the randomisation 
can 
be 
stratified 
by 
polysomnography/MWT assessment with one single randomisation list and so guaranteeing a 
similar 1:1:1:1 distribution between strata.  
The randomisation number will consist of a 3-digit number which will be linked to the respective 
electronic case report form (eCRF) number. 
At the end of the baseline period, subjects will be randomly allocated to 1 of the 4 treatment 
groups and given the IMP with the next available randomisation number in either ascending or 
descending sequence. The 3-digit randomisation number is printed on the labels of the study 
medication and will uniquely identify the IMP which is assigned to the subject. Each subject must 


 
 
 
 
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be given only the IMP carrying his or her randomisation number. The investigator will document 
the randomisation number in the eCRF and IMP accountability records. 
The randomisation schedule will link sequential medication numbers to treatment codes. The 
medication numbers will be blocked to facilitate attainment of a homogeneous distribution of 
treatment groups. 
The randomisation schedule will be kept at Nuvisan’s CTS department. 
The investigator must keep a subject identification list including sufficient information to link 
records, i.e. eCRF, eDiary, and subject files/hospital records. Furthermore, a list of all subjects 
screened for the study should be kept in the ISF. The identity of the study subjects (subject 
number, year of birth, and age at screening), date of informed consent, and date of inclusion, or 
the reason for non-inclusion of the subjects at screening must be recorded in this subject 
screening/enrolment randomisation log. 
 
8.6.7 
Blinding 
Study treatments are blinded and the randomisation schedule and the allocation to treatment 
groups will not be known to the investigator, the sponsor, or any other person involved in the 
conduct of the study, except in case of an emergency if knowledge of the IMP is necessary to 
provide optimal treatment to the subject in an emergency situation. 
For each subject, the investigator will receive an emergency envelope identified by the study code 
and the medication number, and containing information about the therapy regimen. In case of any 
subject-related event that requires unblinding (e.g. emergency), the investigator will be allowed 
to open the emergency envelope and find out the therapy regimen of the subject. If possible the 
sponsor or his responsible representative should be contacted prior to opening the envelope. Any 
unblinding must be documented with the date, time, and reason for unblinding and the sponsor or 
his responsible representative must be notified; the subject should be withdrawn from the study 
if medically indicated. However, such subjects may remain in the study “under observation” only. 
To ensure the scientific integrity of the study, it is imperative that all emergency envelopes (open 
or sealed), as well as any documentation on unblinding of emergency envelope(s) be returned to 
the sponsor at the end of the study. 
 
8.6.8 
Treatment Adherence 
The IMP will be self-administered by the subjects as once daily oral tablet in the morning. At visit 
2 and visit 3, subjects will return any empty and non-used treatments providing information to 
study personnel regarding their compliance with study medication. Compliance will be monitored 
by study personnel at the site by using the source documents and will be recorded in the eCRF. 
Every visit after baseline will be used for dispensing new medication and collecting used 
medication in order to closely promote the treatment adherence.  
 


 
 
 
 
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8.6.9 
Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to the individual subject according 
to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE eCRF(s).  
SAEs associated with overdose should be reported according to the procedure outlined in Section 
9.7.1. 
In the event of drug overdose, the subject should be treated symptomatically. 
 
8.6.10 Drug Accountability 
The investigator or designee must document the receipt, dispensing, and return of IMP supplies 
and materials provided for this study in specific accountability forms included in the investigator’s 
study file (ISF). The original form will be retrieved from the study site by the responsible monitor, 
and the investigator will retain a copy. Documentation of drug accountability for individual 
subjects will be captured in the eCRF. 
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dispensed only to subjects enrolled in the study. Upon receipt of sponsor-
supplied drug, the investigator or designee must verify the contents of the shipments against the 
packing list. The verifier should ensure that the quantity is correct, and the medication is in good 
condition. If quantity and conditions are acceptable, they should acknowledge the receipt of the 
shipment (by signing the bottom half of the packing list and faxing per instructions provided on 
the form). If there are any discrepancies between the packing list and the actual product received, 
Linical must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed. Proper drug accountability includes, but is not limited to: 
 
Continuously monitoring expiration dates if expiry date is provided to the investigator or 
designee. 
 
Frequently verifying that actual inventory matches documented inventory. 
 
Verifying that the log is completed with the drug lot/medication ID/job number used to 
document each dose. 
 
Verifying that all containers used/assigned are documented accurately on the log. 
 
Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 


 
 
 
 
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Residual medication (complete blisters) must be returned to the sponsor, who will be responsible 
for accountability and destruction. If the site is responsible for destruction, the process must be 
done once the accountability is verified by the study monitor. The investigator is not permitted to 
dispense any study medication to persons not taking part in the study. Non-used drug will be 
returned to the centre at week 2 and week 6, and compliance will be assessed as: 
 
Compliance ሺ%ሻ= ሺTablets dispensedሻ−ሺ�ܾܽ�݁ݐݏ ݎ݁ݐݑݎ�݁݀ሻ
Total number of days between visits
× ͳͲͲ 


 
 
 
 
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9.0 
Pretreatment Events (PTEs) and Adverse Events (AEs) 
9.1. Definitions 
9.1.1 
Adverse Event 
A Pre-Treatment Event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation. 
An adverse event (AE) is defined as any unfavourable and unintended sign (including a clinically 
significant abnormal laboratory finding), symptom or disease, temporally associated with the use 
of a medicinal product, regardless of its nature, intensity, seriousness, or presumed relationship 
(causality) to the product or experimental procedure used. 
All adverse events which occur after the first study medication intake and within 4 weeks after 
the treatment stop date will be considered as treatment emergent adverse events (TEAEs).  
Each TEAE will be evaluated for duration, intensity, and relationship to (or association with) the 
study treatment (or other causes). Additionally, the actions taken (e.g., administration of 
treatment) and the resulting outcome of the adverse event will be indicated on the eCRF. All 
adverse events will be followed up until resolved or as clinically required.  
All subjects will be followed-up for safety reasons, including those subjects who withdraw or stop 
participation due to premature termination of the study, especially if the reason for withdrawal is 
an AE, by means of a phone call 4 weeks after the end of the study treatment. 
Any AE, which remains unresolved after completion of the trial, requires detailed 
evaluation and follow-up until the AE has been resolved or a reasonable explanation for its 
persistence is found. 
If a worsening of any pathological condition that the subject had before the start of the study or 
medical problems that are present prior to the start of treatment but worsen during treatment occur, 
these must be considered as a new adverse event and will require a complete evaluation and the 
relevant explanation in the case report form.  
 
9.1.2 
Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
 
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. 
(Intermittent events for pre-existing conditions or underlying disease should not be 
considered PTEs or AEs.) 
 
Necessitate therapeutic intervention. 
 
Require an invasive diagnostic procedure. 
 
Require discontinuation or a change in dose of study medication or a concomitant 
medication. 
 
Be considered unfavourable by the investigator for any reason. 


 
 
 
 
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 
PTEs/AEs caused by a study procedure (e.g., a bruise after blood draw) should be 
recorded as a PTE/AE. 
Diagnoses vs signs and symptoms: 
 
Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
 
Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs 
if they are judged to be clinically significant (i.e., if some action or intervention is 
required or if the investigator judges the change to be beyond the range of normal 
physiologic fluctuation). A laboratory re-test and/or continued monitoring of an abnormal 
value are not considered an intervention. In addition, repeated or additional noninvasive 
testing for verification, evaluation or monitoring of an abnormality is not considered an 
intervention. 
 
If abnormal laboratory values or ECG findings are the result of pathology for which there 
is an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only 
should be reported appropriately as a PTE or as an AE. 
Pre-existing conditions: 
 
Pre-existing conditions (present at the time of signing of informed consent) are 
considered concurrent medical conditions and should NOT be recorded as PTEs or AEs. 
Baseline evaluations (e.g., laboratory tests, ECG, X-rays etc.) should NOT be recorded 
as PTEs unless related to study procedures. However, if the subject experiences a 
worsening or complication of such a concurrent condition, the worsening or complication 
should be recorded appropriately as a PTE (worsening or complication occurs before start 
of study medication) or an AE (worsening or complication occurs after start of study 
medication). Investigators should ensure that the event term recorded captures the change 
in the condition (e.g., “worsening of…”). 
 
If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence 
of an episode should only be captured as a PTE/AE if the episodes become more frequent, 
serious or severe in nature, that is, investigators should ensure that the AE term recorded 
captures the change in the condition from Baseline (e.g., “worsening of…”). 
 
If a subject has a degenerative concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE 
term recorded captures the change in the condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
 
If the subject experiences a worsening or complication of a PTE after starting 
administration of the study medication, the worsening or complication should be recorded 
appropriately as an AE. Investigators should ensure that the AE term recorded captures 
the change in the condition (e.g., “worsening of…”). 


 
 
 
 
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 
If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”). 
Changes in severity of AEs /Serious PTEs: 
 
If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
 
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure 
is performed early (e.g., as an emergency) due to a worsening of the pre-existing 
condition, the worsening of the condition should be captured appropriately as a PTE or 
an AE. Complications resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
 
Elective procedures performed where there is no change in the subject’s medical 
condition should not be recorded as PTEs or AEs, but should be documented in the 
subject’s source documents. Complications resulting from an elective surgery should be 
reported as AEs. 
Insufficient clinical response (lack of efficacy): 
 
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded 
as an AE. The investigator must make the distinction between exacerbation of pre-
existing illness and lack of therapeutic efficacy. 
Overdose: 
 
Cases of overdose with any medication without manifested side effects are NOT 
considered PTEs or AEs, but instead will be documented on an Overdose page of the 
eCRF. Any manifested side effects will be considered PTEs or AEs and will be recorded 
on the AE page of the eCRF. 
 
9.1.3 
Serious Adverse Event 
Serious adverse events are defined as any untoward medical occurrence that at any dose:  
 
result in subject’s death. 
 
are life-threatening.  
 
result in permanent or significant disability/incapacity.  
 
cause hospital admission or prolong hospital stay.  
 
result in congenital anomalies or birth defects.  
 
medically important condition that may jeopardize the subject or may require intervention 
to prevent any of the outcomes listed above. Examples of such events are intensive 
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or convulsions that do not result in hospitalisation; or development of drug dependency 
or drug abuse. 
NOTE: The term “life-threatening” in the definition of “serious” refers to any adverse event that 
places the subject, in the view of the investigator, at immediate risk of death from the event as it 
occurred, i.e., it does not include an event that, had it occurred in a more severe form, might have 
caused death.  
An overnight stay in the hospital that is only due to transportation, organisation or accommodation 
problems and without medical background does not need to be handled/documented as a SAE. 
Hospitalisations due to surgical procedures for pre-existing conditions that have been planned 
before enrolment of the subject are not considered SAEs. 
 
9.1.4 
Unexpected Adverse Event 
Any adverse event, which is not described in the Reference Safety Information (RSI) of the 
Investigator Brochure (IB) in nature, severity or frequency is unexpected. Expectedness will be 
assessed in relation to the RSI of the IB. For details, please check the IB version 9, 2017. 
 
9.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a suspected adverse reaction 
related to the treatment that is both unexpected and serious. 
 
9.2. Adverse Event Severity 
Severity of adverse events will be classified according to the following criteria:  
 
Mild  
 
Trivial adverse events, of low significance and short duration that 
require no special treatment, and do not substantially impair the 
normal life of the subject.  
Moderate  
Adverse events causing enough discomfort to interfere with normal 
life of the subject but are usually ameliorated by simple therapeutic 
measures.  
Severe 
Adverse events causing disability to work or perform the daily 
activities of the subject, and require systemic drug therapy or other 
treatment 
 
9.3. Relationship to Study Drug 
The causal relationship of an adverse event with the study medication will be established based 
on the following definitions:  
 
Unrelated 
 
There is little or no chance that the study medication caused the AE; 
other conditions, including concurrent illnesses, progression or 
expression of the disease state, or a reaction to a concomitant 
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Unlikely 
Event of laboratory test abnormality, with a time to drug intake that 
makes a relationship improbable (but not impossible). Disease or 
other drugs provide plausible explanations. 
Possible  
A reasonable temporal association exists between the AE and 
treatment administration and/or the AE follows a known response 
pattern to the study drug; but could have been produced by other 
factors such as the subject clinical state, therapeutic intervention or 
concomitant therapy.  
Probable 
A reasonable temporal association exists between the AE and 
treatment administration and/or the AE follows a known response 
pattern to the study drug; and could not have been produced by other 
factors such as the subject clinical state, therapeutic intervention or 
concomitant therapy. 
Definite 
A definite temporal association exists between the AE and treatment 
administration and/or the AE follows a known response pattern to 
the study drug; and could not have been produced by other factors 
such as the subject clinical state, therapeutic intervention or 
concomitant therapy, and the event either occurs immediately 
following 
study 
drug 
administration 
or 
abates 
following 
discontinuation of study treatment and may be confirmed by 
reappearance on repeat exposure. 
For the purpose of safety analyses, all AEs which are classified as ‘Possible’ or ‘Probable’ or 
‘Definite’ will be considered treatment-related events.  
Any subject who is withdrawn from the study because of an AE will be followed until the outcome 
of the event is determined, and the investigator will prepare a written summary of the event and 
document the available follow-up information on the eCRF.  
 
9.4. Action Concerning Study Medication 
 
Drug withdrawn – a study medication is stopped due to the particular AE. 
 
Dose not changed – the particular AE did not require stopping a study medication. 
 
Unknown – only to be used if it has not been possible to determine what action has been 
taken. 
 
Not Applicable – a study medication was stopped for a reason other than the particular 
AE e.g., the study has been terminated, the subject died, dosing with study medication 
was already stopped before the onset of the AE. 
 
Dose Interrupted – the dose was interrupted due to the particular AE. 
 
9.5. Outcome 
 
Recovered/Resolved – Subject returned to first assessment status with respect to the 
AE/PTE. 
 
Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
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has not returned to the normal range or to baseline; the subject died from a cause other 
than the particular AE/PTE with the condition remaining “recovering/resolving”. 
 
Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the 
observed study period has got worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE/PTE state remaining 
“Not recovered/not resolved”. 
 
Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (e.g., recovered from a cardiovascular accident but 
with some persisting paresis). 
 
Fatal – the AEs/PTEs which are considered as the cause of death.  
 
Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
 
9.6. Adverse Event Collection Period 
Adverse events will be collected throughout the whole study period (screening of 3 weeks, 
baseline of 1 week, treatment period of 6 weeks and safety follow-up of 4 weeks). 
A safety follow-up call will be performed 4 weeks after subject’s discharge at the end of the 
treatment period. Information regarding any ongoing AEs, new AEs and SAEs and concomitant 
medications will be collected. Subjects who completed the treatment who cannot be contacted for 
this follow-up call will be considered to have completed the study. Documentation of 
unsuccessful follow-up phone contact, after 3 attempts, should be included in the subject’s source 
document. 
 
9.7. Adverse Event Reporting 
All adverse events occurring during the trial must be documented in the CRF. This applies not 
only to those adverse events supposedly related to the study medication, but also to any undesired 
experience, whether or not a causal relationship is suspected. 
For this, the CRF includes a specific section for collecting information related to the adverse 
events. In addition, for the serious adverse events, a standard Serious Adverse Event report form 
will be included.  
 
9.7.1 
Serious Adverse Events 
All serious adverse events will be reported by the investigator to the monitor responsible for the 
clinical trial or to the Pharmacovigilance Manager at Linical within 24 hours after their 
knowledge. Such report will be made by telephone, fax or email message. The Serious Adverse 
Event report form, duly completed, should be made available to the Pharmacovigilance Manager 
at Linical within 48 hours. The Medical Manager at Linical will review the reported 
documentation for any medical clarification.  
Address and contact phone: 


 
 
 
 
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Reporting time for the phone communication: 24 hours 
Reporting time for the written report: 48 hours 
 
LINICAL 
All notifications calls will be made to Linical Safety department: 
e-mail address: BEN01.safetydesk@linical.com 
Rosa de Lima, 1-bis – EDIFICIO ALBA  
28290 Las Matas (Madrid), Spain  
Tel. +34 91 372 6035  
Fax: +34 91 372 6074 
Reporting of serious adverse events using the Serious Adverse Event report form does not exempt 
from the need to complete all information relating to such adverse events in the specific eCRF 
section.  
If the serious adverse event is still active at the time of reporting or further information is obtained 
after the initial report, this information must be updated on a new Serious Adverse Event Report 
Form, clearly identifying the case in order to avoid duplicity.  
 
9.7.2 
Non Serious Adverse Events  
Non-serious adverse events will be documented in the specific section for reporting in the eCRF 
that will be submitted to BenevolentAI Bio once the participation of the subject in the clinical 
trial is completed. 
 
9.7.3 
Data Monitoring Committee  
No data monitoring committee will be used in this study. 
 
 


 
 
 
 
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10.0 Protocol Deviations 
10.1. Protocol Deviations 
Generally, a protocol deviation is not imperative for subject withdrawal. Before the statistical 
analysis begins, the protocol deviations must be taken into account for the population analysis. 
The mandatory withdrawal reasons will be considered as major protocol deviations. Other 
protocol deviations will be classified as minor protocol deviations. Additionally, the following 
major protocol deviations will be considered: 
1) Violation of one of the inclusion/exclusion criteria after enrolment into the study. 
2) Treatment incorrectly administered, or overdose. 
3) Use of prohibited medication. 
Any protocol deviation must be recorded in the eCRF.  
 
10.2. Procedure for protocol amendments 
Any amendment to this protocol involving a substantial change may be made as an amendment 
or addendum in writing. In order to be formalised, it is necessary to obtain the agreement of all 
the responsible people who signed the original protocol. 
Amendments that can result in substantial changes in the original protocol must be submitted and 
approved by the IRB/IEC and the Health Authorities. 
 


 
 
 
 
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11.0 Statistical Methods and Determination of Sample Size 
11.1. Statistical and analytical plans 
The statistical analysis will be performed by the Department of Biostatistics of Linical, using 
SAS®(53) version 9.2 or later. 
Statistical significance will be assessed for two-sided probability values < 0.05. 
All descriptive variables will be tabulated. Quantitative variables will be described showing their 
number of available and missing observations, mean, median, standard deviation (SD), the range 
(minimum and maximum) and the first and third quartiles. Frequency and percentage will 
describe qualitative variables. Missing values will be tabulated with their frequency but will not 
be included in the calculation of percentages. 
The main population for the efficacy analysis will be the intent to treat population (ITT). The per 
protocol population (PP) will be analysed also as a sensitivity analysis. 
The main population for the safety analysis will be the safety population (SAF), defined as all the 
subjects who have received at least one dose of study treatment. 
Full details of the statistical analysis will be given in a Statistical Analysis Plan (SAP) which will 
be prepared, approved and signed before the database closure, and so before the subjects’ 
evaluability assessment. 
Any deviation from the original SAP will be included and reported in the clinical study report 
(CSR). 
 
11.1.1 Data Sets Analysed 
The safety population (SAF) will be defined as all subjects who have received at least one dose 
of the study treatment. 
The intent to treat population (ITT) will be defined as all subjects who have taken at least one 
dose of study treatment and who have available a post-baseline evaluation of the primary efficacy 
endpoint at screening/baseline and at week 6. 
The per protocol population (PP) will be defined as all subjects in the FAS who do not experience 
a major protocol deviation. 
 
11.1.2 Demographic and Other Baseline Characteristics 
Baseline characteristics (gender, age, race, weight, height, body mass index, blood pressure, heart 
rate) for the safety population will be summarised descriptively. 
Categorical data will be summarised with absolute and relative frequencies (percentage), and 
numerical data will be summarised with the number, mean, median, standard deviation (SD), the 
range (minimum and maximum), and the first and third quartiles (if applicable). 
 


 
 
 
 
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11.1.3 Efficacy Analyses 
11.1.4 Primary Efficacy Analyses 
ESS mean absolute change from baseline to the end of the 6-week treatment period will be 
analysed with an ANCOVA model, with the baseline ESS as a covariate, region and treatment as 
a factor. Missing data in the 6-week ESS evaluation will be considered as a treatment failure , that 
is imputing the missing ESS reduction as 0. Least-squared (LS) absolute mean changes will be 
presented by treatment group together with their corresponding 95% confidence interval. Paired-
comparisons will be performed without any multiplicity adjustment.   
As sensitivity analyses: 
a) A mixed-effect model with repeated measures (MMRM) approach will be used, under the 
missing at random framework carried out using an adequate contrast at Week 2 or Week 6, 
accordingly. The model will include fixed categorical effects of treatment group, region, visit and 
treatment-by-visit interaction as well as the continuous fixed covariates of mean baseline ESS. 
This MMRM model will be run with an unstructured correlation matrix to model the within-
subject errors. 
b) MCP-Mod approach will be applied to identify the most suitable dose-response curve. Further 
details about the curve selection and validation procedures being used will be stated in the 
Statistical Analysis Plan. 
c) Similar to the  primary analysis a Rank ANCOVA will be modelled in order to provide evidence 
of the treatment effect in case of violation of normality assumption. 
d) Primary Analysis, and sensitivity analysis as described above will be performed in the Per 
Protocol Population. 
 
11.1.5 Secondary Efficacy Analyses 
All secondary variables assessing a mean absolute or a mean relative change will follow a similar 
methodology as for the primary variable; i.e., mean changes of ESS (up to 2-week treatment 
period), SCOPA-Sleep (up to 2-week and 6-week treatment period), PDSS-2 (2-week and 6-
week), MWT (6-week), polysomnography (6-week), UPDRS Part III (2-week and 6-week), motor 
function assessed by the wrist worn device (6-week), HAM-D (2-week, 6-week and follow-up), 
MoCA (6-week), and FSS (6-week). 
The percentage of subjects who showed ESS clinical response (defined as an ESS decrease from 
baseline of at least 3.0 points and/or final ESS score ≤10) after 2 and 6 weeks of treatment will 
be described and compared between groups by means of a Chi-square test (or Fisher's exact test 
according to corresponding applicability). Percentages and difference between treatments will be 
expressed with their 95% confidence interval calculated with a binomial exact method.  
 
11.1.6 Exploratory Analyses 
All variables obtained with the wearable tool assessing a mean absolute or a mean relative change 
will follow a similar methodology as for the primary variable. Categorical variables will be 
described and compared between groups by means of a Chi-square test (or Fisher's exact test 


 
 
 
 
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according to corresponding applicability). Percentages and difference between treatments will be 
expressed with their 95% confidence interval calculated with a binomial exact method. 
Both univariate and multivariate statistical methods will be used as an exploratory 
pharmacogenomic analysis in order to identify genetic reasons why certain people respond 
differently to Bavisant, to find out more information about how Bavisant works, and to generate 
information needed for research, development, and regulatory approval of tests to predict 
response to Bavisant, and to identify variations in genes related to the biological target of 
Bavisant. 
 
11.1.7 Safety Analyses 
Adverse events, adverse events of special interest, serious adverse events, serious and related 
adverse events will be coded using the latest available MedDRA version and their corresponding 
incidences will be summarised as overall events, related events, and events by intensity. AEs will 
be summarised by MedDRA preferred term and system organ class (primary SOC). Summaries 
of AEs by preferred term and decreasing frequency and by maximum severity will also be 
prepared. 
Physical examination changes, vital signs changes, laboratory tests changes, cardiovascular 
changes, ocular changes, suicidal ideation (C-SSRS) findings, and positive psychotic symptoms 
(BPRS+) findings will be described for the different treatment groups and assessed as either 
clinically or non-clinically significant findings. 
 
11.1.8 Other Analyses 
No other analyses are planned. 
 
11.2. Determination of sample size 
A total of 200 completed subjects will be evaluated for the study (50 completed subjects per 
treatment group, with expected early withdrawal rate of around 15%). 
The assumptions used for the sample size calculation are a mean absolute change in the Epworth 
Sleepiness Scale (ESS) from baseline to the end of the 6-week treatment period of at least 3.0 
points (minimum change considered as clinically relevant) and a standard deviation of 5.0 (based 
on a comparable study of Modafinil in a similar population recruited at one centre(32) which 
showed a standard deviation in the ESS between 3.5 at baseline and 4.8 at the end of the treatment 
period) and a reduction in ESS of 2.7 points for subjects treated with Modafinil. 
The confirmation of the hypothesis of detecting a mean difference in ESS of 3.0 points vs. 
baseline requires a sample size of 25 subjects per group (intragroup =3.0; SD=5.0; two-side 
=0.05; =0.20; power=80%; one-sample t-test). 
The additional endpoint of showing a statistically significant difference of at least 3.0 points in 
ESS between Bavisant and. placebo requires a sample size of 50 subjects per group (between 
treatment =3.0; SD=5.0; two-side =0.05; =0.20; power=80%; two-sample equal-variance t-
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The effect size of Bavisant in EDS is unknown and smaller changes in ESS may be clinically 
useful according to its profile, and higher variability is expected in this multicentre study; so the 
sample size of 200 completed subjects (50 per treatment group) is proposed in order to cover both 
the confirmation of an intragroup change of at least 3.0 points vs. baseline, and the between-group 
difference of at least 3.0 points change vs. placebo. 
The Maintenance of Wakefulness Test (MWT) will be performed in a minimum of 20 subjects 
per group (80 overall) in order to be enough to show statistically significant differences if the 
expected MWT absolute change from baseline differs at least in one standard deviation (effect 
size = 1.0). 
 
11.3. Randomisation Methods 
Three regions will be defined: USA, Western Europe and Eastern Europe. Regionally 
randomization list will be performed to guarantee a ratio of 1:1:1:1 for the treatment groups by 
region. As the study intends on keeping that ratio of 1:1:1:1 both in the subjects who will perform 
a polysomnography/MWT assessment, and in subjects who will not do that assessment, a down-
up / up-down strategy will be followed in order to simplify the stratified randomisation. This way, 
if the subject will perform both the polysomnography and the MWT assessment, he/she will 
receive the lowest available subject number at the respective study site; otherwise he/she will 
receive the maximum available subject number.  
The randomisation schedule will be generated by Nuvisan CTS following a computer-generated 
randomisation scheme. The randomisation schedule will link sequential medication numbers to 
treatment codes. The medication numbers will be blocked to facilitate attainment of a 
homogeneous distribution of treatment groups. 
 
11.4. Interim Analysis 
No interim evaluation of data is planned. 
 
11.5. Handling of dropouts or missing data 
For the primary analysis ESS missing at 6-weeks will be inputed under the treatment failure 
approach. 
As sensitivity analyses, a mixed-effect model with repeated measures (MMRM) approach will be 
used, under the missing at random framework carried out using an adequate contrast at Week 2 
or Week 6, accordingly. The model will include fixed categorical effects of treatment group, visit 
and treatment-by-visit interaction as well as the continuous fixed covariates of mean baseline 
ESS. This MMRM model will be run with an unstructured correlation matrix to model the within-
subject errors. 
11.6. Multiple Comparisons/ Multiplicity 
No adjustments for multiplicity of assessments will be considered. 
 


 
 
 
 
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11.7. Examination of subgroups 
Not applicable. 
 


 
 
 
 
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12.0 Ethics 
12.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
The participating centres have their IRB/IEC (or an IRB/IEC tutoring them) established and 
authorised by the respective authorities, whose composition is available to them and is not shown 
here. 
The Principal Investigator at each site is responsible for obtaining IRB/IEC approval for the final 
protocol, informed consent form and patient information sheet, any advertisements to recruit 
subjects, and documents to be handed out to the subjects at the next available meeting. 
Written approval of these documents must be obtained from the committee before any subject is 
enrolled at a site. 
When in accordance with local regulations IRB/IEC submission and interaction can be also 
covered by the assigned CRO. 
Each investigator will also be responsible for complying with ethical standards for clinical trials 
as per local and European laws and regulations, during the study. 
 
12.2. Ethical Conduct of the Study 
This study will be conducted with the highest respect for the individual participants (i.e., subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki (18th World Medical Assembly, 1964) and its last revision (Fortaleza, October 2013)(54), 
the ICH Harmonised Tripartite Guideline for GCP and local laws and regulations of the country 
where the study is performed. 
 
12.3. Subject Information and Consent 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorisation form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes 
of conducting the study. The informed consent form and the subject information sheet (if 
applicable) further explain the nature of the study, its objectives, and potential risks and benefits, 
as well as the date informed consent is given. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorisation form. The informed consent 
form, subject authorisation form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use. 
The informed consent form, subject authorisation form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 


 
 
 
 
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form, subject authorisation form (if applicable), and subject information sheet (if applicable) to 
the subject. Information should be given in both oral and written form whenever possible and in 
the manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of 
rendering adequate written informed consent, then the subject’s legally acceptable representative 
may provide such consent for the subject in accordance with applicable laws and regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorisation form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and date 
the informed consent form and subject authorisation (if applicable) at the time of consent and 
prior to subject entering into the study; however, the sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable law. 
Before being enrolled in the clinical study, subjects must consent to participate after the nature, 
scope and possible consequences of the clinical study have been explained in a form 
understandable to them. 
The investigator will provide the subject with an information form on the product and the study 
characteristics that should be read to and/or discussed with the subject in an understandable way. 
In this document, the subjects willing to consent to participate in this study will be informed of 
the nature, extent, design and conduct of the study and their consent will be obtained in writing 
prior to inclusion to the study schedule. Subjects will be given the opportunity to ask questions 
and will be informed of their right to withdraw from the study at any time, for any reason. 
After reading the informed consent document, the subject must give consent in writing. The 
consent must be confirmed at the time of consent by the personally dated signature of the subject 
and the personally dated signature of the person conducting the informed consent discussions. A 
copy of the subject information sheet and the signed consent forms must be given to the subjects. 
The original signed consent will be retained in the investigator’s site file. 
The principal investigator will not undertake any measures specifically required only for the 
clinical study until valid consent has been obtained. 
The investigator will not include in the study any subject without previously obtaining written 
consent from the subject. 
 
12.4. Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 


 
 
 
 
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date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorisation of the subject as part of the informed consent process. 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF). 
 
12.5. Insurance Policy 
BenevolentAI Bio will obtain liability insurance, in accordance with the national requirements 
established in the laws of the participating countries, which covers health impairments resulting 
from medications and/or substances/investigational products administered in the course of this 
study for which the subject has given his/her written informed consent to participate. 
 
 


 
 
 
 
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13.0 Source Documents and Case Report Form Completion 
13.1. Source Documents 
According to the guidelines on Good Clinical Practice, the Monitors Team must check the 
electronic case report form (eCRF) entries against the source documents, except for the pre-
identified source data directly recorded in the eCRF. 
During the study, the investigator will maintain adequate records for the study, including medical 
records, records detailing the progress of the study for each subject, laboratory reports, eCRFs, 
signed informed consent forms, drug disposition records, AE reports, and information regarding 
subject discontinuation and completion of the study. 
The Informed Consent Form will include a statement by which the subject allows the Sponsor’s 
duly authorised personnel, the IRB/IEC, and the regulatory authorities to have direct access to 
source data which supports the data on the eCRF (e.g., subject’s medical file, appointment books, 
original laboratory records, etc.). These personnel, bound by professional secrecy, will not 
disclose any personal identity or personal medical information. 
The process for source data verification will be documented in the monitoring plan. 
 
13.2. Case Report Forms 
The investigator must keep a written or electronic file for each subject that participates in the 
clinical trial. In that file, the subjects’ demographic and medical data, especially: name, birthday, 
gender, medical history, diseases and concomitant drug, physical examination and clinical signs, 
observed adverse events, etc. should be recorded. It must be possible, in any moment, to identify 
the subject with his/her personal file. The period that the subject participates in the clinical trial 
must be clearly specified. The data collection will be done using the Electronic Data Capture 
(EDC) market leader tool from Oracle® called InForm®. The InForm® platform has been 
validated according to the highest industry standards and practices. The InForm® software uses 
a secure web browser to provide access to clinical study data and management of the clinical 
study process. 
All documentation will be transcribed to an electronic CRF (eCRF). Any created documentation, 
especially the files that would be created by the technicians, must be filed. This includes the 
results of laboratory tests, ECGs, etc. These documents must be identified with the subject 
number, date of making and study code, in order to specify clearly the subject to whom this 
document belongs, and to identify the participants. 
The main objective is to get the most complete files of each candidate. 
Any result obtained during the study development will be reported in the subject’s electronic case 
report form, and if it is used, the serious adverse event form must be sent to BenevolentAI Bio. 
The investigator will guarantee that all the documents sent to BenevolentAI Bio, including the 
eCRF and other type of documents, do not contain any mention to the name of the subject. It is 
an investigator’s duty to guarantee adequate filing and storage of the study documentation after 
the end of the study as specified in the Guidelines for Good Clinical Practice. All the original files 


 
 
 
 
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must be kept as much as possible following the hospital rules, research institutes or local 
regulation, but for at least 25 years according to the legislation in force. 
 
All the eCRFs must be completed in its entirety. Any correction or amendment will be corrected 
by the investigator and the previous value recorded in the audit trail of the EDC system along 
with the reason and date of the change. 
The eCRF is considered an official document, and it must be available for the Health Authorities. 
Additional information on the data management and quality process is included in Section 13.0 
and Section 15.0. 
 
13.3. Monitoring 
Representatives of Sponsor must be allowed to visit all study site locations periodically to assess 
the data quality and study integrity. They will review study records on site and will compare them 
with source documents. They will also discuss the conduct of the study with the Investigator, and 
will verify that the facilities remain compliant with the study requirements. 
 
 


 
 
 
 
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14.0 Data Quality Assurance 
For the purpose of ensuring compliance with the protocol, Good Clinical Practice (GCP) and 
applicable regulatory requirements, the sponsor’s Quality Assurance department (or authorised 
representatives) may conduct on site audits of all aspects of the clinical study either during the 
study or after the study has been completed. The investigator/institution will permit study related 
monitoring, audits, IRB/IEC review and regulatory inspection(s) by providing direct access to 
source documents. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel are bound by professional secrecy, and 
as such will not disclose any personal identity or personal medical information. 
As soon as the Investigator is notified of a future inspection by the authorities, he will inform the 
Sponsor and authorize the Sponsor to participate at this inspection. 
The confidentiality of the data verified and the anonymity of the subjects should be respected 
during these inspections. 
The study will be conducted with an electronic case report form with a qualified single data entry 
performed by the investigators with controlled and restricted access. Additional information on 
the data management will be provided in a specific document (Data Handling Manual [DHM]). 
A full data validation plan will be performed and described in this DHM which should be 
approved before the data entry process starts. 
The database quality will be assessed before the database closure; and only when the Statistical 
Analysis Plan (SAP) is approved and the populations are determined, the database will be locked 
and moved to Statistics to perform the statistical analysis and prepare the Clinical Study Report 
(CSR). 
Additional information on the data management process is included in Section 16.0. 
 


 
 
 
 
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15.0 Practical Issues 
15.1. Early Termination of the Study 
The sponsor can prematurely terminate or suspend the study. Study sites will be closed upon study 
completion. 
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance. 
Reasons for discontinuation of the study may include but are not limited to the following: 
 
The risks and benefits of the study are re assessed. 
 
The incidence of AEs constitutes a potential health hazard. 
 
New scientific data on the investigational medication do not justify a continuation of the 
clinical study. 
 
Serious and/or persistent non adherence to the protocol, GCP, and/or applicable 
regulatory requirements by an investigator/institution occurs. 
 
Subject enrolment is unsatisfactory. 
 
The IRB/IEC or other regulatory authority decides to terminate or suspend approval for 
the investigation or investigator. 
Additionally, the sponsor has the right to terminate the study for any reason at any time. 
If the study is prematurely terminated or suspended for any reason, the investigator has to inform 
the subjects and assure appropriate follow up for the subjects. The sponsor should promptly 
inform the investigators or institutions and the regulatory authorities of the termination or 
suspension and the reasons for the termination or suspension within the timeframes referred to in 
applicable regulations. The IRB/IEC should also be informed promptly and provided the reasons 
for the termination or suspension by the sponsor or by the investigator or institution as specified 
by the applicable regulatory requirements. 
The last visit of the last patient (LPLV) indicates the end of the study and that end of study will 
be communicated to the IRBs/IECs and the regulatory authorities of each participating country. 
Last visit of the last subject at each site/country also indicates the end of the study for that 
site/country. 
 
15.2. Publication Policy 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 


 
 
 
 
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review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail. 
 
15.2.1 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, BenevolentAI Bio will, at a minimum 
register interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites before start of study. BenevolentAI Bio contact information, 
along with investigator’s city, state (for American investigators), country, and recruiting status 
will be registered and available for public viewing.  
 
15.2.2  Clinical Trial Results Disclosure 
BenevolentAI Bio will post the results of clinical trials on ClinicalTrials.gov or other publicly 
accessible websites, as required by BenevolentAI Bio Policy/Standard, applicable laws and/or 
regulations. 


 
 
 
 
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16.0 Data Management Procedures  
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organisation Drug Dictionary. 
 
16.1. Review and Confirmation of Case Report Forms  
Electronic case report forms will be filled directly by the investigators.  
Prior to obtaining the clean file, checks of consistency of inclusion/non-inclusion criteria, clinical 
assessment, visit dates, compliance, concomitant treatment, adverse event, withdrawal 
information and efficacy evaluation will be performed.  
Data query forms will be generated to the investigator in order to clarify the data inconsistencies 
through the source data verification.  
 
16.2. Database production and verification  
16.2.1 Data Management Plan  
A validation plan is set-up according to the protocol requirements, which describes the validation 
rules to be applied. Actions that should be taken in case of data abnormalities are detailed. In case 
of missing values, out of range values, data inconsistencies or values that fail logical checks, 
correction forms (queries) are edited and transmitted to the investigator for clarification.  
 
16.2.2 Database  
A database will be created in order to collect all clinical and other data from the clinical trial. The 
data management will take place at the Data Management Department of Linical. 
 
16.2.3 Database access  
Access to the database will be restricted to the investigators, data managers and clinical monitors. 
Any entry in the database will be traceable through its identification and date. Audit trail of data 
changes will be assured.  
 
16.2.4 Quality and consistency controls  
The investigators will enter the clinical data in the electronic case report form.  
Prior to obtaining the clean file, checks of consistency of inclusion/exclusion criteria, clinical 
assessment, visit dates, compliance, concomitant treatment, adverse event, withdrawal 
information and efficacy evaluation will be performed.  
 
16.2.5 Data queries  
Data query forms will be generated to the investigator in order to clarify the data inconsistencies 
through the source data verification.  


 
 
 
 
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Only then and after all detected errors, inconsistencies or doubts cleared, will the database be 
declared a clean file and protected accordingly. 
 
16.2.6 Clean File 
A clean file will be created and registered, to which further changes will be disallowed. A 
document with the eligibility of subjects will be generated. 
 
16.2.7 Data coding  
Coding will be carried out according to standard dictionaries partly by program and then validated 
and completed by a medical doctor according to the Linical dictionaries. The latest available 
version of the following dictionaries will be used:  
 
Concomitant treatments: WHO DRUG 
 
Adverse Events: MedDRA 
All case report forms and data checking records will be retained as permanent records of the study. 


 
 
 
 
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16. Lin JS, Sergeeva OA, Haas HL. Histamine H3 receptors and sleep-wake regulation. The 
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Parkinson's disease: a clinico-pathological study of 100 cases. Journal of neurology, 
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maintenance of wakefulness test and the epworth sleepiness scale: failure of the MSLT as a 
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21. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the 
treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy 
Multicenter Study Group. Annals of neurology. 1998;43(1):88-97. Epub 1998/02/05. 
22. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
Sleep. 1991;14(6):540-5. Epub 1991/12/01. 
23. Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep. 
1992;15(4):376-81. Epub 1992/08/01. 
24. Johns MW. Daytime sleepiness, snoring, and obstructive sleep apnea. The Epworth 
Sleepiness Scale. Chest. 1993;103(1):30-6. Epub 1993/01/01. 
25. Johns MW. Sleepiness in different situations measured by the Epworth Sleepiness Scale. 
Sleep. 1994;17(8):703-10. Epub 1994/12/01. 
26. Littner MR, Kushida C, Wise M, Davila DG, Morgenthaler T, Lee-Chiong T, et al. Practice 
parameters for clinical use of the multiple sleep latency test and the maintenance of 
wakefulness test. Sleep. 2005;28(1):113-21. Epub 2005/02/11. 
27. Adler CH, Caviness JN, Hentz JG, Lind M, Tiede J. Randomized trial of modafinil for 
treating subjective daytime sleepiness in patients with Parkinson's disease. Movement 
disorders : official journal of the Movement Disorder Society. 2003;18(3):287-93. Epub 
2003/03/07. 
28. Hogl B, Saletu M, Brandauer E, Glatzl S, Frauscher B, Seppi K, et al. Modafinil for the 
treatment of daytime sleepiness in Parkinson's disease: a double-blind, randomized, 
crossover, placebo-controlled polygraphic trial. Sleep. 2002;25(8):905-9. Epub 2002/12/20. 
29. Chen NH, Johns MW, Li HY, Chu CC, Liang SC, Shu YH, et al. Validation of a Chinese 
version of the Epworth sleepiness scale. Quality of life research : an international journal of 
quality of life aspects of treatment, care and rehabilitation. 2002;11(8):817-21. Epub 
2002/12/17. 
30. Izci B, Ardic S, Firat H, Sahin A, Altinors M, Karacan I. Reliability and validity studies of 
the Turkish version of the Epworth Sleepiness Scale. Sleep & breathing = Schlaf & Atmung. 
2008;12(2):161-8. Epub 2007/10/09. 
31. Manni R, Politini L, Ratti MT, Tartara A. Sleepiness in obstructive sleep apnea syndrome 
and simple snoring evaluated by the Epworth Sleepiness Scale. Journal of sleep research. 
1999;8(4):319-20. Epub 2000/01/26. 


 
 
 
 
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32. Ondo WG, Fayle R, Atassi F, Jankovic J. Modafinil for daytime somnolence in Parkinson's 
disease: double blind, placebo controlled parallel trial. Journal of neurology, neurosurgery, 
and psychiatry. 2005;76(12):1636-9. Epub 2005/11/18. 
33. EMA - European Medicines Agency. EMA/828546/2015 Assessment Report - Wakix2005. 
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from: 
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_Public_assessment_report/human/002616/WC500204749.pdf. 
34. Dauvilliers Y, Bassetti C, Lammers GJ, Arnulf I, Mayer G, Rodenbeck A, et al. Pitolisant 
versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. 
The Lancet Neurology. 2013;12(11):1068-75. Epub 2013/10/11. 
35. Levey AS, Stevens LA. Estimating GFR using the CKD Epidemiology Collaboration (CKD-
EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, 
and better risk predictions. American journal of kidney diseases : the official journal of the 
National Kidney Foundation. 2010;55(4):622-7. Epub 2010/03/27. 
36. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Annals of internal medicine. 
2009;150(9):604-12. Epub 2009/05/06. 
37. Marinus J, Visser M, van Hilten JJ, Lammers GJ, Stiggelbout AM. Assessment of sleep and 
sleepiness in Parkinson disease. Sleep. 2003;26(8):1049-54. Epub 2004/01/30. 
38. Trenkwalder C, Kohnen R, Hogl B, Metta V, Sixel-Doring F, Frauscher B, et al. Parkinson's 
disease sleep scale--validation of the revised version PDSS-2. Movement disorders : official 
journal of the Movement Disorder Society. 2011;26(4):644-52. Epub 2011/02/12. 
39. Hjollund NH, Andersen JH, Bech P. Assessment of fatigue in chronic disease: a 
bibliographic study of fatigue measurement scales. Health and quality of life outcomes. 
2007;5:12. Epub 2007/03/01. 
40. Ahmadi N, Chung SA, Gibbs A, Shapiro CM. The Berlin questionnaire for sleep apnea in a 
sleep clinic population: relationship to polysomnographic measurement of respiratory 
disturbance. Sleep & breathing = Schlaf & Atmung. 2008;12(1):39-45. Epub 2007/08/09. 
41. Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the Berlin Questionnaire to 
identify patients at risk for the sleep apnea syndrome. Annals of internal medicine. 
1999;131(7):485-91. Epub 1999/10/03. 
42. Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. 
Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating 
Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Movement disorders 
: official journal of the Movement Disorder Society. 2008;23(15):2129-70. Epub 
2008/11/26. 
43. Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, et al. The 
Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive 
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2005/04/09. 
44. Hamilton M. A rating scale for depression. Journal of neurology, neurosurgery, and 
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45. Overall JE, Gorham DR. The brief psychiatric rating scale. Psychological Reports. 
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46. DeWilde KE, Levitch CF, Murrough JW, Mathew SJ, Iosifescu DV. The promise of 
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47. Moskal JR, Burch R, Burgdorf JS, Kroes RA, Stanton PK, Disterhoft JF, et al. GLYX-13, 
an NMDA receptor glycine site functional partial agonist enhances cognition and produces 


 
 
 
 
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antidepressant effects without the psychotomimetic side effects of NMDA receptor 
antagonists. Expert opinion on investigational drugs. 2014;23(2):243-54. Epub 2013/11/21. 
48. Shiroma PR, Albott CS, Johns B, Thuras P, Wels J, Lim KO. Neurocognitive performance 
and serial intravenous subanesthetic ketamine in treatment-resistant depression. The 
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49. Janssen Research & Development L. A Long-term, Safety and Efficacy Study of Intranasal 
Esketamine in Treatment-resistant Depression (SUSTAIN-2). ClinicalTrials.gov Identifier: 
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50. Janssen Research & Development L. Long-term Safety Study of Rapastinel as Adjunctive 
Therapy in Patients With Major Depressive Disorder. ClinicalTrials.gov Identifier: 
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18.0 Appendices 
18.1. Administrative Information - Contacts 
 
Issue 
Contact* 
Serious Adverse Event Reporting 
Linical (CRA / PhV Officer) (see section 9.7) 
Safety Questions 
Linical (CRA / PhV Officer) (see section 9.7) 
Pregnancy Reporting 
Linical (CRA / PhV Officer) (see section 9.7) 
Unblinding 
Linical (CRA / PM / BST) 
Protocol Deviations 
Linical (CRA / PM / BST) 
Protocol Guidance 
Linical (CRA / PM / MM) 
Emergency contact 
Business hours weekdays (08:00 to 16:00 CET) 
Linical (CRA / MM)  
BEN01.medical.emergency@linical.com 
Dr. Isabel Caballero (+34 610 134 109) 
Dr. Carlos Hortelano (+34 670 836 340) 
 
24 emergency contact 
Non business hours and weekends 
Country 
In Country Number  
International Back 
Up Number 
Czech Republic  
296849801 
+441204684560 
Germany  
08005891887 
+441235239958 
Italy 
0236007792  
+441228899357 
Poland  
124207010 
 +441204684450 
Spain  
966990007 
 +441204684092 
United Kingdom  
01242649524 
+441242649524 
USA  
18666151825 
+441204684544 
Insurance 
Linical (CRA / PM) 
* CRA (Clinical Research Associate / Study Monitor), PhV Officer (Pharmacovigilance Officer),  
   PM (Project Manager), BST (Biostatistician), MM (Medical Manager) 
 
 
 


 
 
 
 
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Study-Related Responsibilities 
 
Activity 
Organisation 
Site selection, management and monitoring 
Linical / BenevolentAI Bio 
Central Laboratory 
LKF 
Data Management 
Linical 
Electronic Data Capture System 
Linical (Oracle Inform 6.1) 
Clinical supply packaging and distribution 
Nuvisan CTS 
Clinical supply return 
Nuvisan CTS 
Rater vendor 
Bracket 
 
 
 


 
 
 
 
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18.2. UK PDS Brain Bank Diagnostic Criteria for Parkinson's Disease 
 
UK PARKINSON’S DISEASE SOCIETY BRAIN BANK CLINICAL DIAGNOSTIC 
CRITERIA* 
Step 1. Diagnosis of Parkinsonian Syndrome 
 
Bradykinesia 
 
At least one of the following 
• 
Muscular rigidity 
• 
4-6 Hz rest tremor 
 
postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive 
dysfunction 
Step 2 Exclusion criteria for Parkinson’s disease 
 
history of repeated strokes with stepwise progression of parkinsonian features 
 
history of repeated head injury 
 
history of definite encephalitis 
 
oculogyric crises 
 
neuroleptic treatment at onset of symptoms 
 
more than one affected relative 
 
sustained remission 
 
strictly unilateral features after 3 years 
 
supranuclear gaze palsy 
 
cerebellar signs 
 
early severe autonomic involvement 
 
early severe dementia with disturbances of memory, language, and praxis 
 
Babinski sign 
 
presence of cerebral tumor or communication hydrocephalus on imaging study 
 
negative response to large doses of levodopa in absence of malabsorption 
 
MPTP exposure 
Step 3 supportive prospective positive criteria for Parkinson’s disease 
Three or more required for diagnosis of definite Parkinson’s disease in combination with step one 
 
Unilateral onset 
 
Rest tremor present 
 
Progressive disorder 
 
Persistent asymmetry affecting side of onset most 
 
Excellent response (70-100%) to levodopa 
 
Severe levodopa-induced chorea 
 
Levodopa response for 5 years or more 
 
Clinical course of ten years or more 
 
 
*From: Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic 
Parkinson’s disease. A clinico-pathological study of 100 cases. JNNP 1992;55:181-184(19).  


 
 
 
 
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18.3. Epworth Sleepiness Scale (ESS) 
 
EPWORTH SLEEPINESS SCALE FORM 
Instructions: Be as truthful as possible. Print the form. Read the situation in the first 
column; select your response from the second column; enter that number in the third 
column. Total all of the entries in the third column and enter the total in the last box. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Situation 
Responses 
Score 
Sitting and Reading 
0 = would never doze 
1 = slight chance of dozing 
2 = moderate chance of dozing  
3 = high chance of dozing 
Watching Television 
0 = would never doze 
1 = slight chance of dozing 
2 = moderate chance of dozing  
3 = high chance of dozing 
Sitting inactive in a public place, for 
example, a theater or a meeting 
0 = would never doze 
1 = slight chance of dozing 
2 = moderate chance of dozing 
3 = high chance of dozing 
As a passenger in a car for an hour 
without a break 
0 = would never doze 
1 = slight chance of dozing 
2 = moderate chance of dozing 
3 = high chance of dozing 
Lying down to rest in the afternoon 
0 = would never doze 
1 = slight chance of dozing 
2 = moderate chance of dozing  
3 = high chance of dozing 
Sitting and talking to someone 
0 = would never doze 
1 = slight chance of dozing 
2 = moderate chance of dozing  
3 = high chance of dozing 
Sitting quietly after lunch when you’ve 
had no alcohol 
0 = would never doze 
1 = slight chance of dozing 
2 = moderate chance of dozing  
3 = high chance of dozing 
In a car while stopped in traffic 
0 = would never doze 
1 = slight chance of dozing 
2 = moderate chance of dozing  
3 = high chance of dozing 
TOTAL SCORE 
© The Associated Professional Sleep Societies, Westchester, IL. Johns MW. A new method for measuring daytime 
sleepiness: the Epworth sleepiness scale. Sleep 1991;14(6):540-545. 


 
 
 
 
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18.4. Maintenance of Wakefulness Test (MWT) 
 
The Clinical Use of the MSLT and MWT – AASM Practice Parameters(26) 
(Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for clinical use of 
the multiple sleep latency test and the maintenance of wakefulness test. SLEEP 2005;28(1):113-121.) 
Box 2 
Recommendations for the MWT protocol 
(Developed from methods of Doghramji and colleagues, A normative study of the 
maintenance of wakefulness test (MWT), 1997. 10 
Modified by collective expert opinion using Rand/UCLA Appropriateness Method) 
 
1. The 4-trial MWT 40-minute protocol is recommended. The MWT consists of four trials performed 
at two hour intervals, with the first trial beginning about 1.5 to 3 hours after the patient’s usual 
wake-up time. This usually equates to a first trial starting at 0900 or 1000 hours. 
2. Performance of a PSG prior to MWT should be decided by the clinician based on clinical 
circumstances. 
3. Based on the Rand/UCLA Appropriateness Method, no consensus was reached regarding the use 
of sleep logs prior to the MWT; there are instances, based on clinical judgment, when they may be 
indicated. 
4. The room should be maximally insulated from external light. The light source should be positioned 
slightly behind the subject’s head such that it is just out of his/her field of vision, and should deliver 
an illuminance of 0.10-0.13 lux at the corneal level (a 7.5 W night light can be used, placed 1 foot 
off the floor and 3 feet laterally removed from the subject’s head). Room temperature should be set 
based on the patient’s comfort level. The subject should be seated in bed, with the back and head 
supported by a bedrest (bolster pillow) such that the neck is not uncomfortably flexed or extended. 
5. The use of tobacco, caffeine and other medications by the patient before and during MWT should 
be addressed and decided upon by the sleep clinician before MWT. Drug screening may be 
indicated to ensure that sleepiness/wakefulness on the MWT is not influenced by substances other 
than medically prescribed drugs. Drug screening is usually performed on the morning of the MWT 
but its timing and the circumstances of the testing may be modified by the clinician. A light 
breakfast is recommended at least 1 hour prior to the first trial, and a light lunch is recommended 
immediately after the termination of the secondnoon trial. 
6. Sleep technologists who perform the MWT should be experienced in conducting the test. 
7. The conventional recording montage for the MWT includes central EEG (C3-A2, C4-A1) and 
occipital (O1-A2, O2-A1) derivations, left and right eye electrooculograms (EOGs), 
mental/submental electromyogram (EMG), and electrocardiogram (EKG). 
8. Prior to each trial, the patient should be asked if they need to go to the bathroom or need other 
adjustments for comfort. Standard instructions for bio-calibrations (i.e., patient calibrations) prior 
to each trial include: (1) sitlie quietly with your eyes open for 30 seconds, (2) close both eyes for 


 
 
 
 
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30 seconds, (3) without moving your head, look to the right, then left, then right, then left, right and 
then left, (4) blink eyes slowly for 5 times, and (5) clench or grit your teeth tightly together. 
9. Instructions to the patient consist of the following: “Please sit still and remain awake for as long as 
possible. Look directly ahead of you, and do not look directly at the light.” Patients are not allowed 
to use extraordinary measures to stay awake such as slapping the face or singing. 
10. Sleep onset is defined as the first epoch of greater than 15 sec of cumulative sleep in a 30-sec epoch. 
11. Trials are ended after 40 minutes if no sleep occurs, or after unequivocal sleep, defined as three 
consecutive epochs of stage 1 sleep, or one epoch of any other stage of sleep. 
12. The following data should be recorded: start and stop times for each trial, sleep latency, total sleep 
time, stages of sleep achieved for each trial, and the mean sleep latency (the arithmetic mean of the 
four trials). 
13. Events that represent deviation from standard protocol or conditions should be documented by the 
sleep technologist for review by the sleep specialist. 
 
 
 


 
 
 
 
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18.5. Polysomnography (PSG) 
 
The American Association of Sleep Technologists developed the Technical Guideline on Sleep 
Technology for Standard Polysomnography – Updated July 2012 (52). The following is the summary of 
the technical aspects of the referred guidelines. 
 
SUMMARY: The scope of polysomnography encompasses the monitoring of patients in a sleep facility 
using an array of medical equipment that is simultaneously recorded on a multi-channel analog or digital 
system. Sleep technologists are specially trained to perform polysomnography for the diagnosis and 
treatment of sleep and arousal disorders. They are part of a team under the direction of a physician who 
practices sleep disorders medicine. The team works in concert to ensure the proper diagnosis, 
appropriate management, and education for individuals that experience sleep disorders. They follow 
patient sensitive standards of care, which are the foundation for clinical/technical decision-making. The 
sleep technologist prepares for and monitors the recording, requiring expertise in normal and abnormal 
sleep and multiple technical and medical monitors. Much of the utility of the polysomnogram (PSG) 
depends on the ability to correlate specific changes or abnormalities of one physiological parameter with 
specific conditions defined by another parameter or parameters. Consequently, polysomnography is a 
significantly more powerful and complex tool than could be provided by individual or independent 
measurements of each variable. The sleep technologist verifies and maintains the quality of the recording 
and can decipher artifact from true physiological signals. The technologist can recognize when medical 
intervention is required and responds according to the protocols provided by the medical director. 
Therefore, attended polysomnography by a trained sleep technologist produces the highest quality 
clinical tool. The standard diagnostic PSG requires the recording and evaluation of sleep stages and 
arousals, respiration, limb movements, snoring, oximetry, body position, and cardiac rhythm 
disturbances. The resulting documentation is used to diagnose or assess the treatment of sleep disorders.  
 
Electrode Preparation and Application  
Electrodes used in polysomnography conduct biopotentials from the patient to the recording circuit. 
Electrodes are used to record EEG, EOG, EMG, ECG, and sometimes respiratory effort.  
 
Electroencephalogram (EEG)  
The EEG is the primary variable to document wakefulness, arousals and sleep stages during the sleep 
study. A single central channel referenced to an ear mastoid site (C4-M1), a single frontal channel 
referenced to an ear mastoid site (F4-M1) and a single occipital channel referenced to an ear mastoid 
site (O2-M1) is sufficient for evaluating waveforms. The mastoid is located posterior to each ear. 


 
 
 
 
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However, additional channels (C3-M2, F3-M2, O1-M2) are recommended to provide redundancy in 
case of electrode malfunction.  
 
Electrooculogram (EOG)  
The EOG recording aids the identification of sleep onset by monitoring for slow, rolling eye movements 
that occur with transition to Stage N1 sleep and identification of REM sleep when rapid eye movements 
(REMs) that occur during Stage R (REM) sleep are present in the recording.  
 
Chin Electromyogram (EMG)  
The recording of EMG activity in the chin area is used for determining the level of muscle tone, which 
significantly decreases during Stage R (REM) sleep and may also be reduced with sleep onset. This 
channel also provides supplemental information regarding patient movements and arousals and may be 
useful in distinguishing artifact in other channels.  
 
Limb Movement  
Additional causes of sleep disturbances that may need to be identified and treated are periodic limb 
movements of sleep (PLMS). These movements are often visually detectable during the monitoring 
process. Monitoring the anterior tibialis muscles allows for the determination of the severity of the 
disorder by quantifying the rate of movements as well as the correlation with EEG arousal. Limb EMG 
of the upper extremities may also be recorded if clinically indicated.  
 
Electrocardiogram (ECG)  
The ECG monitors the heart rhythm. A single ECG channel is sufficient for standard PSG monitoring.  
 
Upper Airway Sound Recording  
Detecting snore bursts can be a valuable supplemental tool for determining and verifying the nature of 
arousals. There are several commercially available devices but snoring is typically measured with a 
snore microphone or sound transducer.  
 
Respiration (Measures of Airflow and Respiratory Effort)  
Airflow and respiratory effort channels are utilized during the standard PSG to monitor respiration 
specifically for the detection of apneas, hypopneas, RERA’s and other sleep related breathing events. 
RERA is an acronym for Respiratory Effort Related Arousal. It is important to record at least three 
respiratory parameters: nasal/oral airflow, thoracic effort and abdominal effort.  
 


 
 
 
 
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Blood Oxygenation (Oxygen Saturation - SpO2)  
The diagnosis of obstructive sleep apnea during the standard PSG requires the continuous monitoring 
and display of blood oxygen saturation levels to provide crucial information about the severity of the 
sleep related breathing disorder. Pulse oximeters are generally built in to or can be easily interfaced with 
the PSG acquisition equipment. It is necessary to carefully evaluate the pulse oximeter for use in the 
sleep facility for sampling rate and analog output to interface with the polygraph. The output on the 
oximeter must be through a DC amplifier and the signal must be displayed simultaneously with other 
pertinent PSG variables. In modern PSG systems oximetry is integrated as a DC channel in the system 
amplifier. The polygraph DC amplifier requires calibration and the output can be displayed linearly or 
numerically, depending on the acquisition system. Whichever method is used to record pulse oximetry, 
the device must be capable of a signal averaging time of 3 seconds or less.  
 
Capnography  
Capnography can be used to measure the patient’s carbon dioxide (CO2) level.  
 
Body Position  
Many disorders such as apnea can be exacerbated by body orientation during sleep. Therefore, a valuable 
tool for accurate diagnosis and treatment of sleep disorders is a determination of body position on a 
continuous basis throughout the recording.  
 
Behavioral Observation  
The capability of observing the patient during the recording of the standard PSG is required for patient 
safety as well as clinical and technical assessment. The recommendation is to use audio monitoring and 
digital video recording that is synchronized with the PSG.  
 
Montage Filter & Sensitivity Settings  
The standard PSG recording montage should consist of the measurement of the above-defined 
parameters. An example of a montage is as follows:  
Channel 
Derivation 
Sensitivity 
High Filter 
Low 
Filter 
Sampling 
Rate 
L outer canthus 
E1- M2 
5–7 µv/mm 
35 Hz 
0.3 Hz 
500 Hz 
R outer canthus 
E2 - M2 
5-7 µv/mm 
35 Hz 
0.3 Hz 
500 Hz 
Chin EMG 
EMG1- 
EMG2- EMG3 
10 µv/mm 
100 Hz 
10 Hz 
500 Hz 
Frontal EEG 
F4-M1 
5-7 µv/mm 
35 Hz 
0.3Hz 
500 Hz 


 
 
 
 
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Channel 
Derivation 
Sensitivity 
High Filter 
Low 
Filter 
Sampling 
Rate 
F3-M2 
Central EEG 
C4-M1  
C3-M2 
5-7 µv/mm 
35 Hz 
0.3 Hz 
500 Hz 
Occipital EEG 
O2-M1  
O1-M2 
5-7 µv/mm 
35 Hz 
0.3 Hz 
500 Hz 
Left Anterior Tibialis 
LAT1 LAT2 
10 µv/mm 
100 Hz 
10 Hz 
500 Hz 
Right Anterior Tibialis 
RAT1 RAT2 
10 µv/mm 
100 Hz 
10 Hz 
500 Hz 
ECG 
ECG1 ECG2 
20 µv/mm 
70 Hz 
0.3 Hz 
500 Hz 
Snore 
 
20 µv/mm 
100 Hz 
10 Hz 
500 Hz 
Pressure Flow 
 
20 µv/mm 
15 Hz 
0.1 Hz 
100 Hz 
Thermal Flow 
 
20 µv/mm 
15 Hz 
0.1 Hz 
100 Hz 
Thoracic Effort Belts 
 
10-100 
µv/mm 
15 Hz 
0.1 Hz 
100 Hz 
Abdominal Effort Belts 
 
10-100 
µv/mm 
15 Hz 
0.1 Hz 
100 Hz 
CPAP 
DCx 
 
5 Hz 
 
100 Hz 
SpO2 
DCx 
 
5 Hz 
 
25 Hz 
60 Hz notch filters should not ordinarily be used in EEG or EOG, as this may conceal the presence of 
artifact, and the use of 60 Hz notch filters should be avoided in the EMG channels. The sleep facility 
director should determine the specific montage and the equipment and recording devices used.  
 
Technical Documentation  
Log  
The sleep technologist should log notable events that occur during the study in chronological order. 
Notable events include “Lights Off”, sleep onset, “Lights On”, the sleep technologist entering or leaving 
the patient’s room, the patient getting out of bed, initiating or adjusting PAP or oxygen therapy, position 
changes, technical difficulties, environmental disturbances, and any other observation that might be 
helpful to the interpreting physician.  
Summary  
The sleep technologist should completely summarize all technical and behavioral observations at 
completion of the standard PSG. This can be done on a form designed by the sleep facility, within the 
context of the format set forth by the manufacturer of the PSG data acquisition equipment, or on a 
flowsheet within an electronic medical record. The summary should include comments on sleep 


 
 
 
 
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architecture, behavioral observations, myoclonus/limb movements, respiratory characteristics including 
respiratory events and desaturations, initiation of PAP, if applicable, and heart rate/ECG observations. 
The technologist should also add any significant medical or sleep-related information discovered during 
patient assessment, testing, or before discharge.  
Sleep Parameters  
The report summary should include the details of the analysis of sleep stage scoring as well as clinical 
event scoring.  
Sleep Stage Parameters  
Total Recording Time (TRT) is defined as the time from “lights out” to “lights on”. Total Sleep Time 
(TST) is the total time asleep after sleep onset. To determine the how well the patient slept, the Sleep 
Efficiency (SE) is calculated by dividing the TST by the TRT and multiplying by 100. Sleep studies are 
recorded on 30 second “epochs”. Sleep onset is defined as the first epoch scored as any stage other than 
stage W. Sleep Latency (SL) is the time from “lights out” to the sleep onset. Latencies to sleep stages 
are determined from sleep onset to the first epoch of that sleep stage. Wake after Sleep Onset (WASO) 
is the time awake after sleep onset until “lights on”. To determine the percentage time spent in each of 
the sleep stages during the sleep study, the total minutes of the sleep stage is divided by the TST and 
multiplied by 100.  
Clinical Event Parameters  
To determine the severity of sleep disturbances, the indices of the clinical events scored are compared 
to normative values. The sleep technologist calculates these indexes by dividing the number of clinical 
events by the TST. These indices include the apnea index (AI), hypopnea index (HI), apnea/hypopnea 
index (AHI), periodic limb movement (PLMS) index, PLMS arousal index, Respiratory Effort Related 
Arousal (RERA) index, and the overall arousal index. Usually the PSG equipment will analyze the heart 
rate and oxygen saturation and report the mean, maximum and lowest value by TRT, TST and sleep 
state, i.e. stage N1, N2, N3 (NREM) and stage R (REM). The technologist is responsible for manually 
verifying these parameters.  
Sleep Related Breathing Events  
The study summary should document sleep related breathing events with respect to sleep state. 
Information should be provided concerning the respiratory rate while awake and asleep, the presence or 
absence of snoring, the presence of paradoxical breathing, the number and index of apnea and/or 
hypopnea events, the longest apnea and/or hypopnea event, the mean and minimum oxygen saturation. 
Notation should be made if sleep state or body position is related to the apnea/hypopnea index and/or 
desaturation. The absence or occurrence of Cheyne Stokes breathing pattern should be documented in 
all patients who demonstrate central apnea events.  
Heart Rate/ECG Observation  


 
 
 
 
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The average and highest heart rate while asleep and the highest heart rate during the recording should 
be annotated and the summary should document bradycardia (lowest rate observed), asystole (longest 
pause observed), sinus tachycardia (highest rate observed), narrow complex tachycardia (highest rate 
observed), wide complex tachycardia (highest rate observed) and atrial fibrillation on a yes/no basis. All 
other arrhythmias should be documented with respect to frequency of occurrence and type. It is 
particularly important to describe the occurrence of heart rate changes or arrhythmias with respect to 
sleep state (REM, NREM) and sleep related breathing events such as O2 desaturations and apneic 
events.  
Limb Movements  
Limb movement activity is recorded from the extremities and must be evaluated in terms of frequency 
of occurrence and periodicity, sleep/wake status, and presence or absence of subsequent arousal. 
Rhythmic leg movements observed during wakefulness can indicate Restless Legs Syndrome (RLS). 
The sleep technologist should ask about symptoms of RLS during patient assessment (difficulty 
initiating sleep due to a need to move) and document any relevant patient comments as well as evidence 
of RLS seen prior to or during the recording.  
Behavioral Observations  
Any unusual or atypical behavioral events occurring during the patient’s sleep and/or during 
wakefulness should be documented by the sleep technologist during the standard PSG. The sleep 
technologist should describe in detail what the behavior is and how it relates to the polysomnographic 
recording (i.e. nocturnal eating, enuresis, body rocking). When arousals are noted during the PSG 
recording, the sleep technologist should document the cause of the arousal, i.e. as the result of apneic 
events, limb movements, spontaneous or environmentally evoked. 
 
 
 


 
 
 
 
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18.6. Parkinson's Disease Sleep Scale (PDSS-2) 
 
 
   Reproduced from Trenkwalder et al (Movement Disorders, Vol. 26, No. 4, 2011)(38) 
 
 


 
 
 
 
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18.7. Scales for Outcome in Parkinson's Disease Sleep (SCOPA-Sleep) 
 
SCOPA-SLEEP SCALE 
Aim of the Questionnaire 
By means of this questionnaire, we would like to find out to what extent in the past month you 
have had problems with sleeping. Some of the questions are about problems with sleeping at 
night, such as, for example, not being able to fall asleep or not managing to sleep on. Another set 
of questions is about problems with sleeping during the day, such as dozing off (too) easily and 
having trouble staying awake. 
First read these instructions before you answer the questions! 
Place a cross in the box above the answer which best reflects your situation. If you wish to change 
an answer, fill in the ‘wrong’ box and place a cross in the correct one. If you have been using 
sleeping tablets, then the answer should reflect how you have slept while taking these tablets. 
NS: Nighttime Sleep Problems 
response options: not at all – a little – quite a bit – a lot 
In the past month, … 
1. … have you had trouble falling asleep when you went to bed at night? 
2. … to what extent do you feel that you have woken too often? 
3. … to what extent do you feel that you have been lying awake for too long at night? 
4. … to what extent do you feel that you have woken up too early in the morning? 
5. … to what extent do you feel you have had too little sleep at night? 
Overall, how well have you slept at night during the past month? 
response options: very well – well – rather well – not well but not badly - rather badly – badly - 
very badly 
DS: Daytime Sleepiness 
response options: never – sometimes – regularly – often 
1. How often in the past month have you fallen asleep unexpectedly either during the day or in 
the evening? 
2. How often in the past month have you fallen asleep while sitting peacefully? 
3. How often in the past month have you fallen asleep while watching TV or reading? 
4. How often in the past month have you fallen asleep while talking to someone? 
5. In the past month, have you had trouble staying awake during the day or in the evening? 
6. In the past month, have you experienced falling asleep during the day as a problem? 
 
   Reproduced from Marinus et al (SLEEP 2003;26(8):1049-54)(37)  
 
 
 


 
 
 
 
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18.8. Unified Parkinson's Disease Rating Scale Part III (UPDRS Part III) 
 
III. MOTOR EXAMINATION 
Speech 
 0-normal 
 1-slight loss of expression, diction,volume 
 2-monotone, slurred but understandable, mod. impaired 
 3-marked impairment, difficult to understand 
 4-unintelligible 
 
Facial Expression 
 0-Normal 
 1-slight hypomymia, could be poker face 
 2-slight but definite abnormal diminution in expression 
 3-mod. hypomimia, lips parted some of time 
 4-masked or fixed face, lips parted 1/4 of inch or more with complete loss of expression 
 
Tremor at Rest 
 + Face 
 0-absent 
 1-slight and infrequent 
 2-mild and present most of time 
 3-moderate and present most of time 
 4-marked and present most of time 
 + Right Upper Extremity (RUE) 
 0-absent 
 1-slight and infrequent 
 2-mild and present most of time 
 3-moderate and present most of time 
 4-marked and present most of time 
 + LUE 
 0-absent 
 1-slight and infrequent 
 2-mild and present most of time 
 3-moderate and present most of time 


 
 
 
 
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 4-marked and present most of time 
 + RLE 
 0-absent 
 1-slight and infrequent 
 2-mild and present most of time 
 3-moderate and present most of time 
 4-marked and present most of time 
 + LLE 
 0-absent 
 1-slight and infrequent 
 2-mild and present most of time 
 3-moderate and present most of time 
 4-marked and present most of time 
 
Action or Postural Tremor 
 + RUE 
 0-absent 
 1-slight, present with action 
 2-moderate, present with action 
 3-moderate present with action and posture holding 
 4-marked, interferes with feeding 
 + LUE 
 0-absent 
 1-slight, present with action 
 2-moderate, present with action 
 3-moderate present with action and posture holding 
 4-marked, interferes with feeding 
 
Rigidity 
 + Neck 
 0-absent 
 1-slight or only with activation 
 2-mild/moderate 
 3-marked, full range of motion 


 
 
 
 
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 4-severe 
 + RUE 
 0-absent 
 1-slight or only with activation 
 2-mild/moderate 
 3-marked, full range of motion 
 4-severe 
 + LUE 
 0-absent 
 1-slight or only with activation 
 2-mild/moderate 
 3-marked, full range of motion 
 4-severe 
 + RLE 
 0-absent 
 1-slight or only with activation 
 2-mild/moderate 
 3-marked, full range of motion 
 4-severe 
 + LLE 
 0-absent 
 1-slight or only with activation 
 2-mild/moderate 
 3-marked, full range of motion 
 4-severe 
 
Finger taps 
 + Right 
 0-normal 
 1-mild slowing, and/or reduction in amp. 
 2-moderate impaired. Definite and early fatiguing, may have occasional arrests 
 3-severely impaired. Frequent hesitations and arrests. 
 4-can barely perform 
 + Left 


 
 
 
 
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 0-normal 
 1-mild slowing, and/or reduction in amp. 
 2-moderate impaired. Definite and early fatiguing, may have occasional arrests 
 3-severely impaired. Frequent hesitations and arrests. 
 4-can barely perform 
 
Hand Movements (open and close hands in rapid succession) 
 + Right 
 0-normal 
 1-mild slowing, and/or reduction in amp. 
 2-moderate impaired. Definite and early fatiguing, may have occasional arrests 
 3-severely impaired. Frequent hesitations and arrests. 
 4-can barely perform 
 + Left 
 0-normal 
 1-mild slowing, and/or reduction in amp. 
 2-moderate impaired. Definite and early fatiguing, may have occasional arrests 
 3-severely impaired. Frequent hesitations and arrests. 
 4-can barely perform 
 Rapid Alternating Movements (pronate and supinate hands) 
 + Right 
 0-normal 
 1-mild slowing, and/or reduction in amp. 
 2-moderate impaired. Definite and early fatiguing, may have occasional arrests 
 3-severely impaired. Frequent hesitations and arrests. 
 4-can barely perform 
 + Left 
 0-normal 
 1-mild slowing, and/or reduction in amp. 
 2-moderate impaired. Definite and early fatiguing, may have occasional arrests 
 3-severely impaired. Frequent hesitations and arrests. 
 4-can barely perform 
 
Leg Agility (tap heel on ground, amp should be 3 inches) 


 
 
 
 
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 + Right 
 0-normal 
 1-mild slowing, and/or reduction in amp. 
 2-moderate impaired. Definite and early fatiguing, may have occasional arrests 
 3-severely impaired. Frequent hesitations and arrests. 
 4-can barely perform 
 + Left 
 0-normal 
 1-mild slowing, and/or reduction in amp. 
 2-moderate impaired. Definite and early fatiguing, may have occasional arrests 
 3-severely impaired. Frequent hesitations and arrests. 
 4-can barely perform 
 
Arising From Chair (pt. arises with arms folded across chest) 
 0-normal 
 1-slow, may need more than one attempt 
 2-pushes self up from arms or seat 
 3-tends to fall back, may need multiple triesbut can arise without assistance 
 4-unable to arise without help 
 
Posture 
 0-normal erect 
 1-slightly stooped, could be normal for older person 
 2-definitely abnormal, mod. stooped, may lean to one side 
 3-severely stooped with kyphosis 
 4-marked flexion with extreme abnormality of Posture 
 
Gait 
 0-normal 
 1-walks slowly, may shuffle with short steps,no festination or propulsion 
 2-walks with difficulty, little or no assistance, some festination, short steps or propulsion 
 3-severe disturbance, frequent assistance 
 4-cannot walk 
 


 
 
 
 
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Postural Stability (retropulsion test) 
 0-normal 
 1-recovers unaided 
 2-would fall if not caught 
 3-falls spontaneously 
 4-unable to stand 
 
Body Bradykinesia/ Hypokinesia 
 0-none 
 1-minimal slowness, could be normal, deliberate character 
 2-mild slowness and poverty of movement, definitely abnormal, or dec. amp. Of movement 
 3-moderate slowness, poverty, or small amplitude 
 4-marked slowness, poverty, or amplitude 
 
 
 
 


 
 
 
 
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18.9. Hamilton Rating Scale for Depression (HAM-D)  
 
HAMILTON  DEPRESSION  RATING SCALE (HAM-D) 
(To be administered by a health care professional) 
Patient Name  
 
Today’s Date     
 
The HAM-D is designed to rate the severity of depression in patients. Although it contains 21 areas, 
calculate the patient’s score on the first 17 answers. 
  
1. DEPRESSED MOOD 
(Gloomy attitude, pessimism about the future, feeling of sadness, tendency to weep) 
0 = Absent 
1 = Sadness, etc. 
2 = Occasional weeping  
3 = Frequent weeping 
4 = Extreme symptoms 
 
2. FEELINGS OF GUILT 
0 = Absent 
1 = Self-reproach, feels he/she has let people down 
2 = Ideas of guilt 
3 = Present illness is a punishment; delusions of guilt 
4 = Hallucinations of guilt 
 
3. SUICIDE 
0 = Absent 
1 = Feels life is not worth living  
2 = Wishes he/she were dead 
3 = Suicidal ideas or gestures  
4 = Attempts at suicide 
 
4. INSOMNIA - Initial  
(Difficulty in falling asleep)  
0 = Absent 
1 = Occasional 
2 = Frequent 
 
5. INSOMNIA - Middle 
(Complains of being restless and disturbed during the night. Waking during the night.) 0 = Absent 
1 = Occasional 
2 = Frequent 
  
6. INSOMNIA - Delayed 
(Waking in early hours of the morning and unable to fall asleep again) 
0 = Absent 
1 = Occasional 
2 = Frequent 
 
 
 


 
 
 
 
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7. WORK AND INTERESTS 
0 = No difficulty 
1 = Feelings of incapacity, listlessness, indeci- sion and vacillation 
2 = Loss of interest in hobbies, decreased social activities 
3 = Productivity decreased 
4 = Unable to work. Stopped working because of present illness only. (Absence from work after treatment 
or recovery may rate a lower score). 
 
8. RETARDATION 
(Slowness of thought, speech, and activity; apathy; stupor.) 
0 = Absent 
1 = Slight retardation at interview 
2 = Obvious retardation at interview 3 = Interview difficult 
4 = Complete stupor 
 
9. AGITATION 
(Restlessness associated with anxiety.)  
0 = Absent 
1 = Occasional 
2 = Frequent 
 
10. ANXIETY - PSYCHIC 
0 = No difficulty 
1 = Tension and irritability 
2 = Worrying about minor matters  
3 = Apprehensive attitude 
4 = Fears 
 
11. ANXIETY - SOMATIC  
Gastrointestinal, indigestion Cardiovascular, palpitation, Headaches Respiratory, Genito-urinary, etc. 
0 = Absent 
1 = Mild 
2 = Moderate 
3 = Severe 
4 = Incapacitating 
 
12. SOMATIC SYMPTOMS - GASTROINTESTINAL 
(Loss of appetite , heavy feeling in abdomen; constipation) 
0 = Absent 
1 = Mild 
2 = Severe 
 
13. SOMATIC SYMPTOMS - GENERAL  
(Heaviness in limbs, back or head; diffuse backache; loss of energy and fatiguability)  
0 = Absent 
1 = Mild 
2 = Severe 
 
14. GENITAL SYMPTOMS 
(Loss of libido, menstrual disturbances)  
0 = Absent 
1 = Mild 
2 = Severe 
 
 
 


 
 
 
 
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15. HYPOCHONDRIASIS 
0 = Not present 
1 = Self-absorption (bodily) 
2 = Preoccupation with health  
3 = Querulous attitude 
4 = Hypochondriacal delusions 
 
16. WEIGHT LOSS  
0 = No weight loss  
1 = Slight 
2 = Obvious or severe 
  
17. INSIGHT 
(Insight must be interpreted in terms of patient’s understanding and background.) 
0 = No loss 
1 = Partial or doubtfull loss  
2 = Loss of insight 
 
 
 
TOTAL ITEMS 1 TO 17:   
 
0 - 7 = Normal 
8 - 13 = Mild Depression 
14-18 = Moderate Depression 
19 - 22 = Severe Depression 
> 23 = Very Severe Depression 


 
 
 
 
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18. DIURNAL VARIATION 
(Symptoms worse in morning or evening. Note which it is. ) 
0 = No variation 
1 = Mild variation; AM (    )  PM (    )  
2 = Severe variation; AM (    )  PM (  ) 
 
19. DEPERSONALISATION AND DEREALISATION 
(feelings of unreality, nihilistic ideas)  
0 = Absent 
1 = Mild 
2 = Moderate 
3 = Severe 
4 = Incapacitating 
 
20. PARANOID SYMPTOMS  
(Not with a depressive quality)  
0 = None 
1 = Suspicious 
2 = Ideas of reference 
3 = Delusions of reference and persecution  
4 = Hallucinations, persecutory 
 
 
21. OBSESSIONAL SYMPTOMS 
(Obsessive thoughts and compulsions against which the patient struggles) 
0 = Absent 
1 = Mild 
2 = Severe 
 
 
 
 
 
 
 
 


 
 
 
 
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18.10. Brief Psychiatric Rating Scale Positive Subscale (BPRS+) 
 
Overall JE, Gorham DR (1962). The brief psychiatric rating scale. Psychological Reports 1962 vol. 10, 
pp799-812 
 
BRIEF PSYCHIATRIC RATING SCALE POSITIVE SUBSCALE (BPRS+) 
BPRS+ includes just the 4 questions shaded in gray color (#4, #11, #12, and #15) 
Please enter the score for the term which best describes the patient’s condition. 
0 = not assessed, 1 = not present, 2 = very mild, 3 = mild, 4 = moderate, 5 = moderately severe,  
6 = severe, 7 = extremely severe 
 
1. SOMATIC CONCERN Degree of 
concern over present bodily health. Rate the 
degree to which physical health is 
perceived as a problem by the patient, 
whether complaints have a realistic basis or 
not. 
 
 
SCORE
10. HOSTILITY Animosity, contempt, 
belligerence, disdain for other people 
outside the interview situation. Rate solely 
on the basis of the verbal report of feelings 
and actions of the patient toward others; do 
not infer hostility from neurotic defenses, 
anxiety, nor somatic complaints. (Rate 
attitude 
toward 
interviewer 
under 
“uncooperativeness”). 
 
 
 
 
 
 
 
 
 
SCORE
 
2. ANXIETY Worry, fear, or over-concern 
for present or future. Rate solely on the 
basis of verbal report of patient’s own 
subjective experiences. Do not infer 
anxiety 
 
 
 
 
 
 
SCORE
 
11. SUSPICIOUSNESS Brief (delusional 
or otherwise) that others have now, or have 
had in the past, malicious or discriminatory 
intent toward the patient. On the basis of 
verbal report, rate only those suspicions 
which are currently held whether they 
concern past or present circumstances. 
 
 
 
 
 
 
SCORE
 
3. 
EMOTIONAL 
WITHDRAWAL 
Deficiency in relating to the interviewer 
and to the interviewer situation. Rate only 
the degree to which the patient gives the 
impression of failing to be in emotional 
contact with other people in the interview 
situation 
 
 
 
 
 
 
SCORE
 
12. 
HALLUCINATORY 
BEHAVIOR 
Perceptions 
without 
normal 
external 
stimulus correspondence. Rate only those 
experiences which are reported to have 
occurred within the last week and which are 
described as distinctly different fro 
 
 
 
 
 
 
SCORE
 
4. CONCEPTUAL DISORGANIZATION 
Degree to which the thought processes are 
confused, disconnected, or disorganized. 
Rate on the basis of integration of the 
verbal products of the patient; do not rate 
on the basis of patient’s subjective 
impression of his own level of functioning.  
 
 
 
 
 
 
 
SCORE
13. MOTOR RETARDATION Reduction 
in energy level evidenced in slowed 
movements. Rate on the basis of observed 
behavior of the patient only; do not rate on 
the ba 
 
 
 
 
 
 
 
SCORE
5. GUILT FEELINGS Over-concern or 
remorse for past behavior. Rate on the basis 
of the patient’s subjective experiences of 
guilt as evidenced by verbal report with 
appropriate affect; do not infer guilt 
feelings from depression, anxiety or 
neurotic defenses. 
 
 
 
 
 
 
 
 
 
SCORE
 
14. UNCOOPERATIVENESS Evidence of 
resistance, unfriendliness, resentment, and 
lack of readiness to cooperate with the 
interviewer. Rate only on the basis of the 
patient’s attitude and responses to the 
interviewer and the interview situation; do 
not rate on basis of reported resentment or 
uncooperativeness outside the interview 
situation. 
 
 
 
 
 
 
 
 
 
SCORE
 


 
 
 
 
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6. 
TENSION 
Physical 
and 
motor 
manifestations of tension “nervousness”, 
and heightened activation level. Tension 
should be rated solely on the basis of 
physical signs and motor behavior and not 
on the basis of subjective experiences of 
tension reported by the patient. 
 
 
 
 
 
 
SCORE
 
15. UNUSUAL THOUGHT CONTENT 
Unusual, odd, strange or bizarre thought 
content. 
Rate 
here 
the 
degree 
of 
unusualness, 
not 
the 
degree 
of 
disorganization of thought processes. 
 
 
 
 
 
 
SCORE
 
7. MANNERISMS AND POSTURING 
Unusual and unnatural motor benavior, the 
type of motor behavior which causes 
certain mental patients to stand out in a 
crowd of normal people. Rate only 
abnormality of movements; do not rate 
simple heightened motor activity here. 
 
 
 
 
 
 
SCORE
 
16. 
BLUNTED 
AFFECT 
Reduced 
emotional tone, apparent lack of normal 
feeling or involvement. 
 
 
 
 
 
 
SCORE
 
8. GRANDIOSITY Exaggerated self-
opinion, conviction of unusual ability or 
powers. Rate only on the basis of patient’s 
statements about himself or self-in-
relation-to-others, not on the basis of his 
demeanor in the interview situation. 
 
 
 
 
 
SCORE
17. EXCITEMENT Heightened emotional 
tone, agitation, increased reactivity. 
 
 
 
 
 
SCORE
9. DEPRESSIVE MOOD Despondency in 
mood, sadness. Rate only degree of 
despondency; do not rate on the basis of 
inferences concerning depression based 
upon general retardation and somatic 
complaints. 
 
 
 
 
 
SCORE
 
18. DISORIENTATION Confusion or lack 
of proper association for person, place or 
time. 
 
 
 
 
 
SCORE
 
 
 
 


 
 
 
 
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Instructions for the Clinician: 
 
The Brief Psychiatric Rating Scale (BPRS) is a widely used instrument for assessing the positive, negative, 
and affective symptoms of individuals who have psychotic disorders, especially schizophrenia. It has 
proven particularly valuable for documenting the efficacy of treatment in patients who have moderate to 
severe disease. 
It should be administered by a clinician who is knowledgeable concerning psychotic disorders and able to 
interpret the constructs used in the assessment. Also considered is the individual's behavior over the 
previous 2-3 days and this can be reported by the patient's family. 
The BPRS consists of 18 symptom constructs and takes 20-30 minutes for the interview and scoring. The 
rater should enter a number ranging from 1 (not present) to 7 (extremely severe). 0 is entered if the item is 
not assessed. 
First published in 1962 as a 16-construct tool by Drs. John Overall and Donald Gorham, the developers 
added two additional items, resulting in the 18-item scale used widely today to assess the effectiveness of 
treatment. 
 
 
 
BPRS Scoring Instructions: 
Sum the scores from the 18 items. Record the total score and compare the total score from one evaluation 
to the next as the measure of response to treatment. 
 
 
 
 
 
 


 
 
 
 
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18.11. Montreal Cognitive Assessment (MoCA) 
 
Montreal Cognitive Assessment  
(MoCA) 
Administration and Scoring Instructions 
 
The Montreal Cognitive Assessment (MoCA) was designed as a rapid screening instrument for mild 
cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive 
functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and 
orientation. Time to administer the MoCA is approximately 10 minutes. The total possible score is 30 
points; a score of 26 or above is considered normal. 
  
1. Alternating Trail Making:  
Administration: The examiner instructs the subject: "Please draw a line, going from a number 
to a letter in ascending order. Begin here [point to (1)] and draw a line from 1 then to A then to 
2 and so on. End here [point to (E)]."  
Scoring: Allocate one point if the subject successfully draws the following pattern:  
1 −A- 2- B- 3- C- 4- D- 5- E, without drawing any lines that cross. Any error that is not 
immediately self-corrected earns a score of 0.  
 
2. Visuoconstructional Skills (Cube):  
Administration: The examiner gives the following instructions, pointing to the cube: “Copy this 
drawing as accurately as you can, in the space below”.  
Scoring: One point is allocated for a correctly executed drawing.  
• Drawing must be three-dimensional  
• All lines are drawn  
• No line is added  
• Lines are relatively parallel and their length is similar (rectangular prisms are 
accepted)  
 
A point is not assigned if any of the above-criteria are not met.  
 
3. Visuoconstructional Skills (Clock):  
Administration: Indicate the right third of the space and give the following instructions: “Draw 
a clock. Put in all the numbers and set the time to 10 after 11”.  
Scoring: One point is allocated for each of the following three criteria:  
Contour (1 pt.): the clock face must be a circle with only minor distortion 
acceptable (e.g., slight imperfection on closing the circle);  
Numbers (1 pt.): all clock numbers must be present with no additional numbers; 
numbers must be in the correct order and placed in the approximate quadrants 
on the clock face; Roman numerals are acceptable; numbers can be placed 
outside the circle contour;  
Hands (1 pt.): there must be two hands jointly indicating the correct time; the 
hour hand must be clearly shorter than the minute hand; hands must be centred 
within the clock face with their junction close to the clock centre.  
 
A point is not assigned for a given element if any of the above-criteria are not met.  


 
 
 
 
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4. Naming:  
Administration: Beginning on the left, point to each figure and say: “Tell me the name of this 
animal”.  
Scoring: One point each is given for the following responses: (1) camel or dromedary, (2) lion, (3) 
rhinoceros or rhino.  
 
5. Memory:  
Administration: The examiner reads a list of 5 words at a rate of one per second, giving the 
following instructions: “This is a memory test. I am going to read a list of words that you 
will have to remember now and later on. Listen carefully. When I am through, tell me as 
many words as you can remember. It doesn’t matter in what order you say them”. Mark a 
check in the allocated space for each word the subject produces on this first trial. When the 
subject indicates that (s)he has finished (has recalled all words), or can recall no more words, 
read the list a second time with the following instructions: “I am going to read the same list for 
a second time. Try to remember and tell me as many words as you can, including words you 
said the first time.” Put a check in the allocated space for each word the subject recalls after the 
second trial.  
At the end of the second trial, inform the subject that (s)he will be asked to recall these words 
again by saying, “I will ask you to recall those words again at the end of the test.”  
Scoring: No points are given for Trials One and Two.  
 
6. Attention:  
Forward Digit Span: Administration: Give the following instruction: “I am going to say some 
numbers and when I am through, repeat them to me exactly as I said them”. Read the five 
number sequence at a rate of one digit per second.  
Backward Digit Span: Administration: Give the following instruction: “Now I am going to say 
some more numbers, but when I am through you must repeat them to me in the backwards 
order.” Read the three number sequence at a rate of one digit per second.  
Scoring: Allocate one point for each sequence correctly repeated, (N.B.: the correct response 
for the backwards trial is 2-4-7).  
Vigilance: Administration: The examiner reads the list of letters at a rate of one per 
second, after giving the following instruction: “I am going to read a sequence of letters. Every 
time I say the letter A, tap your hand once. If I say a different letter, do not tap your hand”.  
Scoring: Give one point if there is zero to one errors (an error is a tap on a wrong letter 
or a failure to tap on letter A).  
Serial 7s: Administration: The examiner gives the following instruction: “Now, I will 
ask you to count by subtracting seven from 100, and then, keep subtracting seven from your 
answer until I tell you to stop.” Give this instruction twice if necessary.  
Scoring: This item is scored out of 3 points. Give no (0) points for no correct 
subtractions, 1 point for one correction subtraction, 2 points for two-to-three correct 
subtractions, and 3 points if the participant successfully makes four or five correct subtractions. 
Count each correct subtraction of 7 beginning at 100. Each subtraction is evaluated 
independently; that is, if the participant responds with an incorrect number but continues to 
correctly subtract 7 from it, give a point for each correct subtraction. For example, a participant 
may respond “92 – 85 – 78 – 71 – 64” where the “92” is incorrect, but all subsequent numbers 
are subtracted correctly. This is one error and the item would be given a score of 3.  
 
 


 
 
 
 
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7. Sentence repetition:  
Administration: The examiner gives the following instructions: “I am going to read you a 
sentence. Repeat it after me, exactly as I say it [pause]: I only know that John is the one to 
help today.” Following the response, say: “Now I am going to read you another sentence. 
Repeat it after me, exactly as I say it [pause]: The cat always hid under the couch when dogs 
were in the room.”  
Scoring: Allocate 1 point for each sentence correctly repeated. Repetition must be exact. Be 
alert for errors that are omissions (e.g., omitting "only", "always") and substitutions/additions 
(e.g., "John is the one who helped today;" substituting "hides" for "hid", altering plurals, etc.).  
 
8. Verbal fluency:  
Administration: The examiner gives the following instruction: “Tell me as many words as you 
can think of that begin with a certain letter of the alphabet that I will tell you in a moment. You 
can say any kind of word you want, except for proper nouns (like Bob or Boston), numbers, or 
words that begin with the same sound but have a different suffix, for example, love, lover, 
loving. I will tell you to stop after one minute. Are you ready? [Pause] Now, tell me as many 
words as you can think of that begin with the letter F. [time for 60 sec]. Stop.”  
Scoring: Allocate one point if the subject generates 11 words or more in 60 sec. Record 
the subject’s response in the bottom or side margins.  
 
9. Abstraction:  
Administration: The examiner asks the subject to explain what each pair of words has in 
common, starting with the example: “Tell me how an orange and a banana are alike”. If the 
subject answers in a concrete manner, then say only one additional time: “Tell me another way 
in which those items are alike”. If the subject does not give the appropriate response (fruit), say, 
“Yes, and they are also both fruit.” Do not give any additional instructions or clarification.  
After the practice trial, say: “Now, tell me how a train and a bicycle are alike”. Following the 
response, administer the second trial, saying: “Now tell me how a ruler and a watch are alike”. 
Do not give any additional instructions or prompts.  
Scoring: Only the last two item pairs are scored. Give 1 point to each item pair correctly 
answered. The following responses are acceptable:  
Train-bicycle = means of transportation, means of travelling, you take trips in both;  
Ruler-watch = measuring instruments, used to measure.  
The following responses are not acceptable: Train-bicycle = they have wheels; Ruler-watch = 
they have numbers.  
 
10. Delayed recall:  
Administration: The examiner gives the following instruction: “I read some words to you earlier, 
which I asked you to remember. Tell me as many of those words as you can remember. Make a 
check mark () for each of the words correctly recalled spontaneously without any cues, in the 
allocated space.  
Scoring: Allocate 1 point for each word recalled freely without any cues.  
Optional:  
Following the delayed free recall trial, prompt the subject with the semantic category cue 
provided below for any word not recalled. Make a check mark () in the allocated space if the 
subject remembered the word with the help of a category or multiple-choice cue. Prompt all 
non-recalled words in this manner. If the subject does not recall the word after the category cue, 
give him/her a multiple choice trial, using the following example instruction, “Which of the 
following words do you think it was, NOSE, FACE, or HAND?”  


 
 
 
 
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Use the following category and/or multiple-choice cues for each word, when appropriate:  
FACE: category cue: part of the body multiple choice: nose, face, hand  
VELVET: category cue: type of fabric multiple choice: denim, cotton, velvet  
CHURCH: category cue: type of building multiple choice: church, school, hospital  
DAISY: category cue: type of flower multiple choice: rose, daisy, tulip  
RED: category cue: a colour multiple choice: red, blue, green  
Scoring: No points are allocated for words recalled with a cue. A cue is used for clinical 
information purposes only and can give the test interpreter additional information about the type 
of memory disorder. For memory deficits due to retrieval failures, performance can be improved 
with a cue. For memory deficits due to encoding failures, performance does not improve with a 
cue.  
 
11. Orientation:  
Administration: The examiner gives the following instructions: “Tell me the date today”. If the 
subject does not give a complete answer, then prompt accordingly by saying: “Tell me the [year, 
month, exact date, and day of the week].” Then say: “Now, tell me the name of this place, and 
which city it is in.”  
Scoring: Give one point for each item correctly answered. The subject must tell the exact date 
and the exact place (name of hospital, clinic, office). No points are allocated if subject makes 
an error of one day for the day and date.  
 
TOTAL SCORE: Sum all subscores listed on the right-hand side. Add one point for an individual 
who has 12 years or fewer of formal education, for a possible maximum of 30 points. A final total 
score of 26 and above is considered normal. 
 
 


 
 
 
 
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18.12. Columbia-Suicide Severity Rating Scale (C-SSRS) 
Columbia–Suicide Severity Rating Scale 
Scoring and Data Analysis Guide 
************************************************************************ 
Contributors: Mary E. Nilsson, Shailaja Suryawanshi, Cristiana Gassmann-Mayer, Sarah Dubrava, 
Paul McSorley, and Kaihong Jiang. 
 
Introduction 
The Columbia–Suicide Severity Rating Scale (C-SSRS) is an assessment tool that evaluates suicidal 
ideation and behavior. This guide outlines the proposed safety outcomes and statistical analysis 
strategy for the C-SSRS for an individual clinical trial. 
The actual tables or combination of tables may vary to be consistent with a sponsor’s standards, or to 
be consistent with the needs of a particular regulatory agency/division. 
As such this document serves as a general guideline and is not a proposal for mandatory analyses 
involving the C-SSRS. When analyzing the C-SSRS across studies, the same safety outcomes can be 
used. However, different statistical methodology would apply to combining data across studies, and is 
not discussed in this document. The briefing document for the 13 December 2006 Food and Drug 
Administration (FDA) Advisory Committee Meeting contains a discussion of meta-analytical methods 
to consider when analyzing suicide-related outcomes across studies 
(http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-index.htm). The CSSRS may also be 
used to assess efficacy, but specific guidance related to efficacy assessment will be a topic for a 
separate document. 
As noted in the August 2012 draft guidance titled “Suicidal Ideation and Behavior: Prospective 
Assessment of Occurrence in Clinical Trials”, the FDA has adopted the 11 categories defined in the C-
SSRS (five subtypes of suicidal ideation, five subtypes of suicidal behavior, and self-injurious 
behavior without suicidal intent) as their standard. 
Some data collected on the C-SSRS are not included in these proposed displays for safety analysis 
(e.g., suicidal behavior lethality and suicidal ideation intensity), but are used for individual clinical 
management, safety monitoring, or other research purposes. 
 
Analysis Set: 
The analysis set should be defined consistently with the sponsor’s standards for the safety analysis set. 
Frequently, this means including patients who have been exposed to at least one dose of study drug. 
When analyzing the C-SSRS, it is recommended to include patients having at least 1 post-baseline C-
SSRS measurement, regardless of whether they had a baseline C-SSRS measurement. For some 


 
 
 
 
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analyses of the C-SSRS (e.g., treatmentemergent assessments and shift tables), a pre-treatment C-
SSRS measurement is also required. 
 
Outcomes: 
There is current debate on whether suicidal ideation and suicidal behavior should be combined and 
analyzed as a single outcome. Researchers agree on the need for having analyses that keep suicidal 
ideation and suicidal behavior separate, but disagree on whether there is value to having any outcome 
that combines them. This document currently includes the combined outcomes measure. 
The following outcomes are C-SSRS categories and have binary responses (yes/no). The categories 
have been re-ordered from the actual scale to facilitate the definitions of the composite and 
comparative endpoints, and to enable clarity in the presentation of the results. 
Category 1 – Wish to be Dead 
Category 2 – Non-specific Active Suicidal Thoughts 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
Category 6 – Preparatory Acts or Behavior 
Category 7 – Aborted Attempt 
Category 8 – Interrupted Attempt 
Category 9 – Actual Attempt (non-fatal) 
Category 10 – Completed Suicide 
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (athough not suicide-related) 
and has a binary response (yes/no). 
The following outcome is a numerical score derived from the C-SSRS categories. The score is created 
at each assessment for each patient and is used for determining treatment emergence. 
 
Suicidal Ideation Score: The maximum suicidal ideation category (1-5 on the CSSRS) present 
at the assessment. Assign a score of 0 if no ideation is present. 
 
Endpoints: 
Composite endpoints based on the above categories are defined below. 
 
Suicidal ideation: A “yes” answer at any time during treatment to any one of the five suicidal 
ideation questions (Categories 1-5) on the C-SSRS. 
 
Suicidal behavior: A “yes” answer at any time during treatment to any one of the five suicidal 
behavior questions (Categories 6-10) on the C-SSRS. 


 
 
 
 
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 
Suicidal ideation or behavior: A “yes” answer at any time during treatment to any one of the 
ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS. 
Comparative endpoints of interest are defined below. “Treatment emergence” is used for outcomes 
that include events that first emerge or worsen. “Emergence” is used for outcomes that include events 
that first emerge. 
 
Treatment-emergent suicidal ideation compared to recent history: An increase in the 
maximum suicidal ideation score during treatment from the maximum suicidal ideation 
category during a specified pre-treatment period (C-SSRS scales taken during the specified 
pre-treatment period; excludes “lifetime” scores from the Baseline C-SSRS scale or 
Baseline/Screening C-SSRS scale). 
 
Treatment-emergent serious suicidal ideation compared to recent history: An increase in the 
maximum suicidal ideation score to 4 or 5 on the C-SSRS during treatment from not having 
serious suicidal ideation (scores of 0-3) during a specified pre-treatment period (C-SSRS 
scales taken during the specified pretreatment period; excludes “lifetime” scores from the 
Baseline C-SSRS scale or Baseline/Screening C-SSRS scale). 
 
Emergence of serious suicidal ideation compared to recent history: An increase in the 
maximum suicidal ideation score to 4 or 5 on the C-SSRS during treatment from no suicidal 
ideation (scores of 0) during a specified pre-treatment period (CSSRS scales taken during the 
specified pre-treatment period; excludes “lifetime” scores from the Baseline C-SSRS scale or 
Baseline/Screening C-SSRS scale). 
 
Improvement in suicidal ideation at a time point of interest compared to baseline: An 
improvement in this endpoint can be considered as a decrease in suicidal ideation score at the 
time point of interest (e.g., the last measurement during treatment) from the baseline 
measurement (e.g., the measurement taken just prior to treatment. This analysis should only be 
performed for studies in which a baseline C-SSRS can be defined (i.e., having improvement 
from the worse event over a lifetime is not clinically meaningful). 
 
Emergence of suicidal behavior compared to all prior history: The occurrence of suicidal 
behavior (Categories 6-10) during treatment from not having suicidal behavior (Categories 6-
10) prior to treatment (includes “lifetime” and/or “screening” scores from the Baseline C-
SSRS scale, Screening C-SSRS scale, or Baseline/Screening C-SSRS scale, and any “Since 
Last Visit” from the Since Last Visit C-SSRS scales taken prior to treatment). 
Additional comparative endpoints for consideration are defined below. These are not 
necessarily recommended for all treatment programs, but if used, should follow the 
nomenclature. 


 
 
 
 
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 
Treatment-emergent suicidal ideation compared to all prior history: An increase in the 
maximum suicidal ideation score during treatment from the maximum suicidal ideation score 
prior to treatment (includes “lifetime” and/or “screening” scores from the Baseline C-SSRS 
scale, Screening C-SSRS scale, or Baseline/Screening C-SSRS scale, and any “Since Last 
Visit” from the Since Last Visit C-SSRS scales taken prior to treatment). 
 
Emergence of serious suicidal ideation compared to all prior history: An increase in the 
maximum suicidal ideation score to 4 or 5 during treatment from no suicidal ideation (scores 
of 0) prior to treatment (includes “lifetime” and/or “screening” scores from the Baseline C-
SSRS scale, Screening C-SSRS scale, or Baseline/Screening C-SSRS scale, and any “Since 
Last Visit” from the Since Last 
 
Visit C-SSRS scales taken prior to treatment). 
 
Treatment-emergent serious suicidal ideation compared to all prior history: An increase in the 
maximum suicidal ideation score to 4 or 5 on the C-SSRS during treatment from not having 
serious suicidal ideation (scores of 0-3) prior to treatment (includes “lifetime” and/or 
“screening” scores from the Baseline CSSRS scale, Screening C-SSRS scale, or 
Baseline/Screening C-SSRS scale, and any “Since Last Visit” from the Since Last Visit C-
SSRS scales taken prior to treatment). 
Outcomes that can be used for clinical management and safety monitoring or potentially for research 
purposes are described below. 
 
Suicidal behavior lethality rating taken directly from the C-SSRS 
 
Suicidal ideation score 
Any score greater than 0 is important and may indicate the need for mental health 
intervention. The protocol procedures related to clinical care of patients with treatment 
emergent suicidal ideation and behaviors will then be implemented to ensure proper 
management of the event and protection of the patient’s safety. For example, a score of 4 
(active suicidal ideation with some intent to act) or 5 (active suicidal ideation with specific 
plan and intent) on suicidal ideation can be used to indicate serious suicidal ideation and can 
be used to trigger further evaluation and immediate contact with patient’s mental health 
practitioner (for non-psychiatry trials this may be used to trigger a prompt referral to a mental 
health professional) and/or possibly the emergency room. 
 
Suicidal ideation intensity rating 
Add the five intensity item scores to create a total score (range 0 to 25) to represent the 
intensity rating. If the patient did not endorse any suicidal ideation set the intensity rating to 0. 
 
 


 
 
 
 
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Analytical and Statistical Methods: 
The sponsor’s standard approaches to present safety data should be used consistently.  
Suicidal ideation and suicidal behavior are relatively rare events in individual, doubleblind, controlled 
clinical trials, except possibly for a population particularly susceptible to this safety risk. In general, no 
formal statistical hypothesis testing is recommended for individual studies as only few events are 
typically observed and descriptive summaries will then suffice. 
See the mock tables, the mock listing, and mock figure for suggested summaries and presentation of 
the data. Note that these mock tables can be easily extended to include multiple treatment 
groups/comparisons as needed. Tables should be modified to fit the needs of the specific analyses 
performed. 
For very small studies (e.g., Phase 1 studies), or indications where suicide-related events are expected 
to be rare, it may be sufficient to plan on providing a listing only (see Listing 1). Otherwise, Tables 1 
and 2 as shown may be provided. 
The specific statistical method (or lack of an inferential method) should be consistent with the 
sponsor’s standards. When inferential analyses are not performed the p-value column should be 
eliminated. Tables 3-4 (options for a shift table) will likely be used when there are findings to 
understand in more detail and/or when the expected number of suicide-related events is large either 
due to having a large study or having a population at high risk. A graphical presentation, for example a 
stacked bar chart, may also be used when appropriate (see Figure 1). 
A summary of pre-treatment data is generally desirable and can be added to existing planned tables for 
patient characteristics (e.g., percent of subjects with lifetime suicidal ideation, baseline suicidal 
ideation, lifetime suicidal behavior, baseline suicidal behavior, lifetime self-injurious behavior without 
suicidal intent, and baseline self-injurious behavior without suicidal intent). Alternatively, if all 
categories of suicidal ideation and suicidal behavior are of interest for pre-treatment summaries, Table 
1 can be repeated for providing a summary of lifetime outcomes and again for baseline outcoments. 
The specific timeframe used for defining baseline will need to be defined. 
When inferential statistics are used, methods for consideration include: the Miettinen and Nurminen 
method, an unconditional, asymptotic method; the Fisher's exact test; 95% confidence intervals (CIs) 
based on Wilson's score method; and forest plots to present effect across treatment arms or subgroups 
of interest. 
A further consideration for inferential analysis may be the requirement that at least 4 patients in any 
treatment group exhibit the event. Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in review, not a 
formal method for assessing the statistical significance of the between-group differences in adverse 


 
 
 
 
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experiences. Appropriate cautionary statements on the interpretation of inferential statistics for 
purposes of summarizing information or signaling trends should be made. 
Methods for assessing dose-response relationships should be consistent with the sponsor's standards. 
Calculating and presenting incidence rates (e.g., n/patient-years) should be considered, especially for 
studies with long patient exposures and expected differential drop-out rates between treatment groups. 
In long-term trials where the suicidality scale is administered frequently, a time-to-event analysis 
where the event is any suicidal event (either ideation or behavior whichever occurs first) can be 
performed using methods such as Kaplan-Meier method, log-rank test, generalized Wilcoxon test and 
Cox proportional hazards model adjusting for a limited number of covariates. It is noted that event 
type-specific analysis (i.e., timeto-first-ideation and time-to-first-behavior analyses) may not be 
interpretable due to the presence of-competing risks and informative censoring. In situations that 
warrant an assessment by age, gender and/or other risk factors summary statistics of scores on 
suicidality endpoints of interest can be presented by visit. For studies with longer duration, scores can 
be summarized by visit or time period (treatment phase, posttreatment phase etc.). 
Based on the individual program strategy, active treatment groups may be pooled for comparisons to 
placebo/active comparator, or for performing all pair-wise dose comparisons. Analysis methods for 
assessing effects over several trials, subgroups or indications are presented in. 
Note that missing data should not be imputed. 
 
 


 
 
 
 
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Table 1: Number of Patients with Suicidal Ideation, Suicidal Behavior, and Self-Injurious Behavior 
without Suicidal Intent Based on the C-SSRS During Treatment; [Define Analysis Set] 
 
 
 
 


 
 
 
 
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Table 2: Number of Patients with Suicide-Related Treatment-Emergent Events Based on the C-SSRS 
During Treatment; [Define Analysis Set] 
 
 
 


 
 
 
 
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Table 3. Shift-table to Demonstrate Changes in C-SSRS Categories from Baseline During Treatment; 
[Define Analysis Set] 
 
Table 4. Shift-table to Demonstrate Changes in C-SSRS Suicidal Ideation Scores 
from Baseline During Treatment; [Define Analysis Set] 
 


 
 
 
 
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Listing 1: Listing of Subjects with Suicidal Ideation, Suicidal Behavior, or Self-Injurious Behavior 
without Suicidal Intent Based on the C-SSRS During Treatmenta; [Define Analysis Set] 
 
 
 
 


 
 
 
 
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18.13. Fatigue Severity Scale (FSS) 
 
Fatigue Severity Scale (FSS) of Sleep Disorders 
 
The Fatigue Severity Scale (FSS) is a method of evaluating the impact of fatigue on you. The 
FSS is a short questionnaire that requires you to rate your level of fatigue. 
 
The FSS questionnaire contains nine statements that rate the severity of your fatigue symptoms. 
Read each statement and circle a number from 1 to 7, based on how accurately it reflects your 
condition during the past week and the extent to which you agree or disagree that the statement 
applies to you. 
 
• A low value (e.g., 1) indicates strong disagreement with the statement, whereas a high value 
(e.g., 7) indicates strong agreement. 
 
• It is important that you circle a number (1 to 7) for every question. 
 
FSS Questionnaire 
During the past week, I have found that: 
Disagree <--------> Agree 
My motivation is lower when I am fatigued. 
1 
2 
3 
4 
5 
6 
7 
Exercise brings on my fatigue. 
1 
2 
3 
4 
5 
6 
7 
I am easily fatigued. 
1 
2 
3 
4 
5 
6 
7 
Fatigue interferes with my physical functioning. 1 
2 
3 
4 
5 
6 
7 
Fatigue causes frequent problems for me. 
1 
2 
3 
4 
5 
6 
7 
My fatigue prevents sustained physical 
functioning. 
1 
2 
3 
4 
5 
6 
7 
Fatigue interferes with carrying out certain 
duties and responsibilities. 
1 
2 
3 
4 
5 
6 
7 
Fatigue is among my three most disabling 
symptoms. 
1 
2 
3 
4 
5 
6 
7 
Fatigue interferes with my work, family, or 
social life. 
1 
2 
3 
4 
5 
6 
7 
Total Score: 
 
Copyright Lauren B. Krupps. Reproduced with permission of the author. 
 
 
 


 
 
 
 
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18.14. Berlin Questionnaire (BQ) 
 
 
 
Netzer, N. C., R. A. Stoohs, et al. (1999). "Using the Berlin Questionnaire to identify patients at risk for 
the sleep apnea syndrome." Ann Intern Med 131(7): 485-491 (41). 
 


 
 
 
 
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18.15. Schedule of Assessments 
VISITS 
Week 
Screening 
period 
(W-4) 
Baseline 
period 
(W-1) 
Randomisation 
Visit 1 
 
 
Treatment 
Visit 2 
(W2) 
 
Treatment 
Visit 3 or 
Early Term 
(W6) 
FUP 
(1) 
 
Study days (referred to D1 [Day of first 
administration] 
(allowed deviation days in brackets) 
D-28  
to D-8 
D-7  
to D-2 
D-1  
 
D14  
(± 2) 
D35  
(2) 
D42  
(± 3) 
+D28  
(± 2) 
Informed consent 
X 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X(3) 
X(3) 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history and previous medication 
X(4) 
X 
 
 
 
 
 
Concurrent Medical Condition 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
X 
 
Vital signs (including heart rate and blood 
pressure) 
X 
 
 
X 
 
X 
X 
Pregnancy test 
X 
 
X(5) 
 
 
X 
 
Laboratory tests 
X 
X(6) 
 
 
 
X 
 
Pharmacogenomic blood sample 
X(7) 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
X 
 
Eye examination 
X 
 
 
 
 
X(8) 
 
Epworth Sleepiness Scale (ESS) 
X 
 
X 
X 
 
X 
 
Scales for Outcome in Parkinson's Disease 
Sleep (SCOPA-Sleep) 
 
 
X 
X 
 
X 
 
Parkinson's Disease Sleep Scale (PDSS-2) 
 
 
X 
X 
 
X 
 
Fatigue Severity Scale (FSS) 
X 
 
 
 
 
X 
 
Berlin Questionnaire (BQ) 
X 
 
 
 
 
 
 
Unified Parkinson's Disease Rating Scale 
(UPDRS Part III)(9) 
 
 
X 
X 
 
X 
 
Cognitive Impairment (Montreal Cognitive 
Assessment – MoCA 
X 
 
 
 
 
X 
 
Hamilton Rating Scale for Depression (HAM-
D)(10) 
X 
 
 
X 
 
X 
X 
Columbia-Suicide Severity Rating Scale (C-
SSRS) (10) 
X 
 
 
X 
 
X 
X 
Brief Psychiatric Rating Scale positive 
subscale (BPRS+)(10) 
X 
 
 
X 
 
X 
X 
Maintenance of Wakefulness Test (MWT)(11) 
 
X 
 
 
 
X 
 
Polysomnography(11) 
 
X 
 
 
 
X 
 
Free living activity (GENEActiv ®)(2) 
 
X 
X 
 
X 
X 
 
Randomisation 
 
 
X 
 
 
 
 
Treatment intake(12) 
 
 
 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Concomitant medication 
 
X 
X 
X 
X 
X 
 
(1)All subjects will perform a safety follow-up visit 28 days after last study visit performed.  
     Additional unscheduled visits may be arranged in case of eye examination, ECG, or adverse event findings. 
(2) GENEActiv® to be worn for 7 days continuously on the non-dominant hand day -7 to day -1 at baseline and before the last dose,  
      day 35 to day 42. 
(3) Inclusion / Exclusion criteria to be reconfirmed before randomisation 
(4) Prohibited medical history will be assessed 4 weeks before Screening D-28 
(5) Dipstick pregnancy test to be completed before randomisation 
(6) If there are more than 14 days between screening and baseline 
(7) Pharmacogenomic blood sample to be obtained in subjects who specifically consented for this exploratory analysis. 
(8) The eye examination should be performed after the last treatment on Day 42 and before the follow up safety call. 
(9) Subjects will be instructed to have already taken their normally scheduled dose of anti-parkinsonian medication and their IMP prior to 
      arriving at the study site in order to have their UPDRS Part III evaluated in ON (within approximately 1 to 3 hours after taking their 
      levodopa dose). UPDRS in OFF will not be evaluated. 
      It is recommended that all assessment (s) establishing eligibility for the study to be performed first. 
(10) Any positive finding on the HAM-D, C-SSRS, or BPRS+ scales during the study will be referred to a trained mental health professional 
      to be followed. 
(11) MWT and Polysomnography will be performed on a minimum of 50% of subjects (all recruited in sites with sleep units available) 
(12) Treatment will be taken from Day 1 to Day 42, both inclusive.  

SAP_001.pdf: 
 
Sponsor  ...........  BenevolentAI Bio 
Project Code  ...  BB-2001-201b 
 
 
 
 
FILE NAME 
STAT.04.EU.WD.01_SAP-Template_V1 
Version 1.0 (25OCT2018)     [  ] Draft / [ x ] Final 
PAGE 
1 of 26 
 
Standard FORM 
STAT.04.EU.WD.01_SAP-Template_V1 
Effective date: 01-SEP-2015 
 
 
 
Statistical Analysis Plan 
 
Study title:  
Dose finding phase IIb study of Bavisant to evaluate its safety and effiCacy in treAtment of 
exceSsive daytime sleePiness (EDS) in PARkinson’s Disease (PD). CASPAR study. 
 
Protocol Number: BB-2001-201b 
 
Linical-Code: BEN01 
 
 
Control Versions 
STATUS AND 
 VERSION NUMBER 
REASON FOR CHANGE- 
LOCATION OF CHANGE 
DATE 
MODIFIED BY 
Draft 0.1 
First document  
11MAY2018 
Eduardo Sobreviela 
Draft 0.2 
Comments for Draft 0.1 
16JUL2018 
Eduardo Sobreviela 
Final 1.0 
Comments to Draft 0.2 
25OCT2018 
Eduardo Sobreviela 
 
 
 
 
PREPARED BY: 
_______________________________________ 
___________ 
 
Eduardo Sobreviela, 
Date 
Director Biostatistics, Linical 
 
 
 
 
REVIEWED BY: 
________________________________________ 
____________ 
Dr Kevin Carroll  
Date 
Director, KJC Statistics Ltd. 
 
 
 
 
APPROVED: 
________________________________________ 
____________ 
Dr Leo James 
Date 
Medical Director, BenevolentAI Bio 
 
 
 
 
 
31 October 2018


 
Sponsor  ...........  BenevolentAI Bio 
Project Code  ...  BB-2001-201b 
 
 
 
 
FILE NAME 
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Effective date: 01-SEP-2015 
 
INDEX 
1 
INTRODUCTION ................................................................................................................. 4 
2 
RESPONSIBILITIES ........................................................................................................... 4 
3 
STUDY OBJECTIVES ......................................................................................................... 4 
3.1 
Primary Objectives ............................................................................................. 4 
3.2 
Secondary objectives ......................................................................................... 4 
3.3 
Exploratory Objectives ....................................................................................... 4 
4 
DESIGN OF THE STUDY ................................................................................................... 4 
4.1 
STUDY WINDOWS ............................................................................................ 6 
5 
SAMPLE SIZE AND POWER ESTIMATION ...................................................................... 6 
6 
ANALYSIS SETS ................................................................................................................ 6 
7 
PRESENTATION OF DATA ............................................................................................... 7 
8 
SOFTWARE ........................................................................................................................ 7 
9 
EFFICACY ENDPOINTS ..................................................................................................... 8 
9.1 
Primary Endpoint for Efficacy ............................................................................ 8 
9.2 
Secondary Endpoints for Efficacy ...................................................................... 8 
9.2.1 
Epworth Sleepiness Scale (ESS) ........................................................................................ 8 
9.2.2 
SCOPA-Sleep ...................................................................................................................... 9 
9.2.3 
Parkinson’s Disease Sleep Scale (PDSS-2) ....................................................................... 9 
9.2.4 
Maintenance of Wakefulness Test (MWT) .......................................................................... 9 
9.2.5 
Polysomnography ..............................................................................................................10 
9.2.6 
Unified Parkinson’s disease Rating Scale Part III (UPDRS Part III) .................................11 
9.2.7 
Hamilton Rating Scale for Depression (HAM-D) ...............................................................11 
9.2.8 
Montreal Cognitive Assessment (MoCA)...........................................................................11 
9.2.9 
Fatigue Severity Scale (FSS) ............................................................................................12 
9.2.10 Berlin Questionnaire (BQ) .................................................................................................12 
9.3 
Exploratory Efficacy Endpoints ........................................................................13 
9.4 
Analysis sets Analysed for Efficacy .................................................................13 
10 
STATISTICAL METHODOLOGY FOR EFFICACY ENDPOINTS ....................................14 
10.1 
Primary Efficacy Analysis.................................................................................14 
10.1.1 Sensitivity analyses missing reductions imputed to 0: ......................................................14 
10.1.2 Sensitivity analyses MMRM Model: ...................................................................................14 
10.1.3 Sensitivity analysis using MCP-Mod ..................................................................................14 
10.1.4 Sensitivity analyses Rank ANCOVA ..................................................................................17 
10.1.5 Sensitivity three-parameter sigmoidal Hill dose-response curve analyses .......................18 
10.1.6 Primary Analysis with new missing data allocation windows ............................................18 
10.2 
Secondary Efficacy Analysis ............................................................................19 
10.3 
Exploratory Efficacy Analysis ...........................................................................19 
10.4 
Efficacy analysis Considerations .....................................................................20 
10.4.1 Pooling of Regions.............................................................................................................20 
10.4.2 Handling of missing data ...................................................................................................20 
11 
SAFETY ENDPOINTS.......................................................................................................21 
11.1 
Analysis Sets Analysed for Safety ...................................................................21 
12 
STATISTICAL METHODOLOGY FOR SAFETY ENDPOINTS........................................21 
12.1 
Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events 
of Special Interest (AESIs) such as headache, nausea and insomnia ..............................21 


 
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12.2 
Incidence of suicidal ideation (C-SSRS) findings from screening/baseline to the end of the 
2-week and the 6-week treatment period and safety follow-up .........................................22 
12.3 
Incidence of positive psychotic symptoms (BPRS+) findings from screening/baseline to 
the end of the 2-week and the 6-week treatment period and safety follow-up ..................22 
12.4 
Incidence of physical examination, vital signs .................................................22 
12.5 
Incidence of laboratory tests findings (haematology and biochemistry) ..........23 
12.6 
Incidence of cardiovascular safety findings (blood pressure, heart rate, ECG QT/QTc) 23 
12.7 
Incidence of eye exam findings .......................................................................23 
13 
OTHER ANALYSES..........................................................................................................24 
13.1 
Demographic and Baseline Characteristics .....................................................24 
13.2 
Prior or Concomitant Medications ....................................................................24 
13.3 
Prohibited Medication ......................................................................................24 
13.4 
Medical History ................................................................................................25 
13.5 
Extent of investigational medicinal product exposure and compliance ...........25 
14 
CHANGES FROM THE PROTOCOL ...............................................................................25 
15 
INTERIM ANALYSES .......................................................................................................25 
16 
REFERENCES ..................................................................................................................25 
17 
GENERAL FORMAT OF TABLES, FIGURES AND SUBJECT DATA ...........................26 
 
  


 
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1 
INTRODUCTION 
The objective of this statistical analysis plan (SAP) is to specify the statistical analysis in more 
detail than stated in the protocol for the trial.  The statistical analysis plan does not change the 
analysis described in the protocol, but it should be precise enough to serve as a guideline for 
statistical programming and creation of tables. The statistical analysis plan (SAP) will ensure the 
credibility of the study findings by specifying the statistical approaches to the analysis of the 
double-blind data prior to database lock.  
 
This Statistical Analysis Plan was developed based on the International Conference on 
Harmonization (ICH) E3 and E9 Guidelines and with reference the valid protocol (final version 
v1.0 amendment 03, dated 23Aug2017).  Deviations from the planned methods should also be 
summarized in Section 14 of this SAP. Any deviations during the analysis and reporting process 
from the current statistical analysis plan will be described and justified in the final report 
 
2 
RESPONSIBILITIES 
 
The statistical analysis, interpretation and reporting will be the responsibility of the assigned project 
biostatistician. 
 
All analyses and reporting will be subject to a quality check process. 
 
3 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
To assess the efficacy of Bavisant compared to placebo after a 6-week treatment period on the 
excessive daytime sleepiness in Parkinson's disease. 
3.2 
Secondary objectives 
To assess the efficacy and safety assessment of Bavisant compared to placebo after 2 weeks and 6 
weeks of treatment. The efficacy assessment will include excessive daytime sleepiness, motor control, 
and depression. 
3.3 
Exploratory Objectives 
Exploratory objectives will include the assessment of free living activity in subjects on Bavisant 
compared to placebo after 6 weeks of treatment using a wrist-worn actigraphy. 
 
4 
DESIGN OF THE STUDY 
This phase 2b study is designed as multicentre, multinational, randomized, double blind, parallel 
group and placebo controlled with three doses of Bavisant (0.5, 1, and 3 mg/d) in subjects with 
excessive daytime sleepiness with Parkinson's disease. This study will involve approximately 230 


 
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subjects from around 48 sites globally. Eligible subjects will be randomly allocated at a ratio of 
1:1:1:1 to either Bavisant (at doses of 0.5, 1 and 3 mg/d) or placebo. After signing the study informed 
consent, subjects meeting the UK PDS Brain Bank Clinical Diagnostic Criteria for Parkinson's 
disease (see details in the protocol Appendix 18.2) will enter a screening period (lasting up to 3 weeks) 
followed by a baseline period (lasting up to 1 week). Key inclusion / exclusion criteria will be verified 
to determine subject eligibility at the screening, baseline periods and prior to randomisation, including 
the suicide risk assessment following the FDA Guidance for Industry on Suicidal Ideation and 
Behavior. There is a 6 weeks treatment period, starting on Day 1, followed by a safety follow-up at 
least 4 weeks after completion of the treatment period. Additional unscheduled visits may be required 
based on the investigators' judgement at the end of study visit or at the safety follow-up. For early 
termination, all the assessments of the treatment week 6 visit should be performed, if possible, 
including the safety follow-up 4 weeks after the last investigational medicinal product (IMP) 
administration. The figure below describes the study flow graphically. 
 
Figure 1 
 
 
 


 
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4.1 
STUDY WINDOWS 
The process described here will be applied for visit re-allocation except any other approach was 
described in section 10 or 13 of this SAP for the corresponding statistical analysis. No re-allocation 
will be performed for nominal visits already provided in the clinical database (visit 1, visit 2 and visit 
3). However, unscheduled visits or Early Termination visit may be used to complete any missing 
information not gathered in the scheduled visit 2 and visit 3, according to the table below. 
 
Table 1: Reallocation time windows definition 
Scheduled Visit Post-baseline 
Target Study Day 
Analysis window  
in study days 
Visit 2 (week 2) 
14 
10 to 21 
Visit 3 (week 6) 
42 
22 to 45 
 
Unscheduled visits occurring outside of the analysis windows will not be re-allocated. 
5 
SAMPLE SIZE AND POWER ESTIMATION 
A total of 200 completed subjects will be evaluated for the study (50 completed subjects per treatment 
group, with expected early withdrawal rate of around 15%). 
The assumptions used for the sample size calculation are a mean absolute change in the Epworth 
Sleepiness Scale (ESS) from baseline to the end of the 6-week treatment period of at least 3.0 points 
(minimum change considered as clinically relevant) and a standard deviation of 5.0 (based on a 
comparable study of Modafinil in a similar population recruited at one centre (3) which showed a 
standard deviation in the ESS between 3.5 at baseline and 4.8 at the end of the treatment period) and 
a reduction in ESS of 2.7 points for subjects treated with Modafinil. 
The confirmation of the hypothesis of detecting a mean difference in ESS of 3.0 points vs. baseline 
requires a sample size of 25 subjects per group (intragroup ∆=3.0; SD=5.0; two-side α=0.05; β=0.20; 
power=80%; one-sample t-test). 
The additional endpoint of showing a statistically significant difference of at least 3.0 points in ESS 
between Bavisant and placebo requires a sample size of 50 subjects per group (between treatment 
∆=3.0; SD=5.0; two-side α=0.05; β =0.20; power=80%; two-sample equal-variance t-test). 
The effect size of Bavisant in EDS is unknown and smaller changes in ESS may be clinically useful 
according to its profile, and higher variability is expected in this multicentre study; so the sample size 
of 200 completed subjects (50 per treatment group) is proposed in order to cover both the confirmation 
of an intragroup change of at least 3.0 points vs. baseline, and the between-group difference of at least 
3.0 points change vs. placebo. 
The Maintenance of Wakefulness Test (MWT) will be performed in a minimum of 20 subjects per 
group (80 overall) in order to be enough to show statistically significant differences if the expected 
MWT absolute change from baseline differs at least in one standard deviation (effect size = 1.0).  
6 
ANALYSIS SETS 
The safety population (SAF) will be defined as all subjects who have received at least one dose of the 
study treatment. 
 


 
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The intent to treat population (ITT) will be defined as all randomized subjects who have taken at least 
one dose of study treatment.  
 
The per protocol population (PP) will be defined as all subjects in the FAS who do not experience a 
major protocol deviation.  
 
Protocol deviations will be defined as deviations from the procedure outlined in the protocol. Protocol 
deviations will be identified for each patient in the Data (blind) Review & Evaluability Determination 
meeting will be held prior to the treatment unblinding. They will be assessed as “minor” or “major” 
according to the possible impact expected on efficacy results. Minor and major protocol deviations 
will be fully documented in the Protocol Deviation Document prior to unblinding. Specific data sets 
will be produced and transferred to Biostatistics department in order to allow the appropriate 
definition for the Per Protocol Population. 
Since the reasons for excluding patients from the analysis cannot be entirely foreseen at the time of 
writing the statistical analysis plan evolving trial conduct may require some further definition of 
patients to be excluded, at the end of the trial, but prior to unblinding. 
Aspects to be considered (but not limited to) when determining the evaluability of data are as follows: 
▪ Inclusion and exclusion criteria 
▪ Acceptable timings for visit dates and measurements 
▪ Compliance with treatment 
▪ Incorrect randomization/treatment 
▪ Concomitant therapies 
 
As far as possible ITT principle will be guaranteed so it is not expected to have protocol deviations 
excluding patients from the ITT population. 
 
7 
PRESENTATION OF DATA 
Tables and listings will be produced in accordance with the principles outlined by the ICH E3 
guideline. 
Categorical data will be summarized with absolute and relative frequencies (percentage), missing 
data will not be considered in the percentage calculation, and numerical data will be summarized 
with the number, mean, median, standard deviation (SD), the range (minimum and maximum), and 
the first, third quartiles and 95% confidence interval (if applicable). Throughout the presentation of 
the study results the four treatment groups will be displayed separately. For safety a new column 
summarizing data for the three active treatment arms together will be added. 
8 
SOFTWARE 
All statistical analyses, listing, tabulations and figures will be producing using SAS® Version 9.4 or 
higher.   


 
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9 
EFFICACY ENDPOINTS 
Baseline efficacy value will be defined as the last measure done prior to the randomization.  
9.1 
Primary Endpoint for Efficacy  
ESS mean absolute change from baseline to the end of the 6-week treatment period will be defined 
as the Total ESS score at visit 3 – Baseline ESS score. ESS questionnaire consists of 8 questions 
which subjects are asked to rate their usual chances of dozing off or falling asleep while engaged in 
eight different activities. The answers will be provided on a 4-point scale: 0=’ would never doze’, 1=’ 
slight chance of dozing’, 2=’ moderate chance of dozing’, or 3=’ high chance of dozing’. Total ES is 
the sum of the entries for all of the 8 items-questions. If one or more item-scores are missing, it would 
not be imputed and this ESS total score will be considered invalid. When ESS was missing in some 
scheduled post-baseline visit (visit 2 or visit 3) any other ESS total score measured in whether an 
unscheduled visit or in the early termination visit will be considered according to the re-allocation 
windows rules presented in section 4.1. Remaining missing for baseline ESS will be imputed to the 
baseline average, and remaining post-baseline evaluations will be considered as treatment failure, a 
Multiple Imputation Jumping to Reference Approach will be used (see section 10.4.2 for reference). 
Negative absolute change will mean improvement. 
9.2 
Secondary Endpoints for Efficacy 
9.2.1 Epworth Sleepiness Scale (ESS)  
- 
ESS mean absolute change from baseline to the end of the 2-week treatment will be defined 
as Total ESS score at visit 2 – Baseline ESS score.  
 
- 
ESS clinical response, defined as: 
 
o First approach: ESS absolute decrease from baseline of at least 3.0 points, after 2 and 
6 weeks of treatment. 
 
o Second approach: ESS ≤ 10 after 2 and 6 weeks of treatment. 
 
o Third approach: Either ESS ≤ 10 after 2 and 6 weeks of treatment or ESS absolute 
decrease from baseline of at least 3.0 points after 2 and 6 weeks of treatment. 
 
- 
Mean relative change in the ESS from baseline to the end of the 2-week and 6-week 
treatment periods (percentage of absolute decrease compared to baseline ESS). For each 
patients the relative change will be calculates as: 
 
   Relative change: (post-baseline evaluation - baseline evaluation) / baseline evaluation 
 
The same missing imputation strategy as used for primary endpoint will be used for the ESS 
secondary endpoints (see section 9.1 and 10.4.2 for reference).  


 
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9.2.2 SCOPA-Sleep 
SCOPA-Sleep mean absolute change from baseline to the end of the 6-week treatment will be defined 
as Total SCOPA-sleep score at visit 3 – Baseline SCOPA-sleep score.  
When SCOPA-sleep is missing in some scheduled post-baseline visit (visit 2 or visit 3) any other 
SCOPA-sleep value measured in whether an unscheduled visit or in the early termination visit will 
be considered according to the re-allocation windows rules presented in the point 4.1. 
The SCOPA-Sleep is a specific rating scale for assessing night-time sleep (NS) and daytime 
sleepiness (DS) in the past month. The NS subscale addresses NS problems in the past month and 
includes 5 items with 4 response options. Subjects have to indicate how much they were bothered by 
particular sleep problems, ranging from 0 (not at all) to 3 (a lot). The 5 items address sleep initiation, 
sleep fragmentation, sleep efficiency, sleep duration, and early wakening. The maximum score of this 
scale is 15, with higher scores reflecting more severe sleep problems. One additional question 
evaluates overall sleep quality on a 7-point scale (ranging from “slept very well” to “slept very 
badly”). The score on this item is not included in the score of the NS scale but is used separately as a 
global measure of sleep quality. The Daytime sleepiness (DS) subscale addresses DS problems in the 
past month and includes 6 items with 4 response options, the maximum score of this scale is 18 with 
higher scores reflecting more severe sleep problems. If more than 75% of the items for each sub-scale 
were missing the NS or DS will not be calculated and will be considered as missing as well. This 
threshold could be re-evaluated in advance to the data base lock according to the missingness rate in 
the data.   
 
The same definition will apply for the 2-week evaluation. 
9.2.3 Parkinson’s Disease Sleep Scale (PDSS-2) 
PDSS-2 mean absolute change from baseline to the end of the 6-week treatment will be defined as 
Total PDSS-2 score at visit 3 – Baseline PDSS-2 score. When PDSS-2 was missing in some scheduled 
post-baseline visit (visit 2 or visit 3) any other PDSS-2 value measured in whether an unscheduled 
visit or in the early termination visit will be considered according to the re-allocation windows rules 
presented in the section 4.1. The Parkinson's Disease Sleep Scale (PDSS) is a scale for the assessment 
of sleep disorders in PD in the past week. The scale has 15 items and subjects mark their response 
(0=’Very Often’, 1=’Often’, 2=’Sometimes’, 3=’Occasionally’, 4=’Never’) to each item. Per scoring 
calculation item 1 should be reverted (4=’Very Often’, 3=’Often’, 2=’Sometimes’, 1=’Occasionally’, 
0=’Never’). Total PDSS-2 SCOPA score will be calculated as the sum of the 15 items scores. If more 
than 75% of the items were missing the Total PDSS-2 SCOPA score will not be calculated and will 
be considered as missing. This threshold could be re-evaluated in advance to the data base lock 
according to the missingness rate in the data.   
 
 
The same definition will apply for the 2-week evaluation. 
9.2.4 Maintenance of Wakefulness Test (MWT) 
The MWT is an evaluation used as a quantitative polysomnographic (PSG) measurement of daytime 
wakefulness/somnolence during soporific circumstances. During each trial, subjects will sit quietly 
on the bed with both back and head supported by a pillow, and subjects will be asked to look directly 


 
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ahead and try to stay awake as long as they can. If they fall asleep, they will be woken up after 90 
seconds and the trial will end if the subjects do not fall asleep within 40 minutes. Start and stop times 
for each trial, sleep latency, total sleep time, stages of sleep achieved for each trial, and the mean 
sleep latency (the arithmetic mean in minutes of the four trials) will be recorded, considering sleep 
latency as the time from lights out until the first epoch of greater than 15 sec of cumulative sleep in a 
30-sec epoch of either 3 consecutive epochs of stage 1 sleep, or one epoch of any other stage of sleep. 
Absolute change in the MWT from baseline to the end of the 6-week treatment period. Mean MWT 
sleep latency scores will be calculated for each of the 4 sleep trials. Also the total sleep latency scores 
average will be calculated for each patient according to the 4 round MWT sleep latency scores. If 
some of the latency scores are missing the total sleep latency score average will be calculated just 
considering the available data and dividing it by the number of non-missing tests. Sleep latency scores 
will be analysed and presented in minutes.  
9.2.5 Polysomnography 
Mean absolute change in the polysomnography parameters (as defined below) from baseline to the 
end of the 6-week treatment period: 
 
Sleep Stage Parameters: 
Total Recording Time (TRT) is defined as the time in minutes from “lights out” to “lights on”. Total 
Sleep Time (TST) is the total time in minutes asleep after sleep onset. To determine the how well the 
patient slept, the Sleep Efficiency (SE) is calculated by dividing the TST by the TRT and multiplying 
by 100. Sleep studies are recorded on 30 second “epochs”. Sleep onset is defined as the first epoch 
scored as any stage other than stage W. Sleep Latency (SL) is the time from “lights out” to the sleep 
onset. Latencies to sleep stages are determined from sleep onset to the first epoch of that sleep stage. 
Wake after Sleep Onset (WASO) is the time awake after sleep onset until “lights on”. To determine 
the percentage time spent in each of the sleep stages during the sleep study, the total minutes of the 
sleep stage is divided by the TST and multiplied by 100. 
 
Sleep information: 
Percentage of TST Ni (for i=1 to 3) is calculated as a percentage: (Minutes Ni / TST * 100) 
Percentage of TST REM is calculated as a percentage:  (Minutes REM / TST * 100) 
 
Clinical Event Parameters: 
Event (or arousal) index will be calculated as the number of events (arousal number) divided by TST 
and multiplied by 60 (events per hour).  
 
Events Index= (Events/TST)*60. 
Arousal Index= (Arousal number/TST)*60. 
 
Index will be calculated for the events and arousal detailed below: 
- 
Apnoea 
- 
Hypopnea 
- 
Apnoea + Hypopnea 
- 
Limb Movement 


 
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- 
Periodic Limb Movement 
- 
Arousals index 
- 
Spontaneous Arousals index 
- 
Apnoea Arousals index 
- 
Hypopnea Arousals index 
- 
LM Arousals index 
- 
PLM Arousals index 
- 
Desaturation Arousals index 
- 
Snore Arousals index 
- 
Respiratory Arousals index 
- 
Respiratory Effort Related Arousal (RERA) index 
- 
User Defined Arousals index 
- 
Total Arousals index 
9.2.6 Unified Parkinson’s disease Rating Scale Part III (UPDRS Part III) 
UPDRS III mean absolute change from baseline to the end of the 6-week treatment will be defined 
as Total UPDRS III score at visit 3 – Baseline UPDRS III score. Part III contains 33 scores based on 
18 items, several with right, left or other body distribution scores.  
 
When UPDRS is missing in some scheduled post-baseline visit (visit 2 or visit 3) any other UPDRS 
value measured in whether an unscheduled visit or in the early termination visit will be considered 
according to the re-allocation windows rules presented in the section 4.1. The same analysis will be 
repeated for the 2-week evaluation. If more than 75% of the scores are missing then the total motor 
examination score will not be calculated and considered as not evaluable. The same rule will be 
applied for the subscales calculation. This threshold could be re-evaluated in advance to the data base 
lock according to the missingness rate in the data.   
9.2.7 Hamilton Rating Scale for Depression (HAM-D) 
Mean absolute change in the depression HAM-D score (as defined below) from baseline to the end 
of the 2-week and 6-week treatment period and safety follow-up (defined as 28 days  2 after Visit 3 
or early termination visit). Although the HAM-D form lists 21 items, the scoring is based on the first 
17. For the total sum, 8 items are scored on a 5-point scale, ranging from 0 (not present) to 4 (severe), 
and the remaining 9 are scored from 0 to 2. HAM-D total score is calculated as the sum of the first 
17 items. This threshold could be re-evaluated in advance to the data base lock according to the 
missingness rate in the data.If more than 75% of the scores are missing then the total motor 
examination score will not be calculated and considered as not evaluable. The same rule will be 
applied for the subscales calculation. 
9.2.8 Montreal Cognitive Assessment (MoCA) 
Mean absolute change in the MoCA total score as defined below from screening to the end of the 6-
week treatment period. 
It assesses different cognitive domains: attention and concentration, executive functions, memory, 
language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Sum all sub 
scores listed on the right-hand side. Add one point for an individual who has 12 years or fewer of 


 
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formal education, for a possible maximum of 30 points. The total possible score is 30 points; a score 
of 26 or above is considered normal. 
9.2.9 Fatigue Severity Scale (FSS) 
Mean absolute change in the Fatigue Severity Scale, as defined below.  
The FSS is a self-administered questionnaire with 9 items investigating the severity of fatigue in 
different situations during the past week. There are 9 items ranging from 1 to 7, where 1 indicates 
strong disagreement and 7 strong agreement, and the final score is calculated as the mean value of 
the 9 items. If more than 75% of the items are missing then the FSS total score will not be calculated 
as will be considered as not evaluable. This threshold could be re-evaluated in advance to the data 
base lock according to the missingness rate in the data 
 
9.2.10 Berlin Questionnaire (BQ)  
Percentage of patients with BQ high risk (as defined below) at week 2 and 6 will be determined. 
 
This questionnaire consists of 3 categories (questions 2 to 6 about snoring [category 1], questions 7 
to 9 about daytime somnolence [category 2], and question 10 about hypertension and BMI [category 
3]) and the risk is based on the responses to individual items and overall scores in the symptom 
categories. 
 
Categories and Scoring: 
Category 1: items 2, 3, 4, 5 and 6; 
Item 1: if ‘Yes’, assign 1 point 
Item 2: if ‘c’ or ‘d’ is the response, assign 1 point 
Item 3: if ‘a’ or ‘b’ is the response, assign 1 point 
Item 4: if ‘a’ is the response, assign 1 point 
Item 5: if ‘a’ or ‘b’ is the response, assign 2 points 
Add points. Category 1 is positive if the total score is 2 or more points. 
 
Category 2: items 7, 8, 9 (item 9b should be noted separately). 
Item 7: if ‘a’ or ‘b’ is the response, assign 1 point 
Item 8: if ‘a’ or ‘b’ is the response, assign 1 point 
Item 9: if ‘a’ is the response, assign 1 point 
Add points. Category 2 is positive if the total score is 2 or more points. 
 
Category 3 is positive if the answer to item 10 is ‘Yes’ or if the BMI of the patient is greater than 
30kg/m2. (BMI is defined as weight (kg) divided by height (m) squared, i.e.., kg/m2). 
 
High Risk: if there are 2 or more categories where the score is positive. 
Low Risk: if there is only 1 or no categories where the score is positive. 
 


 
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9.3 
Exploratory Efficacy Endpoints 
- 
Free living activity assessed by means of wrist-worn actigraphy. 
 
9.4 
Analysis sets Analysed for Efficacy 
Primary Analysis, and sensitivity analysis as described above will be based in the ITT Population. In 
the MCP-Mod sensitivity analysis, only patients in the ITT with ESS evaluations at week 6 will be 
considered. Primary analysis will be repeated in the Per Protocol Population also which will be 
considered as a sensitivity analysis. 
 
 


 
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10 STATISTICAL METHODOLOGY FOR EFFICACY ENDPOINTS 
10.1 Primary Efficacy Analysis 
ESS mean absolute change from baseline to the end of the 6-week treatment period will be analysed 
with an ANCOVA model, with the baseline ESS as a covariate, region and treatment as a factor. 
Least-squared (LS) absolute mean changes will be presented by treatment group along with their 
associated 95% CIs and 2sided p-values; these data will then provide estimated for the within arm 
change from baseline.  The difference between each of the 3 dose arms and the placebo arms in Least-
squared (LS) absolute mean changes will also be presented together with the corresponding 95% 
confidence interval and 2-sided p-value. These paired comparisons will be performed without any 
multiplicity adjustment.  Also, the 4 degrees of freedom (DF) associated with the overall F-test for 
differences between the treatment arms will be decomposed using Type I sums of squares into three 
orthogonal single DF contrasts to estimate the linear, quadratic and cubic components of any potential 
dose response. Baseline data will be imputed with the baseline ESS average.  Multiple Imputation 
Jumping to Reference method will be used to impute post-baseline data  (see section 10.4.2fir further 
reference). 
 
10.1.1 Sensitivity analyses missing reductions imputed to 0: 
Same primary analysis will be repeated imputing post-baseline missing ESS evaluations to baseline 
data that is reduction equal to 0. 
 
10.1.2 Sensitivity analyses MMRM Model: 
A mixed-effect model with repeated measures (MMRM) approach will be used, under the missing at 
random framework carried out using an adequate contrast at Week 2 or Week 6, accordingly. The 
model will include fixed categorical effects of treatment group, region, visit and treatment-by-visit 
interaction as well as the continuous fixed covariates of mean baseline ESS. This MMRM model will 
be run with an unstructured correlation matrix to model the within subject errors. In this case missing 
values will not be imputed, since (MMRM) is handling missing data through the Maximum 
Likelihood estimation method. 
 
Unstructured covariance matrix is assumed to explain within subject covariance in MMRM method 
in protecting the type I error rates. In the event if the assumption of unstructured covariance (UN) 
matrix results in non-convergence of the model, only then the following covariance structures will be 
considered in the order mentioned below.  
 
The order of covariance structure to be considered is: 
 
1. Compound Symmetry (CS) 
10.1.3 Sensitivity analysis using MCP-Mod 
This sensitivity analyses will be done for patients in the ITT population having non-missing ESS 
evaluation in the week 6. 


 
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MCP-Mod will be produced following the steps below, (see Pinheiro J 2014 (1) for reference): 
 
I. 
Candidate dose-response shapes 
II. 
Derive optimum contrast coefficients to maximize power to finding dose-response 
association 
III. 
Identify whether dose-response signal could be established 
IV. 
Model Selection 
 
I. 
Candidate dose-response shapes 
The three models detailed below will be considered in the dose-response evaluation. 
 
a. Emax1 (D50=0.2): according to Thomas et al. Emax model can adequately describe the 
observed data in many situations. The Emax model dose–response curve is defined as: 
 
R = E0 + (D × Emax) / (D +ED50) 
 
where: 
 
R = response 
D = dose 
E0 = basal effect corresponding to the response when dose of drug is 0. 
Emax = maximum effect attributable to the drug 
ED50 = dose which produces half of the Emax 
 
              
b. Exponential (δ=1): 
 
R=E0+ E 1*(EXP(D/δ)-1) 
 
E0= basal effect corresponding to the response when dose of drug is 0 
E1= slope parameter for exponential model 
D=dose 
δ= parameter, controlling the convexity of the model 
 
c. Sigmoid Emax (ED50=1, H=8): 
 
E0= basal effect corresponding to the response when dose of drug is 0 
Emax= maximum effect attributable to the drug 
ED50= dose which produces half of the Emax 
H=Hill parameter, determining the steepness of the model at the ED50 
 
 
 


 
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The following plot illustrates visually the shape of these three models used in the MCP part to test 
the dose-response signal: 
 
 
 
II. 
Optimal Contrast identification 
In order to obtain the vector of optimal coefficients ĉ for each dose-response signal contrast, the 
following equation will be maximized as proposed by Pinheiro, Bornkamp, Bretz (2006):  
c′μ √∑𝑐𝑖
2 𝑛𝑖
⁄
⁄
. The following steps will be performed for each curve (e.g. Emax1): 
 
1. A dataset with one single record and four variables µ1, µ2, µ3 and µ4 will be created where 
µ1, µ2, µ3 and µ4 are means for placebo, 0.5, 1, and 3 mg/d respectively compatible with the 
shape of the given curve (e.g. Emax1). 
2. The goal is to obtain the values c1, c2, c3 and c4 that maximize (c′μ)2 (∑𝑐𝑖
2 𝑛𝑖
⁄
)
⁄
 where n1, n2, 
n3 and n4 are the sample sizes for placebo, 0.5, 1, and 3 mg/d respectively. To do so, the 
NLMIXED procedure will be applied on the above-mentioned one-record dataset to obtain 
the “maximum likelihood” parameters c1, c2, c3 and c4 using the following likelihood 
function: 
ll=(mu1*c1 + mu2*c2 + mu3*c3 + mu4*c4)**2/    
(c1**2/n_1 + c2**2/n_2 + c3**2/n_3 + c4**2/n_4); 
There are infinite solutions to the above problem, so we will hold one coefficient to an 
arbitrary value (e.g. c1=-10). 
3. Finally, the obtained coefficients will be normalized as follows (shown for c1): 


 
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nc1=c1/(sqrt(c1**2 + c2**2 +c3**2 + c4**2)); 
 
For validation purposes, the obtained coefficients will be compared with the ones obtained using the 
dose-finding R package developed by te authors of MCP-Mod. 
III. 
Dose Response Test 
For each of the candidate models, dose-response association will be evaluated using the optimal 
coefficients identified in the previous step. These contrasts will be tested using the PROC 
GLIMMIX procedure at an one-sided alpha level of 0.025 and multiplicity adjusted p-values will 
be obtained through parametric resampling ESS mean absolute change from baseline to the end 
of the 6-week treatment period will be included in the model as dependent variable, dose as fixed 
factor and baseline ESS as covariate.  SAS code like the code below will be used: 
 
PROC GLIMMIX; 
CLASS DOSES; 
MODEL ESS = DOSES BASELINE /NOINT; 
LSMEANS DOSES; 
ESTIMATE "EMAX1"        DOSES &C11. &C12. &C13. &C14.,  
         "EXPONENTIAL"  DOSES &C21. &C22. &C23. &C24., 
         "SIGMOID EMAX" DOSES &C31. &C32. &C33. &C34.  
          / UPPERTAILED ADJUST=SIMULATE(NSAMP=100000 SEED=1234) ; 
RUN; 
 
 
IV. 
Model Selection 
The maximum contrast test method will be used to select the best model to be used in the Mod 
stage. The selected model will be fitted with PROC NLMIXED procedure using SAS code similar 
to the script below (shown for the Emax model only):  
 
PROC NLMIXED; 
BOUNDS S2>0, ED50 >0; 
PARMS  S2 BETA E0 EMAX ED50; 
IF DOSE >0 THEN MEAN = E0+(EMAX*DOSE)/(ED50+DOSE) + BETA*BASELINE; 
ELSE IF DOSE = 0 THEN MEAN= E0 + BETA*BASELINE; 
MODEL ESS ~ NORMAL(MEAN, S2); 
RUN; 
  
A graph will be produced presenting the modelled dose-response curve; point estimate and 95% 
confidence limits will be displayed.  
 
10.1.4 Sensitivity analyses Rank ANCOVA 
Similar to the primary analysis a Rank ANCOVA will be modelled in order to provide evidence of 
the treatment effect in case of violation of normality assumption.  
BLOM Ranks will be calculated with the whole sample, regardless of the treatment group. Ties will 
be ranked with the mean for tied values.  


 
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10.1.5 Sensitivity three-parameter sigmoidal Hill dose-response curve analyses  
A three-parameter sigmoidal Hill dose-response curve will be fitted to the data using SAS PROC 
NLIN. The form of the fitted model will be:  
 
𝑦=
a𝑘𝐷𝑒𝑛
(1 −𝑘)𝑏𝑒𝑛+ 𝑘𝐷𝑒𝑛+ 𝜖 
where: 
          y is the outcome 
          D is dose 
          n is the log shape parameter 
          ε is the random error 
          a is the maximum effect 
          k is a fixed constant where 0 < k ≤ 1 
          b is the dose that provides an effect equal to k x a 
          for k=0.5 then b=ED50 
          for k=0.9 then b=ED90 
The parameters a, b and n will be estimated along with their associated SEs and 95% CIs. The dose-
response will be displayed in terms of the estimated value for outcome, together with 90% confidence 
and prediction limits.  
A variation on the dose response model will also be evaluated that corrects for placebo: 
𝑦= 𝑃+
a𝑘𝐷𝑒𝑛
(1 −𝑘)𝑏𝑒𝑛+ 𝑘𝐷𝑒𝑛+ 𝜖 
where: 
          P is the outcome in placebo treated subjects. 
 
10.1.6 Primary Analysis with new missing data allocation windows 
 
The primary analysis will be repeated but considering now the windows below to reallocate missing 
data: 
 
- 
Visit 2: 7 to 21 days 
- 
Visit 3: 35 to 49 days 
 


 
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10.2 Secondary Efficacy Analysis 
All secondary endpoints evaluated through a mean absolute change will follow a similar statistical 
analysis as for the primary variable (ANCOVA, considering baseline corresponding endpoint 
evaluation as covariate and treatment and region as fixed factors): 
 
- 
Mean changes of ESS (up to 2-week treatment period) 
- 
Mean relative change in the Epworth Sleepiness Scale (ESS) from baseline to the end of 
the 2-week and 6-week treatment periods (percentage of absolute decrease compared to 
baseline ESS). 
- 
SCOPA-Sleep (up to 2-week and 6-week treatment period) 
- 
PDSS-2 (2-week and 6- week) 
- 
MWT (6-week) 
- 
Polysomnography (6-week) 
o Sleep Efficiency 
o Percentage of TST REM 
- 
UPDRS Part III (2-week and 6-week) 
- 
Motor function assessed by the wrist worn device (6-week) 
- 
HAM-D (2-week, 6-week and follow-up) 
- 
MoCA (6-week), and FSS (6-week). 
- 
Fatigue Severity scale (FSS) 
- 
Polysomnography (6-week): Baseline index will not be considered in these Logistic 
models. 
o Events Index (Increase in Events Index) 
o Arousal Index (Increase in Arousal Index) 
 
Categorical variables as detailed below will be analysed through fitted logistic regression model 
adjusted on baseline corresponding endpoint evaluation as a covariate and treatment and region as 
fixed factors. This model will estimate the adjusted Odds Ratio between treatment arms, its 
corresponding 95% and P-value. 
 
- 
ESS clinical response, defined as ESS absolute decrease from baseline of at least 3.0 points, 
after 2 and 6 weeks of treatment. 
 
- 
ESS clinical response, defined as ESS ≤ 10 after 2 and 6 weeks of treatment. 
 
- 
ESS clinical response, defined as either ESS ≤ 10 after 2 and 6 weeks of treatment or ESS 
absolute decrease from baseline of at least 3.0 points after 2 and 6 weeks of treatment. 
 
 
10.3 Exploratory Efficacy Analysis 
 
We aim to characterise the changes in free-living activity by means of wrist-worn actigraphy. 
GENEActiv accelerometers are worn on the wrist and measure tri-axial acceleration with a sample 


 
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frequency of 100Hz. The device also measures temperature and light levels. The data is collected 
pre- and post- dosing (V3), each over a period of seven days. We aim to measure differential 
physical activity behaviour, and also the length and frequency of daytime sleep episodes. 
  
The data is to be processed using the calibrated GENEActiv tracker data pre-processing package in 
R. We extract 12-hour daytime records and convert the accelerometer to gravity-subtracted Signal 
Vector Magnitudes (SVMgs), which is our measure of instantaneous physical intensity. The time-
series is downsampled (100x) to one second intervals by averaging the instantaneous SVMgs across 
the 100 time points. The averaged SVMgs are grouped into four intensity levels groups: Sedentary 
(< 4.5), Light (4.5-16.5), Moderate (16.5-42), and Vigourous (> 42). These threshold boundaries 
may change as thresholds used in existing studies are calibrated for different populations. The 
summary statistics we aim to extract are bout lengths and frequencies, where a bout is a continuous 
episode of physical activity at a specific intensity levels band. Using paired t-tests, we aim to 
demonstrate a reduction in sedentary activity and an increase in light to vigourous activity in the 
dosed population. Using automatic changepoint detection methods (such binary segmentation 
methods and its extensions, with the fused lasso total variation regulariser, together with Bayesian 
approaches such as Dirichlet process hidden Markov models.)  for detection of sleep boundary 
times, we also, independently of activity level measurements, aim to quantify the frequency and 
lengths of daytime sleep episodes. 
 
10.4 Efficacy analysis Considerations 
10.4.1 Pooling of Regions 
 
Regions where the low number of subjects is making the statistical model questionable (<20 patients) 
will be merged with the closer region according to the regional location. If some of the investigative 
sites are able to enrol a sufficient number of subjects (≥20) they will not be merged with the others in 
the region and will be considered as an independent fixed effect region category in the model. Any 
required pooling will also be applied to the per-protocol population to allow a valid comparison of 
the study results.  
 
10.4.2 Handling of missing data 
 
- 
For primary analysis, as describes in section 9.1, post-baseline ESS will be imputed 
through a Multiple Imputation Jumping to Reference Model. 
 
 
 
 
 


 
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11 SAFETY ENDPOINTS 
 
The safety analysis will be based on the reported adverse events and other safety information, such 
as clinical laboratory data and physical examination as described in the protocol.  
 
The safety of Bavisant compared to placebo will be assessed by the evaluation of the following: 
 
▪ Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs), Serious and related 
Adverse Events and Adverse Events of Special Interest (AESIs) headache, nausea and 
insomnia 
▪ Incidence of suicidal ideation (C-SSRS) findings from screening/baseline to the end of the 2-
week and the 6-week treatment period and safety follow-up 
▪ Incidence of positive psychotic symptoms (BPRS+) findings from screening/baseline to the 
end of the 2-week and the 6-week treatment period and safety follow-up 
▪ Incidence of physical examination, vital signs and laboratory tests changes from normal to 
abnormal (haematology and biochemistry) 
▪ Incidence of cardiovascular safety findings (blood pressure, heart rate, ECG including 
QT/QTc) 
11.1 Analysis Sets Analysed for Safety 
Safety endpoints will be evaluated in the SAF population as defined in section 6.0, and will be 
presented by treatment group. 
12 STATISTICAL METHODOLOGY FOR SAFETY ENDPOINTS 
The baseline value is defined as the last available value before the first dose of double-blind IMP 
taken. 
The analysis of the safety variables will be essentially descriptive and no systematic testing is 
planned.   
 
The observation period of safety data will be divided into 2 sub-periods: 
• The pre-treatment period is defined as the time between the date of signed informed consent 
and the first dose of double-blind IMP. 
• The on-Treatment period (TEAE period): is defined as the Date/ time from first dose of 
double-blind IMP. 
12.1 Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events 
of Special Interest (AESIs) such as headache, nausea and insomnia 
All adverse events will be analysed and determined to be either pre-treatment or treatment-emergent. 
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pre-treatment or treatment-


 
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emergent.  The algorithm for imputing date/time of onset will be conservative and will classify an 
adverse event as treatment emergent unless there is definitive information to determine it is pre-
treatment. 
 
All adverse events (including serious adverse events and adverse events of special interest) will be 
coded to a lower-level term (LLT), preferred term (PT), high-level term (HLT), high-level group term 
(HLGT), and associated primary system organ class (SOC) using the version of Medical Dictionary 
for Regulatory Activities (MedDRA) version 20.1. Lower-level term (LLT) will not be presented in 
the analysis. Number of patients in the SAF will be used as denominator for the percentages 
calculation. 
12.2 Incidence of suicidal ideation (C-SSRS) findings from screening/baseline to the end of 
the 2-week and the 6-week treatment period and safety follow-up 
Patients with a positive response on the C-SSRS (an answer of ‘yes’ to any of the 6 questions) will 
be described through absolute frequency and percentage at visit 2 (day 14) , visit 3 (day 42) and 
globally (at any time in the follow-up period) in the study. This percentage will be calculated using 
the number of patients with C-SSRS evaluation done at the corresponding visit as denominator.  
12.3 Incidence of positive psychotic symptoms (BPRS+) findings from screening/baseline to 
the end of the 2-week and the 6-week treatment period and safety follow-up 
The BPRS consists of 4 symptom constructs ((#4, #11, #12, and #15) which ranges from 1 (not 
present) to 7 (extremely severe). 0 is entered if the item is not assessed.  The total score is calculated 
as the sum of the scores of the 4 items. Incidence of patients with an increase and incidence of patients 
with a decrease from baseline in the BPRS+ total score will be described at the corresponding visit. 
Also the change from baseline will be descriptively analysed as a numerical data (see section 7 for 
further reference) for all patients, for patients with BPRS+ total score reduction and for patients with 
BPRS+ total score increase. 
12.4 Incidence of physical examination, vital signs  
Physical examinations will consist of the following body systems: (1) general, appearance; (2) 
extremities; (3) skin; (4) head and neck; (5) eyes, ears, nose and throat; (6) lungs and chest; (7) heart/ 
cardiovascular; (8) neurological; (9) abdomen / gastrointestinal; (10) liver; (11) musculoskeletal; and 
(12) other. Each system should be assessed as normal or abnormal and in the last case if that is 
clinically relevant or not. The incidence of patients with at least one change from normal at baseline 
to abnormal at Visit 3 will be calculated for each of the body systems. 
 
Potentially Clinically Significant Abnormality (PCSA) are detailed below for Vital signs: 
 
▪ WEIGHT change from baseline >5% 
▪ Number of breaths per minute <12 or >25. Percentages of patients with a normal respiratory 
rate (RR) at baseline and an abnormally high or low RR at Visit 3 will be summarized by 
treatment. 


 
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Incidences will be calculated using the number of patients in the safety population as 
denominator. 
12.5 Incidence of laboratory tests findings (haematology and biochemistry) 
Clinical laboratory values after conversion will be analysed into standard international units and 
international units will be used in all listings and tables. Shift tables will be produced presenting the 
intra-patient change between below normal, normal and above normal for each of the laboratory 
parameters, according to the appropriate laboratory ranges. 
 
Incidences will be calculated using the number of patients in the safety population as denominator. 
 
12.6 Incidence of cardiovascular safety findings (blood pressure, heart rate, ECG QT/QTc) 
Incidence of Potentially Clinically Significant Abnormality (PCSA) as detailed below will be 
described for blood pressure and ECG: 
 
▪ Blood Pressure 
- 
SBP: ≤95 mmHg or decrease from baseline ≥20 mmHg or ≥160 mmHg or increase from 
baseline ≥20 mmHg 
- 
DBP: ≤45 mmHg or decrease from baseline ≥10 mmHg or ≥110 mmHg or increase from 
baseline ≥10 mmHg 
▪ Heart rate 
- 
<50 bpm or decrease from baseline ≥20 bpm or ≥100 or increase ≥20 bpm from baseline. 
▪ ECG 
- 
QTc (> 450 for males and > 470 for females) for both Bazzet and Friedericia. 
- 
QT > 500 
Incidences will be calculated using the number of patients in the safety population as denominator. 
12.7 Incidence of eye exam findings 
Incidence of patients with any new finding on ophthalmological examination in the follow up 
period will be calculated. Detailed listings of all baseline and on-treatment ophthalmological 
findings will be provided 
 
Incidences will be calculated using the number of patients in the safety population as denominator. 


 
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13 OTHER ANALYSES 
13.1 Demographic and Baseline Characteristics 
Demographic characteristics, age, gender and race will be summarized by treatment group and 
overall using descriptive statistics. Age will be summarized using the number of available data, 
mean, standard, deviation (SD), median, minimum and maximum and 95%CI whenever needed for 
each treatment group. Gender and race will be summarized using the number and percentage of 
patients in each treatment group. 
 
The baseline value is defined as the last available value prior to the randomization. 
All baseline safety and efficacy parameters are presented along with the summary statistics in the 
efficacy and safety sections (Section 9. and Section 11.). 
13.2 Prior or Concomitant Medications 
All medications taken within the past 4 weeks before the date of informed consent and until the end 
of the study are to be reported in the case report form pages. 
 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD_ 
Sep2017) and will be presented in the analysis by the Anatomic and Therapeutic Class. 
 
Prior medications are those the patient used within 4 weeks prior to the date of informed consent and 
from screening to first investigational medicinal product (IMP) intake. Prior medications can be 
discontinued before first administration or can be ongoing during treatment phase. Those ongoing 
will be considered as Concomitant medication also. 
 
Concomitant medications are any treatments received by the patient after first intake of IMP. A given 
medication can be classified both as a prior medication and as a concomitant medication. 
13.3 Prohibited Medication 
The following primary PD medications will be permitted at any time during the study if taken as 
stable medication for at least 4 weeks before screening (date of IC signature): 
▪ Dopaminergics 
▪ L-dopa 
▪ Monoamine oxidase inhibitors (MAOI) 
▪ Short-acting antipsychotics if taken in the evening 
▪ Catechol-O-methyl transferase (COMT) inhibitors 
▪ Amantadine if not used as an alerting agent 
 
At a minimum, the following medications will be prohibited at any time during the study: 
▪ Alerting agents, including r-modafinil, modafinil or methylphenidate 
▪ Benzodiazepines 
▪ Histamine active agents 
▪ Hypnotics 


 
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▪ Cholinergics 
▪ Skeletal muscle relaxants 
▪ Clozapine 
▪ Atomoxetine 
▪ Amitriptyline 
▪ Any other daytime medications which affect sleep 
 
13.4 Medical History 
All Medical History will be coded to a lower-level term (LLT), preferred term (PT), high-level term 
(HLT), high-level group term (HLGT), and associated primary system organ class (SOC) using the 
version of Medical Dictionary for Regulatory Activities (MedDRA) version 20.1. Number of patients 
with at least one medical history and percentage in each HLT will be presented by SOC. Denominator 
used for percentage calculation will be the number of patients in the SAF population. 
13.5 Extent of investigational medicinal product exposure and compliance 
Average number of doses taken per day will be calculated. Percentage of patients will be obtained 
for each of the categories defined below: 
 
- 
<0.9 average doses/day taken  
- 
≥ 0.9 and <1.1  average doses/day taken 
- 
≥1.1 average doses/day taken  
 
Duration of IMP exposure is defined as last dose date – first dose date, regardless of unplanned 
intermittent discontinuations. Duration of IMP exposure will be summarized descriptively as a 
quantitative variable (number, mean, SD, median, minimum, and maximum). 
 
In addition, duration of treatment exposure will also be summarized categorically by numbers and 
percentages for each of the following categories and cumulatively according to these categories: 
Up to 1 weeks, >1 to 2 weeks; >2 to 3 weeks; >3 to 4weeks; >4 to 6 weeks; >6 weeks 
14 CHANGES FROM THE PROTOCOL 
There are no changes to the statistical content specified in the protocol. 
15 INTERIM ANALYSES 
No interim analysis is planned to be done in this study. 
16 REFERENCES 
(1) Model-based dose finding under model uncertainty using general parametric models. 
Pinheiro J, Bornkamp B, Glimm E, Bretz F, Stat Med. 2014 May 10;33(10):1646-61. 
doi:10.1002/sim.6052. Epub 2013 Dec 3. 
 
(2) Combining multiple comparisons and modeling techniques in dose-response studies. Bretz 
F, Pinheiro JC, Branson M. Biometrics. 2005 Sep;61(3):738-48. 


 
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(3) Ondo WG, Fayle R, Atassi F, Jankovic J. Modafinil for daytime somnolence in Parkinson's 
disease: double blind, placebo controlled parallel trial. Journal of neurology, neurosurgery, 
and psychiatry. 2005;76(12):1636-9. Epub 2005/11/18. 
 
(4) Qualification Opinion of MCP-Mod as an efficient statistical methodology for model-based 
design and analysis of Phase II dose finding studies under model uncertainty. 
EMA/CHMP/SAWP/757052/2013. 23 January 2014. 
 
(5) Pinheiro JC, Bornkamp B, Bretz F. Design and analysis of dose finding studies combining 
multiple comparisons and modeling procedures. Journal of Biopharmaceutical Statistics 
2006; 16:639–656. 
 
(6) Request for Qualification of MCP-Mod as an efficient statistical methodology for model-
based design and analysis of Phase II dose finding studies under model uncertainty.  Janssen 
Pharmaceuticals and Novartis Pharmaceuticals. 22 April, 2015. 
 
 
17 GENERAL FORMAT OF TABLES, FIGURES AND SUBJECT DATA 
Table, listings and figures shell documents will be sent to the sponsor for separate review and 
approval.