Conditions: Parkinson Disease
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 77
Healthy volunteers: no

Brief summary:
This is a randomized, placebo-controlled, 3-way cross-over phase IIa trial comparing two dose levels of THN102 to placebo in patients suffering from Parkinson's disease associated with excessive daytime sleepiness.

Detailed description:
The treatment duration is 2 weeks per period. Each treatment period is followed by a one-week washout period.

Arms:
arm 1: THN102 Dosage A is a Placebo arm 2: THN102 Dosage B : 200 mg/2 mg THN102 is a combination of modafinil 100mg and flecainide 1 mg daily dosage is 200 mg of modafinil and 2 mg of flecainide arm 3: THN102 Dosage C : 200 mg/18 mg THN102 is a combination of modafinil 100mg and flecainide 9 mg daily dosage is 200 mg of modafinil and 18 mg of flecainide

Interventions: intervention 1: THN102 Dosage A intervention 2: THN102 Dosage B intervention 3: THN102 Dosage C
Intervention descriptions: intervention 1: THN102 Dosages A: placebo intervention 2: THN102 Dosage B : 200mg/2mg intervention 3: THN102 Dosage C: 200mg/18mg

Protocol document:
Prot_000.pdf: 
THN102-202 
Clinical Trial Protocol 
Page 1 of 74 
Final 6.0, 27 February 2019 
Theranexus S. A. 
Confidential 
CLINICAL TRIAL PROTOCOL 
Randomised, double-blind, placebo-controlled, complete 3-way  
cross-over phase IIa trial to investigate safety and efficacy of two 
THN102 doses in subjects with excessive daytime sleepiness associated 
with Parkinson’s disease 
 
Trial code: 
EudraCT: 
IND No.: 
Phase: 
Version: 
Date: 
THN102-202 
2017-004475-31 
137871 
IIa (proof-of-concept) 
Final 6.0 
27 February 2019 
Product name: THN102 (modafinil, flecainide) 
Indication: Excessive daytime sleepiness in 
subjects with Parkinson’s disease 
 
 
Sponsor's Medically Responsible Person 
 
Theranexus S.A. 
86, rue de Paris 
F-91400 Orsay, France 
Tel. +33 6 80 02 67 79 
www.theranexus.com 
 
 
Sponsor’s Clinical Trial Manager 
 
Theranexus S.A  
86, rue de Paris 
F-91400 Orsay, France 
www.theranexus.com 
Clinical CRO 
 
 
 
 
 
 
 
 
 
 
24/7 Medical contacts 
Europe: 
 
 
 
USA: 
 
 
 
 
 
Information provided herein is strictly confidential and is available for review to 
investigators, Competent Health Authorities, and Ethics Review Committees.  
It is intended solely for the guidance of the clinical investigation and may not be 
disclosed to parties not associated with the clinical investigation or used for any purpose 
without the prior written consent of Theranexus S. A..  
CONFIDENTIAL 
 


THN102-202 
Clinical Trial Protocol 
Page 2 of 74 
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Theranexus S. A. 
Confidential 
Summary of Changes 
Section(s)* 
Change from Final Protocol Version 1.0, 11 January 
2018, to Final Protocol Version 2.0, 08 March 2018 
Change 
requested by 
Title page, 
14.1 
The contact of the medical monitor for the USA has been 
added. 
-- 
1.3.1, 3.1, 3.2, 
6.1.6 
The duration of the washout periods may be extended from 
1 week to 2 weeks, if this is more convenient for the subject. 
As a consequence, the trial duration for the individual subject 
changes from 11 weeks to 11 – 13 weeks.  
-- 
4.2 
It has been emphasised that steroidal contraceptives must be 
combined with barrier methods (bold formatting in inclusion 
criterion no. 7). 
FDA 
4.3 
In exclusion criterion no. 1, shift work sleep disorder has 
been added as a possible cause of excessive daytime 
sleepiness. 
FDA 
5.5 
Information that modafinil may reduce effectiveness of 
steroidal contraception was added. 
FDA (also 
requested by 
SÚKL)  
5.5, 14.4 
Instructions on concomitant medications that are CYP2D6 
inhibitors, CYP3A or CYP2C19 substrates have been added. 
A list of concerned drugs has been provided as Appendix D. 
FDA 
6.1.1 
6.1.1, 6.2.1 
UPDRS Part III will not be completed at VS1. 
It has been clarified that height has to be measured at visit 
VS1. 
FDA 
-- 
6.1.3, 6.1.5, 
6.3.6, 8.1.1, 
8.3.2, 13 
UPDRS part III was replaced by MDS-UPDRS. MDS-
UPDRS will be completed at VR, V1B, V2B and V3B/EDV. 
Statistical methods (safety) and references were updated. 
FDA 
6.1.3 
At visit VR, three measurements of orthostatic vital signs 
will be performed 15-20 min apart. 
FDA 
 
6.1.3, 6.1.5 
QUIP-RS will be assessed. 
FDA 
6.1.6 
The ±1 time windows for visits V1C and V2C have been 
changed to -1/+7 time windows. 
-- 
6.1.6 
UPDRS Part III will not be completed at visits V1C and V2C. 
At visits V1C and V2C, three measurements of orthostatic 
vital signs will be performed 15-20 min apart. 
FDA 
FDA 
6.3.3 
Orthostatic vital signs (supine and standing) will be 
measured instead of sitting vital signs. 
FDA 
6.3.7, 8.1.1, 13 
The QUIP-RS questionnaire has been added. 
FDA 
8.3.1 
Procedure in case of significant treatment by period 
interaction has been added. 
-- 
8.3.2 
Information on vital signs’ analysis has been updated, QUIP-
RS and MDS-UPDRS have been added. 
FDA 
 


THN102-202 
Clinical Trial Protocol 
Page 3 of 74 
Final 6.0, 27 February 2019 
Theranexus S. A. 
Confidential 
Section(s)* 
Change from Final Protocol Version 2.0, 08 March 2018, 
to Final Protocol Version 3.0, 27 April 2018 
Change 
requested by 
6.1.3, 6.1.5, 
6.1.6, 6.3.5 
C-SSRS will be performed at all on-site visits. 
FDA (also 
requested by 
SÚKL) 
4.3 
Exclusion criterion no. 9 has been modified to exclude 
subjects with hepatic or renal impairment, regardless of 
severity. 
FDA 


THN102-202 
Clinical Trial Protocol 
Page 4 of 74 
Final 6.0, 27 February 2019 
Theranexus S. A. 
Confidential 
Section(s)* 
Change from Final Protocol Version 3.0, 27 April 2018 to 
Final Protocol Version 4.0, 30 May 2018 
Change 
requested by 
Title page 
IND number has been added. 
-- 
4.2, 7.3 
Methods of contraception have been modified. 
SÚKL 
4.3 
Multiple system atrophy (Shy-Drager syndrome) has been 
added to exclusion criterion no.2.  
EC of the LÄK 
Thüringen 
4.3 
Exclusion criterion no. 3 has been modified to provide a 
more detailed description of cardiovascular disorders. 
EC of the LÄK 
Thüringen, 
SÚKL and EC 
Sud-Ouest et 
Outre Mer III, 
France 
4.3 
Exclusion criteria no. 8 and 9 have been modified by deleting 
“significant abnormality in physical examination or clinical 
laboratory results at VS1” from criterion no. 9 and adding to 
criterion no.8.  
-- 
4.3, 5.5 
Exclusion criterion no. 11f and the section on prior and 
concomitant medication have been modified. Use of 
efficacious medication for Parkinson’s disease will be 
allowed if maintained at stable dosage levels. 
Centrally acting anti-obesity drugs and TNF-alpha inhibitors 
have been added as exclusion criteria nos. 11g and 11 h, and 
have been included as forbidden concomitant medication in 
Section 5.5. 
SÚKL 
 
 
 
-- 
4.3, 6.1.1, 
6.2.5, 6.3.2, 
13, 14.1, 14.2 
Exclusion criterion no. 9 has been modified to exclude 
subjects with hepatic or renal impairment. New Section 6.2.5 
related to calculation of glomerular filtration rate (for 
verification of renal impairment) has been added. Blood 
coagulation analysis (for verification of hepatic impairment) 
has been added to Sections 6.3.2, 14.1 and 14.2. 
FDA 
4.3, 6.3.5 
Exclusion criterion no.6 will be met if the subject answers 
“yes” to items 4 and/or 5 of the C-SSRS only referring to the 
last month before VS1. 
-- 
4.4.2 
Additional criteria for subject’s withdrawal from the trial 
have been added.  
SÚKL and EC 
of the LÄK 
Thüringen 
6.1.3, 6.1.5, 
6.1.6, 6.5  
No optional PK sampling will be done. 
SÚKL 
6.1.6, 6.3.4 
ECG will be recorded at all on-site visits. 
EC Sud-Ouest 
et Outre Mer 
III, France 
6.3.5 
Subjects who answer “yes” to point 4 and/or 5 of the C-SSRS 
will be withdrawn from the trial and sent for psychiatric 
consultation. 
SÚKL 
7.2.3 
Procedures for SAE reporting have been clarified. 
SÚKL 
7.2.4 
It has been clarified that the current version of the IB at the 
time of SAE reporting will be the reference for the 
assessment of unexpected SAEs. 
SÚKL 
* In addition, the changes have also been implemented in the protocol synopsis and the trial flow chart.  
Note: Minor clarifications and corrections of typing errors are not listed above. 


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Clinical Trial Protocol 
Page 5 of 74 
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Theranexus S. A. 
Confidential 
Section(s)* 
Change from Final Protocol Version 4.0, 30 May 2018 to 
Final Protocol Version 5.0, 19 October 2018 
Change 
requested by 
Synopsis, 4.3 
Exclusion criterion no. 9 has been modified to correct serum 
total bilirubin and prothrombin time values, based on 
Erratum to clinical trial protocol Final Version 4.0, 
14-JUN-2018. 
-- 
14.1 
The contact details of the Medical Monitor in the US were 
updated. 
-- 
Trial flow 
chart; 6.1.3, 
6.1.5, 6.1.6, 
6.4.2 
If the PVT assessment schedule (10:00 h, 12:00 h, 14:00 h 
and 16:00 h) is too burdensome for the subject, it may be 
individually adapted to at least 3 assessments, with a time 
window of not less than 1 h between two PVT assessments.  
This change was implemented to relieve burden for those 
subjects who are not able to attend long-lasting trial visits. Its 
impact on the analysis of the PVT procedure should be 
limited as variables are analysed as a mean of the session 
performed at a given visit and not by timepoint. 
Theranexus 
S.A. 
 
 
 
Section(s) 
Change from Final Protocol Version 5.0, 19 October 2018 
to Final Protocol Version6.0, 27 February 2019 
Change 
requested by 
Synopsis, 4.2 
Inclusion criteria no. 3 and 4 have been modified to increase 
the maximum age of subjects from 75 years to 80 years and 
the upper BMI limit from 30 kg/m2 to 35 kg/m2. 
The rationale for this change was the high pre-screening 
failure rate due to age and BMI restrictions. This change is 
considered acceptable given the exhaustive safety screening, 
including cognitive function (exclusion criterion no. 5) and 
mobility (inclusion criterion no. 2), and the exclusion of 
patients with cardiovascular risk factors (exclusion criterion 
no. 3) as well as the low dose of flecainide used in this trial. 
Theranexus 
S.A. 
1.2, 12.2, 12.3, 
13 
The reference was changed to the updated IB version 4.0, 
24-JAN-2019 instead of the reference to the IB version 3.0, 
20-OCT-2017. The references to the EMA and FDA were 
deleted in Section 1.2. 
- 
 


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Confidential 
TRIAL SYNOPSIS 
Sponsor: Theranexus S. A., 86, rue de Paris, F-91400 Orsay, France. 
Name of active ingredients: Modafinil, flecainide. 
Trial title: 
Randomised, double-blind, placebo-controlled, complete 3-way cross-over phase IIa trial to 
investigate safety and efficacy of two THN102 doses in subjects with excessive daytime sleepiness 
associated with Parkinson’s disease. 
Protocol number: THN102-202 
EudraCT number: 2017-004475-31 
Coordinating investigator:  
 
Investigators / trial sites: An estimated 28 sites in Europe and the USA. 
Planned duration of the trial: 
First subject first visit: Q2/2018 
Last subject last visit: Q4/2018 
Phase: IIa (proof-of-concept) 
Objectives: 
Primary objective: 
• 
To assess the safety profile of THN102 (modafinil/flecainide combination) at two doses 
(200 mg/18 mg and 200 mg/2 mg) versus placebo in subjects with excessive daytime sleepiness 
associated with Parkinson’s disease (PD). 
Secondary objectives: 
1. To quantify the efficacy of THN102 versus placebo in improving sleepiness. 
2. To quantify the efficacy of THN102 versus placebo in improving  
a. attention, vigilance 
b. cognition 
3. To determine the dose response profile of THN102 versus placebo on efficacy parameters. 
4. To determine the plasma levels of modafinil and flecainide at steady state. 
Methods / trial design: 
This is a prospective, double-blind, randomised, controlled trial using a complete 3-way cross-over 
design. Subjects will attend seven on-site visits and five phone call visits.  
The seven trial periods are depicted below: 
Screening 
Treatment I 
Washout I* 
Treatment II 
Washout II* 
Treatment III 
Follow-Up 
1-2 weeks 
2 weeks 
1(2) weeks 
2 weeks 
1(2) weeks 
2 weeks 
1 week 
No treatment 
A, B, or C 
No treatment 
A, B, or C 
No treatment 
A, B, or C 
No treatment 
(Dose A = placebo; Dose B = THN102 200 mg/2 mg; Dose C = THN102 200 mg/18 mg.) 
* Washout periods can be extended to up to 2 weeks, if this is more convenient for the subject. 
At visit VR (baseline visit) the subjects will be equally randomised (1:1:1:1:1:1) double-blind to a 
treatment sequence containing three treatment periods (shown below). 
Sequence 
Treatment period I 
Treatment period II 
Treatment period III 
1 
Dose A 
Dose B 
Dose C 
2 
Dose B 
Dose C 
Dose A 
3 
Dose C 
Dose A 
Dose B 
4 
Dose A 
Dose C 
Dose B 
5 
Dose C 
Dose B 
Dose A 
6 
Dose B 
Dose A 
Dose C 
 
The duration of each treatment period is 2 weeks, with a 1-week washout in between (to avoid carry-
over effects) and a 1-week follow-up period after the last treatment period. Washout periods can be 
extended up to two weeks. THN102 will be administered orally once daily. 
 


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Clinical Trial Protocol 
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Confidential 
Number of subjects (planned): Enrolled and screened: 72, randomised and evaluable (safety): 60, 
evaluable (efficacy): 54. 
Indication: Excessive daytime sleepiness associated with Parkinson’s disease. 
Inclusion criteria: 
1. Subjects with a diagnosis of idiopathic Parkinson’s disease as defined by the Movement Disorders 
Society (MDS). 
2. Subjects with Hoehn and Yahr scale score ≤ 4. 
3. Males or females, aged between 18 and 80 years. 
4. Body mass index > 18 kg/m2 and < 35 kg/m2. 
5. Subjects should have a complaint of daytime sleepiness impacting their quality of life and/or 
daytime functioning (e.g. falling asleep while reading or watching TV, while eating or talking with 
other people). 
6. Epworth Sleepiness Scale (ESS) score ≥ 14. 
7. Women of childbearing potential (not surgically sterile or < 2 years postmenopausal), must use a 
highly effective method of contraception, and must continue for the duration of the trial (and for 
2 months after participation in the trial). Highly effective methods of contraception include 
hormonal contraception associated with inhibition of ovulation (combined estrogen/progestogen: 
oral, intravaginal, transdermal; progestogen-only: oral, implanted, and injected) in conjunction 
with a barrier method (preferably male condom). Highly effective methods further include 
intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, 
vasectomised partner (provided that the partner is the sole sexual partner of the subject and the 
vasectomised partner has received medical assessment of the surgical success) and sexual 
abstinence, i.e. when this is in line with the preferred and usual lifestyle of the subject.  
8. Subjects willing and able to follow trial procedures (including to swallow IMP capsules) and to 
regularly attend scheduled clinic visits as specified in the protocol, and who have signed the 
informed consent prior to any screening procedure. 
All above-mentioned inclusion criteria will be checked at VS1. 
At VR the following inclusion criteria will be re-checked: 5, 6, 7, 8. 
Exclusion criteria 
1. Subjects with known or with a suspected sleep apnea syndrome or who have any other cause of 
excessive daytime sleepiness, such as shift work sleep disorder. 
2. Psychiatric and neurological disorders (other than Parkinson’s disease), such as idiopathic 
narcolepsy, Alzheimer’s disease, Huntington’s Chorea, multiple sclerosis, epilepsy, psychosis, 
bipolar disorder, severe clinical anxiety or depression, multiple system atrophy (Shy-Drager 
syndrome) or other problem that in the investigator’s opinion would preclude the subject’s 
participation and completion of this trial or comprise reliable representation of subjective 
symptoms. 
3. Cardiovascular disorders such as 
a. Uncontrolled moderate to severe hypertension 
b. ECG QTcF duration ≥ 450 ms (men) or ≥ 470 (women) 
c. ECG signs of left ventricular hypertrophy (exclusion if at least one of the three indices is 
abnormal): 
• 
Sokolow-Lyon voltage (sum of amplitude of the S wave in lead V1 and the R wave in 
lead V5 or V6 ≥ 3.5 mV), or 
• 
Cornell voltage (S wave in V3 + R wave in aVL > 2.8 mV in men or > 2.0 mV in women), 
or 
• 
Modified Cornell (R wave in aVL > 1.1 mV) 
d. Recent (less than three months before screening visit VS1) myocardial infarction  
e. Stable or unstable angina pectoris 
f. Cardiac insufficiency 
g. Previous history of heart failure 
h. Previous history of cardiac valvular surgery 
i. 
Ventricular arrhythmias considered as clinically significant 


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j. 
Atrial fibrillation unless it is stable and controlled by stable doses of amiodarone, calcium 
channel blocker or beta-blocker 
k. 2nd or 3rd grade atrioventricular block or chronic bifascicular block, unless an adequate 
pacemaker is present 
l. 
Sinus node dysfunction 
m. Documented Brugada syndrome 
4. Subjects with current impulse control disorder.  
5. Subjects showing dementia or with MoCA < 23. 
6. Subjects with current suicidal risk, based on investigator’s clinical judgement or with a “yes” 
answer to item 4 and/or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at VS1, 
referring to the last month before screening. 
7. Current or recent (within one year) history of substance abuse or dependence disorder as defined 
in Diagnostic and Statistical Manual of Mental Disorders (DSM-V), e. g. alcohol. Tobacco use is 
accepted. 
8. Other active clinically significant illness, including unstable cardiovascular or malignant 
pathology, significant abnormality in physical examination or clinical laboratory results at VS1, 
which could interfere with the trial conduct or counter-indicate the trial treatments or place the 
subject at risk during the trial or compromise the trial participation. 
9. Subjects with hepatic impairment (serum total bilirubin ≥2 mg/dL, except in patients diagnosed 
with Gilbert’s syndrome, or prothrombin time [PT] ≥ 13.7 s (except in patients on therapeutic anti-
coagulation), or serum albumin < 3.5 g/dL), or renal impairment (glomerular filtration rate [GFR] 
< 60 mL/min/1.73 m2, according to Kidney Disease Improving Global Outcomes (KDIGO)). 
10. Known hypersensitivity to IMP (active ingredients or excipients of modafinil or flecainide 
capsules). 
11. Subjects currently (or within 6 weeks before VS1) under one of the following medications (isolated 
intake up to 1 week can be accepted):  
a. Neuroleptics, anxiolytics, anticonvulsants. Benzodiazepines and benzodiazepine-like drugs 
are only authorised if used regularly at stable indicated doses with an evening intake as sleep 
promoting agents. 
b. Flecainide or other class I antiarrhythmic drugs. 
c. Psychostimulants (except caffeine if no abuse and stable consumption) such as, but not limited 
to, modafinil, methylphenidate, amphetamine. 
d. Antidepressants except if maintained at stable dose for at least 6 weeks before visit VS1 and 
anticipated to remain stable during the trial in subjects with mild or moderate unipolar 
depression. 
e. Antiemetic medications (except domperidone), myo-relaxing drugs and opioids. 
f. Dopaminergic medications, unless they have been used at stable doses for at least 4 weeks 
before screening and it is anticipated that the doses will not be changed throughout the trial. 
Efficacious medication for Parkinson's disease should not be discontinued for the sole purpose 
of the subject's enrolment into this clinical trial but must be maintained at stable dosage levels. 
g. Centrally acting anti-obesity drugs. 
h. TNF-alpha inhibitors. 
12. Pregnancy or lactation. Women of childbearing potential who intend to be pregnant during the 
next few months.  
13. Subjects protected by the law (legal guardianship). 
14. Subjects participating in any other clinical trial within 60 days prior to visit VS1 in this trial or still 
in the protected period imposed by a previous trial. 
15. Subjects working in an occupation requiring variable shift work or routine night shifts. 
16. Subjects who plan to travel involving time zone changes. 
All above-mentioned exclusion criteria will be checked at VS1. 
At VS2 it will be checked if laboratory results, new AEs or new concomitant medication conflict 
with any of the exclusion criteria. 
At VR the following exclusion criteria will be re-checked: 5, 11-12, 15, 16. 


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Duration of treatment for the individual subject:  
8-10 weeks (including two 1-2-week washout periods in between without treatment),  
the net treatment duration is 6 weeks. 
 
Investigational medicinal products: 
Modafinil capsules (100 mg), or matching placebo. 
Flecainide capsules (1 mg, 9 mg), or matching placebo. 
Oral administration of 2 modafinil and 2 flecainide capsules (i.e. 4 capsules in total), once daily in 
the morning at 08:00 h (± 1:00 h). A 24-hour (± 1:00 h) interval between two consecutive doses is 
required. 
 
Dose 
Modafinil 
Flecainide 
THN102 
A 
2 capsules (0 mg) 
0 mg 2 capsules (0 mg) 
0 mg 
placebo 
B 
2 capsules (100 mg) 
200 mg 2 capsules (1 mg) 
2 mg 
200 mg/2 mg 
C 
2 capsules (100 mg) 
200 mg 2 capsules (9 mg) 
18 mg 
200 mg/18 mg 
 
For subjects aged above 65 years: 
On the first, second and third day of each treatment period, 1 modafinil and 1 flecainide capsule will 
be taken. From the fourth to the last day of each treatment period, the regimen will be as described 
above. 
 
Criteria for evaluation: 
Safety 
• 
Adverse events 
• 
Safety laboratory (haematology, biochemistry, urinalysis) 
• 
Vital signs (blood pressure, heart rate) 
• 
12-lead electrocardiogram (ECG) 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Movement Disorder Society-sponsored version of Unified Parkinson's Disease Rating Scale 
(MDS-UPDRS) 
• 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating Scale 
(QUIP-RS) 
 
Efficacy  
• 
Epworth Sleepiness Scale (ESS) 
• 
Psychomotor Vigilance Test (PVT) 
• 
Montreal Cognitive Assessment (MoCA) 
• 
Actimetry (inactivity evaluation) 
• 
Subject diaries (get-up time, total time [hours] slept last night, wake-up periods during night sleep, 
time of drug intake, number of capsules taken, somnolence episodes, diurnal involuntary sleep 
attacks, voluntary naps, number of caffeinated drinks, going-to-bed time) 
 
Pharmacokinetics  
• 
Modafinil and flecainide concentrations in plasma  
 
Statistical methods 
Safety endpoints 
1. Adverse events 
2. Safety laboratory 
3. Vital signs change  
4. Electrocardiogram assessments  
5. Columbia-Suicide Severity Rating Scale (C-SSRS) 
6. MDS-UPDRS 
7. QUIP-RS 


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Efficacy endpoints 
Key efficacy endpoint 
8. Mean ESS score change from baseline at the end of each treatment period 
Secondary efficacy endpoints 
9. ESS score responder rate, defined as the proportion of subjects with at least 25% ESS improvement 
from baseline, at the end of each treatment period 
10. Absence of residual somnolence, i.e. ESS < 11 at the end of each treatment period 
11. Psychomotor Vigilance Test (PVT) variables change from baseline at the end of each treatment 
period 
12. MoCA score change from baseline at the end of each treatment period 
13. Actimetry change (inactivity) from baseline at the end of each treatment period 
14. Number and duration of diurnal involuntary sleep attacks (subject diaries) change from baseline 
at the end of each treatment period 
15. Episodes of somnolence (subject diaries) change from baseline at the end of each treatment period 
 
Sample size justification  
For the purpose of sample size planning ESS is considered to be the key efficacy endpoint. Solid 
information on the expected difference between placebo and THN102 dose and the associated 
intrasubject variance are not available. Using results reported in Adler et al. as a rough orientation an 
effect size of 0.40 may constitute a conservative estimation for the comparison of the high THN102 
dose with placebo. A sample size of 54 subjects will have a power of 82% to detect this effect size 
based on a paired t-test with a 0.05 two-sided significance level. To account for drop outs 60 subjects 
will be randomised. 
 
Analysis populations 
• 
The Safety Set (SS) includes all subjects who have received IMP at least once. 
• 
The Full Analysis Set (FAS) includes all randomised subjects with an evaluable ESS score at the 
end of at least one treatment period. The efficacy analyses will be conducted on the FAS. 
• 
The Per Protocol (PP) set includes all subjects who have completed the trial without major protocol 
deviation. Major and minor violations will be defined in the SAP. The main secondary endpoints 
(ESS, PVT and cognition) will be analysed with the PP set to demonstrate robustness of the 
primary analysis.  
• 
The pharmacokinetic (PK) analysis set will include all subjects who have received treatment as 
per protocol (even if the trial was not completed) and who present no major protocol deviations 
with an impact on PK. 
 
Efficacy analysis 
Continuous efficacy endpoints – the change from baseline at each key visit (end of treatment period I, 
II, and III) in ESS, PVT and MoCA - will be analysed using a mixed linear regression model. The 
model will include the treatment, period, treatment by period interaction, sequence, and baseline scores 
as fixed effects, and the subject nested within sequence as a random effect.  
 
Categorical efficacy endpoints – absence of residual somnolence and ESS responder status at each key 
visit – will be analysed using a mixed effects logistic regression model, with the treatment, period, 
treatment by period interaction, sequence, and baseline scores as fixed effects, and the subject nested 
within sequence as a random effect. 
 
Treatment least square means and mean differences will be reported with their standard errors and 
95% confidence intervals. The significance of the differences between Treatment A (THN102 
Placebo), Treatment B (THN102 200/2) and Treatment C (THN102 200/18) will be assessed with a 
contrast t-test at the two-sided 5% level. 
 


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Supportive analysis 
The same analysis will be repeated on the PP set, to assess robustness of the analysis of the variables 
from ESS and PVT and possibly on other efficacy results. Subgroup analyses may be performed to 
investigate the effect of the main demographics (age, gender) and disease characteristics (in terms of 
daily sleepiness extent, and cognitive impairment) on the efficacy outcomes. 
 
The presence of a significant treatment by period interaction term in the main model may indicate a 
residual treatment (carryover) effect. In case of a significant treatment by period interaction, period I 
results will be analysed separately, and further analyses will be performed to explore the carry-over 
effects. The methods for evaluation of carryover effects will be defined in the SAP. 
 
Safety analysis 
Safety data will be summarised using summary statistics and frequency tabulations, as appropriate. 
 
Pharmacokinetics 
• 
Plasma concentrations of modafinil and flecainide at visits VR, V1B, V1C, V2B, V2C and V3B, 
considering time after last IMP intake. 
• 
Concentration-time data per treatment and subject for modafinil and for flecainide. Plasma 
concentrations and time post IMP intake, to assess range of exposure at steady state for each 
treatment. 
 






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8. The subject diary will be used continuously (i.e. also during washout periods) to record get-up time, total time (hours) slept last night, wake-up periods during night sleep, 
time of drug intake and number of capsules taken (except screening phase diary issued at VS1), somnolence episodes, diurnal involuntary sleep attacks, voluntary naps, 
number of caffeinated drinks and going-to-bed time.  
9. Visits V1A and V1B should be scheduled so that 3 days of actigraphy data can be collected. (The same for VS2 and VR, V2A and V2B, as well as V3A and V3B.) 
Actigraphy will be assessed using an actigraphy wrist band. 
10. MoCA should be performed in the morning. 
11. In case of early discontinuation, the same procedures as required for V3B will be performed.  
12. One PK blood sample will be taken when the subject arrives on the site. The times of blood withdrawal must be recorded. 
13. Starting from Day 21, the visit day numbers are theoretical, as the washout period is flexible and can be extended to up to 14 days. The 2-week duration of the treatment 
period is fixed. 
 
 


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TABLE OF CONTENTS 
TRIAL SYNOPSIS ................................................................................................................................... 6 
TRIAL FLOW CHART ......................................................................................................................... 12 
LIST OF TABLES .................................................................................................................................. 17 
LIST OF ABBREVIATIONS ................................................................................................................ 18 
1. 
INTRODUCTION ........................................................................................................................... 20 
1.1. 
Background ................................................................................................................................. 20 
1.2. 
Test Drugs .................................................................................................................................. 21 
1.3. 
Rationale for Trial Design and Dose Selection .......................................................................... 23 
1.3.1. 
Trial design ..................................................................................................................................... 23 
1.3.2. 
Dose selection................................................................................................................................. 23 
1.4. 
Risk/Benefit Ratio ...................................................................................................................... 23 
1.4.1. 
Evaluation of risk ........................................................................................................................... 23 
1.4.2. 
Evaluation of benefit ...................................................................................................................... 24 
2. 
OBJECTIVES ................................................................................................................................. 25 
2.1. 
Primary Objective ....................................................................................................................... 25 
2.2. 
Secondary Objectives ................................................................................................................. 25 
3. 
TRIAL DESIGN .............................................................................................................................. 26 
3.1. 
Overall Trial Design and Plan .................................................................................................... 26 
3.2. 
Trial Duration and Dates ............................................................................................................ 26 
4. 
TRIAL POPULATION .................................................................................................................. 27 
4.1. 
Number of Subjects .................................................................................................................... 27 
4.2. 
Inclusion Criteria ........................................................................................................................ 27 
4.3. 
Exclusion Criteria ....................................................................................................................... 27 
4.4. 
Screening Failures and Withdrawals .......................................................................................... 29 
4.4.1. 
Screening failures ........................................................................................................................... 29 
4.4.2. 
Withdrawals ................................................................................................................................... 29 
4.5. 
Subject Identification .................................................................................................................. 30 
5. 
TREATMENTS ............................................................................................................................... 31 
5.1. 
Investigational Medicinal Product (IMP) ................................................................................... 31 
5.1.1. 
Test drug formulations ................................................................................................................... 31 
5.1.2. 
Reference drug formulations .......................................................................................................... 31 
5.1.3. 
Timing of IMP doses and administration ....................................................................................... 32 
5.1.4. 
Labelling and Packaging ................................................................................................................ 32 
5.1.5. 
Drug storage and distribution ......................................................................................................... 33 
5.2. 
Randomisation and Blinding ...................................................................................................... 33 
5.2.1. 
Randomisation ................................................................................................................................ 33 
5.2.2. 
Blinding .......................................................................................................................................... 33 
5.3. 
Clinical Supplies Accountability ................................................................................................ 34 
5.4. 
Treatment Compliance ............................................................................................................... 34 
5.5. 
Prior and Concomitant medication ............................................................................................. 35 
5.6. 
Lifestyle and Diet ....................................................................................................................... 35 
5.7. 
Further Treatment after the End of the Trial .............................................................................. 35 
6. 
ASSESSMENTS .............................................................................................................................. 36 
6.1. 
Description of Trial Visits .......................................................................................................... 36 
6.1.1. 
Visit VS1 ........................................................................................................................................ 36 
6.1.2. 
Visit VS2 ........................................................................................................................................ 36 
6.1.3. 
Visit VR.......................................................................................................................................... 37 
6.1.4. 
Visits V1A, V2A and V3A ............................................................................................................. 37 
6.1.5. 
Visits V1B, V2B and V3B ............................................................................................................. 37 
6.1.6. 
Visits V1C and V2C ....................................................................................................................... 38 
6.1.7. 
Visit V3C ........................................................................................................................................ 39 
6.2. 
Baseline Assessments ................................................................................................................. 39 
6.2.1. 
Demography ................................................................................................................................... 39 
6.2.2. 
Medical history, concomitant diseases ........................................................................................... 39 
6.2.3. 
Prior and concomitant treatments and lifestyle .............................................................................. 39 


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6.2.4. 
Modified Hoehn & Yahr stage ....................................................................................................... 39 
6.2.5. 
Calculation of glomerular filtration rate ......................................................................................... 40 
6.3. 
Safety Assessments .................................................................................................................... 40 
6.3.1. 
Adverse events ............................................................................................................................... 40 
6.3.2. 
Safety laboratory and pregnancy tests ............................................................................................ 40 
6.3.3. 
Vital signs and weight .................................................................................................................... 40 
6.3.4. 
Electrocardiogram (ECG) ............................................................................................................... 41 
6.3.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................................................... 41 
6.3.6. 
Movement Disorder Society-Sponsored Version of Unified Parkinson's Disease Rating Scale 
(MDS-UPDRS) ................................................................................................................................................ 41 
6.3.7. 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating Scale (QUIP-
RS) 
42 
6.3.8. 
Physical examination ...................................................................................................................... 42 
6.4. 
Efficacy Assessments ................................................................................................................. 42 
6.4.1. 
Epworth Sleepiness Scale (ESS) .................................................................................................... 42 
6.4.2. 
Psychomotor Vigilance Test (PVT) ............................................................................................... 42 
6.4.3. 
Montreal Cognitive Assessment (MoCA) ...................................................................................... 42 
6.4.4. 
Actigraphy assessment ................................................................................................................... 43 
6.4.5. 
Subject diaries ................................................................................................................................ 43 
6.5. 
Pharmacokinetics (PK) ............................................................................................................... 44 
7. 
ADVERSE EVENT, PREGNANCY AND EMERGENCY ........................................................ 45 
7.1. 
Adverse Event (AE).................................................................................................................... 45 
7.1.1. 
Definition of an adverse event ........................................................................................................ 45 
7.1.2. 
Severity assessment ........................................................................................................................ 45 
7.1.3. 
Relationship assessment ................................................................................................................. 45 
7.1.4. 
Procedures for reporting of adverse events .................................................................................... 46 
7.2. 
Serious Adverse Event (SAE) .................................................................................................... 47 
7.2.1. 
Definition of a serious adverse event ............................................................................................. 47 
7.2.2. 
Definitions of Suspected Unexpected Serious Adverse Reactions (SUSAR) ................................ 47 
7.2.3. 
Procedures for reporting of SAEs and SUSARs ............................................................................. 48 
7.2.4. 
Procedures for regulatory reporting of serious adverse events ....................................................... 48 
7.3. 
Pregnancy ................................................................................................................................... 49 
7.4. 
Emergency .................................................................................................................................. 49 
8. 
STATISTICAL PROCEDURES ................................................................................................... 51 
8.1. 
Analysis Variables ...................................................................................................................... 51 
8.1.1. 
Safety variables .............................................................................................................................. 51 
8.1.2. 
Efficacy variables ........................................................................................................................... 51 
8.1.3. 
Pharmacokinetic variables .............................................................................................................. 51 
8.2. 
Trial Populations ........................................................................................................................ 51 
8.3. 
Statistical Methods ..................................................................................................................... 52 
8.3.1. 
Efficacy .......................................................................................................................................... 52 
8.3.2. 
Safety .............................................................................................................................................. 52 
8.3.3. 
Pharmacokinetics ............................................................................................................................ 53 
8.4. 
Interim Analysis ......................................................................................................................... 54 
8.5. 
Sample Size Justification ............................................................................................................ 54 
9. 
ETHICAL AND LEGAL ASPECTS ............................................................................................. 55 
9.1. 
Good Clinical Practice ................................................................................................................ 55 
9.2. 
Delegation of Investigator Responsibilities ................................................................................ 55 
9.3. 
Subject Information and Informed Consent ............................................................................... 55 
9.4. 
Confidentiality ............................................................................................................................ 55 
9.5. 
Protocol Amendments ................................................................................................................ 56 
9.6. 
Approval of the Trial Protocol and Amendments ....................................................................... 56 
9.7. 
Ongoing Information for the Independent Ethics Committee / Institutional Review Board ...... 56 
9.8. 
Premature Closure of the Trial ................................................................................................... 56 
9.9. 
Regular Termination of the Trial ................................................................................................ 57 
9.10. Archiving and Record Retention ................................................................................................ 57 
9.11. Liability and Insurance ............................................................................................................... 57 
10. 
TRIAL MONITORING AND AUDITING .............................................................................. 58 


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10.1. Trial Monitoring ......................................................................................................................... 58 
10.2. Source Data Verification and On-Site Audits ............................................................................ 58 
11. 
DATA HANDLING AND RECORD KEEPING ..................................................................... 59 
11.1. Electronic CRF and Database ..................................................................................................... 59 
11.2. Documentation of Trial Findings ............................................................................................... 59 
11.3. Use of Trial Findings .................................................................................................................. 59 
12. 
DECLARATIONS OF SPONSOR AND INVESTIGATOR .................................................. 61 
12.1. Declaration of Sponsor ............................................................................................................... 61 
12.2. Declaration of Coordinating Investigator ................................................................................... 62 
12.3. Declaration of Principal Investigator .......................................................................................... 63 
13. 
REFERENCES ............................................................................................................................ 64 
14. 
APPENDICES ............................................................................................................................. 66 
14.1. Appendix A – Trial Administrative Structure ............................................................................ 66 
14.2. Appendix B – Safety Laboratory Parameters ............................................................................. 69 
14.3. Appendix C – Most Common Antiarrhythmic Drugs Class I .................................................... 70 
14.4. Appendix D – CYP2D6 Inhibitors and CYP3A4,5 and CYP2C19 Substrates .......................... 71 
 
LIST OF TABLES 
Table 1:  Characteristics of modafinil and of flecainide ........................................................................... 22 
Table 2: Trial design ................................................................................................................................. 26 
Table 3: Treatment sequences ................................................................................................................... 26 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALQ  
above limit of quantification (assay) 
ALT 
alanine aminotransferase (SGPT) 
ANSM 
Agence Nationale de Sécurité du Médicament et des Produits de Santé  
 
(French Health Agency) 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the curve i.e. area under the plasma concentration versus time curve over time 
periods (AUC0-t, AUC0- ) 
BMI 
body mass index = body weight (kg) / height2 (m2) 
CA 
competent authority 
CNS 
central nervous system 
Cmax 
maximal plasma concentration after oral treatment 
CMO 
chief medical officer 
CRO 
contract research organisation 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTR 
 
clinical trial report 
CYP450 
cytochrome P450 
CV 
coefficient of variation 
DMP 
data management plan 
DSUR 
development safety update report  
EC 
Ethics Committee 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDS 
excessive daytime sleepiness 
EDV 
early discontinuation visit 
EMA 
European Medicines Agency 
ESS 
Epworth Sleepiness Scale 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration (USA) 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
hCG 
human chorionic gonadotropin  
IB 
investigator’s brochure 
ICD 
impulse control disorder 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC/IRB 
independent ethics committee / institutional review board 
IMP 
investigational medicinal product 
ISF 
investigator site file  
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
KDIGO 
Kidney Disease Improving Outcomes 
LÄK 
State Chamber of Physicians, Germany 
LC-MS/MS 
liquid chromatography-mass spectrometry/mass spectrometry  
 
(liquid chromatography-tandem mass spectrometry) 
LLOQ 
lower limit of quantification (assay) 
MCH 
mean corpuscular haemoglobin 
MCV 
mean corpuscular volume 
MDS-UPDRS Movement Disorder Society-sponsored version of Unified Parkinson's Disease Rating Scale 
MoCA 
Montreal Cognitive Assessment 


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PCA 
Pharmacie Centrale des Armées (Central Army Pharmacy) 
PD 
Parkinson's disease 
PK 
pharmacokinetics 
PP set 
Per Protocol set 
PT 
prothrombin time 
PVT 
Psychomotor Vigilance Test 
QRS 
combination of three of the graphical deflections on an electrocardiogram 
QT 
duration between Q wave and T wave on the ECG (expressed in ms) 
QTcF 
corrected QT-interval (Fridericia’s formula) in ECG (expressed in ms) 
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating Scale 
RBC 
red blood cells 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOP 
standard operating procedure 
SmPC 
summary of product characteristics  
SS 
Safety Set 
SÚKL 
State Institute for Drug Control, Czech Republic 
SUSAR 
suspected unexpected serious adverse reaction 
THN102 
Theranexus internal code for the combination modafinil and flecainide  
TMF 
trial master file 
TNF 
tumour necrosis factor 
t1/2 
terminal elimination half-life  
tmax 
time to reach maximal drug concentration in biological matrix (plasma) 
WBC 
white blood cells 
WHO 
World Health Organisation 
 


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1. 
INTRODUCTION 
1.1. Background 
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders with an estimated 
prevalence of about 1% in subjects over 60 years of age. Among the non-motor symptoms of PD, sleep 
disorders are prominent and have a considerable negative effect on the quality of life of the patients. 
Excessive daytime sleepiness (EDS) occurs in 20-50% of PD patients, it appears to be linked to disease 
severity and duration. Current hypotheses about the etiology of EDS include neurodegenerative dopamine 
denervation, effects of dopaminergic drugs and nocturnal sleep disruption. [1,2] Currently there is no drug 
treatment approved for EDS in PD. Modafinil has been used in three small trials [3,4,5] with positive 
results in two of the three trials and was well tolerated. Pitolisant, an H3 inverse agonist has been tested 
in large scale phase III trials, however, results are not published. Phase II trials in EDS in PD subjects are 
ongoing with JZP-110, a norepinephrine-dopamine reuptake inhibitor and BEN-2001 (bavisant), an H3 
antagonist (Source: ClinicalTrials.gov). 
Modafinil, a wake promoting agent with a unique profile different from amphetamine, produces enhanced 
vigilance and arousal, is generally well tolerated and has been approved in the US for the treatment of 
daytime sleepiness in narcolepsy, [6,7,8,9]obstructive sleep apnea, and shift work disorder. In Europe the 
indication is limited to EDS in narcolepsy. Modafinil also has shown activity in fatigue in cancer, in 
neurodegenerative disorders, etc.). [10] Besides, many common situations involve short or long sleep 
deprivation periods or wake-sleep rhythm modifications. Sleep loss alters attention and vigilance, and 
reduces operational performance. Modafinil works well in sleep-deprived subjects to support vigilance, 
cognitive performance, coping skills, and recovery sleep. [11,12,13,14,15] Positive impact on cognition, 
performance, and mood was seen in healthy subjects. [16,17] 
Context: Theranexus has investigated new potential drugs for treating narcolepsy and cataplexy among 
others. Theranexus has recently demonstrated that flecainide – a class Ic antiarrhythmic compound – can 
significantly modify at very low dose the basic pharmacological profile of modafinil by enhancing 
modafinil activity on wakefulness and cognition. The mode of action of this combination called THN102 
is under investigation, preliminary data have been published. [18] 
Non-clinical safety pharmacology: According to scientific advice from the French Medicines Agency 
(ANSM) a safety pharmacology study was conducted in alert dogs monitored by telemetry over 24 hours 
prior to initiation of phase I and phase II. Vital signs, body temperature, and motor activity were recorded 
as well as ECG to investigate impact on cardiac electrophysiology profile and potential for arrhythmias 
with incremental single doses of 50/3, 50/9 and 75/9 mg/kg modafinil/flecainide acetate. Concomitantly 
to the dose-dependent increase in heart rate and blood pressure linked to spontaneous motor activity and 
estimated to be elicited by modafinil pharmacological activity, the PR and the QT intervals were 
shortened. No significant effects on the QRS or the corrected QT (Fridericia’s and van de Water’s 
formulae) intervals were noted. No arrhythmia and no other morphology change were observed over the 
test periods in any dog in this model, which is considered as highly predictive for man.  
First phase I trial in healthy volunteers: The safety and tolerance of THN102 was recently investigated 
in a 3-way cross-over, randomised, double-blind trial in 9 healthy male volunteers comparing single oral 
doses of THN102 (400 mg modafinil/50 mg flecainide acetate) to 400 mg modafinil/placebo and to 
placebo/placebo (trial THN102-101). The 50 mg dose selected for flecainide in phase I is derived of 
electrophysiological activity when administered alone and more than twice the maximum dose planned 
(18 mg) in this trial. In the phase I trial (THN102-101) body temperature as well as supine blood pressure 
and heart rate were increased over time in subjects with THN102 and modafinil treatment vs. subjects on 
placebo. No orthostatic symptoms were seen for any treatment. Safety and tolerance profile for adverse 
events was good and similar for THN102 and modafinil. In the 24 h Holter analysis performed by a central 
ECG laboratory blinded to treatment, no impact on cardiac electrophysiology was seen on QRS and QTcF 
(Fredericia’s formula) and no indication of arrhythmia or of morphological changes were documented for 


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THN102 and modafinil versus placebo. A marginal PR shortening for both active treatments was seen in 
line with the clear positive chronotropic effect. Addition of flecainide had no impact on the 
pharmacokinetic profile of modafinil, and parameters measured were similar (including Cmax, tmax, t1/2, and 
AUC) to modafinil given alone, and flecainide had the anticipated mean terminal plasma t1/2 (12.2 h) and 
median tmax (3 h) but a lower Cmax, possibly due to lack of dose linearity when administering at low dose. 
Second phase I trial in sleep-deprived healthy volunteers: A phase Ib trial has been terminated in Q2 
2016, in 20 healthy male volunteers undergoing a 40-hour sleep deprivation protocol. This trial THN102-
102 included 20 healthy male subjects, in a double-blind, randomised, incomplete-block 3-period cross-
over design involving 5 treatments (n=12 per group): placebo, modafinil 100 mg, and combinations 
THN102 (modafinil 100 mg and 1, 3 or 9 mg flecainide as THN1, THN3 and THN9), as 3 oral doses over 
18 h. THN102-treated volunteers showed a statistically significant improvement in their vigilance levels 
(PVT with speed as primary endpoint) versus modafinil alone without showing a linear dose effect. 
Secondary endpoints assessing cognition (2-back, Go-NoGo, Wisconsin Sorting Card Task) were 
consistent with this effect. These results reinforce the interest in THN102 for the treatment of excessive 
daytime sleepiness, a debilitating symptom affecting a number of patients with CNS disorders such as 
narcolepsy and Parkinson’s disease. 
Ongoing phase IIa trial in narcoleptic subjects: A phase IIa trial (Trial THN102-201, double-blind, 
crossover design with 3 randomised periods with 300 mg modafinil + placebo, 300 mg modafinil + 3 mg 
flecainide and 300 mg modafinil + 27 mg flecainide per day) is ongoing since September 2016. 48 
narcoleptic subjects will be included in a prospective, 5-site, placebo-controlled trial using a complete 
3-way cross-over design after a 2-week stabilisation period with modafinil and followed by 1-week 
washout.  
Objectives of this phase IIa trial: The most appropriate flecainide dose in THN102 remains to be 
selected in subjects with Parkinson’s disease (PD) experiencing excessive daytime sleepiness (EDS). This 
trial aims at assessing safety of THN102, efficacy on EDS, vigilance and cognition as well as modafinil 
and flecainide plasma levels at steady state.  
It is assumed that THN102 treatment should improve the excessive daytime sleepiness (EDS), without 
changing the safety profile seen with modafinil in Parkinson’s disease subjects. 
1.2. Test Drugs 
Extensive information on modafinil and flecainide can be found in their respective SmPCs (Summary of 
Product Characteristics, see investigator brochure, IB [31] Section 7 and 8). A table summarising the key 
features for both compounds and covering mechanism of action, safety pharmacology, pharmacokinetic 
profile, metabolism, dosing and most prevalent adverse events is provided in Table 1. Both compounds 
have been on the market for more than 20 and 30 years, respectively. At least one million patients have 
received modafinil for narcolepsy and other medical conditions worldwide and several millions have been 
treated with flecainide acetate. 
A review of THN102 pharmacology profile and safety pharmacology is provided in the IB. A dedicated 
electrophysiology study was performed in conscious dogs under telemetry with THN102 and no change 
on QTcF and QRS was detected up to maximum combination given (75 mg/kg modafinil + 9 mg/kg 
flecainide acetate) and no occurrence of arrhythmias was observed. Blood pressure, body temperature, 
and activity especially at night were increased, presumably linked to the awakening effects of THN102. 


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Table 1:  Characteristics of modafinil and of flecainide   
 
Modafinil 
Flecainide Acetate 
Indication and mechanism of action 
 
• Modafinil is approved for the treatment of 
narcolepsy with and without cataplexy.  
• The mechanism of action is partly understood and 
involves modulation of several neurotransmitters in 
the brain  
 
• Flecainide 
is 
used 
to 
prevent 
and 
treat 
tachyarrhythmias.   
• It has local anaesthetic activity and belongs to the 
membrane 
stabilising 
(Class 
1) 
group 
of 
antiarrhythmic agents. 
• It blocks Nav1.5 sodium channel in the heart, 
slowing the upstroke of cardiac potential (especially 
on 
His-Purkinje 
system 
and 
ventricular 
myocardium). 
Safety Pharmacology 
 
• Mild increase of blood pressure, heart rate and 
temperature at mid and high doses (mainly at 200 
and 400 mg) 
• Rare occurrences of ventricular arrhythmia [19] 
• Well tolerated 
• Prolongs QT interval and widens QRS complex. 
 
• Related to systemic exposure in conscious dogs and 
in man [20] 
• Narrow therapeutic range 
Pharmacokinetic Profile 
 
• Oral bioavailability: 40-65% 
• Plasma concentrations linear and time-independent 
• Dose proportional between 200 to 600 mg 
• Tmax: 2 to 4h (tablet)  
• Cmax delayed 1h by food 
• Cmax: 3.7 to 4.8µg/mL (200 mg dose) 
• Terminal half-life: 15 h (range 10-15h) 
• Impact of ethnicity and gender   
• Protein binding: 60% [21] 
• Oral bioavailability: 95% 
• Plasma 
concentrations 
approximately 
dose 
dependent within therapeutic range 
but unclear when below  
• Tmax: 1.5 to 3 h (tablet) 
• No food interaction 
• Cmax: 200 to 1,000 ng/mL (100-300 mg)  
• Terminal half-life: 13 h (mean across single dose 
studies, range wide). 
• Protein binding: 40% [22,23] 
Metabolism (human) 
 
• Amide pathway (major) and oxidative pathway 
(minor) 
• Substrate: 
multiple 
CYP450 
including 
CYP3A4/3A5 
• Metabolised by liver 
• ≤5% intact drug excreted in urine [24] 
 
 
• Substrate:  CYP2D6 (mainly) and 1A2 
 
• Metabolised by liver 
• ~30% intact drug in urine [25] 
 
No anticipated interaction with Flecainide metabolism 
(different CYP450 pathway) 
No anticipated interaction with Modafinil metabolism 
(different CYP450 pathway) 
 
200 to 400 mg/day (in narcolepsy) 
100 to 300 mg/day (in tachyarrhythmia) 
 
Registration: 1992 (France), 2003 (USA) 
Registration: 1983 (France) 
Adverse events cited in SmPC from EMA (chronic therapy, with above posology) 
>10% 
• Headache 
 
• Dizziness, light headedness, headache 
• Visual disturbances  
1-10% 
• Nervousness, insomnia, anxiety, 
 depression, confusion 
• Dizziness, somnolence, paraesthesia 
• Tachycardia, palpitation 
• Blurred vision 
• Abdominal pain, nausea, dry mouth, diarrhea, 
constipation and others 
• Chest pain, asthenia 
• Increased liver function tests 
• Depression, anxiety, insomnia 
 
• Paraesthesia, ataxia, tremor, syncope… 
• Palpitation 
 
• Nausea, vomiting, abdominal pain and others 
 
• Dyspnea 
• Asthenia, fatigue, oedema 
An extensive list of adverse events is presented in each SmPC, albeit from patients on chronic treatment, 
frequently on concomitant therapy and at a much higher dose in case of flecainide. These documents will 
serve as a basis to identify Suspected Unexpected Serious Adverse Reactions (SUSAR) in this trial (also 
see Section 7.2.2).  
Very rare incidence of severe cutaneous skin reactions (such as Stevens-Johnson syndrome, DRESS 
syndrome or Toxic Epidermal Necrosis) may occur with modafinil. As reviewed in the SmPC the 
incidence in clinical trials was found to be 0.8% in children (13 withdrawn out of 1585 cases and also 
including serious cutaneous adverse events) and 0% in adults based on exposure of 4264 patients. 


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1.3. Rationale for Trial Design and Dose Selection 
1.3.1. Trial design 
This proof-of-concept, phase IIa trial with THN102 should collect a sufficient body of information to 
assess the safety and efficacy profile of THN102 versus placebo in Parkinson’s disease subjects suffering 
from excessive daytime sleepiness. The sample size required for a crossover design is approximately one 
third of the size required in a parallel trial. To use a cross-over option is thus a viable alternative design, 
with a sample size of about 60 subjects in this condition. In addition, a direct comparison between THN102 
doses can be performed in the same subject. The selected trial design for this pilot proof-of-concept 
phase IIa trial is consequently a randomised, placebo-controlled, 3-way cross-over trial design comparing 
two dose levels of THN102 to placebo and followed by a washout period of 1-2 weeks. It was perceived 
as essential to take advantage of the cross-over design for exploring two doses of THN102 and comparing 
their impact on safety, ESS and other efficacy endpoints. The treatment duration of 2 weeks per period 
appears sufficient to observe therapeutic activity as the steady state will be reached after about 3 days of 
drug intake. Each treatment period is followed by a one-week washout period, which can be extended up 
to two weeks. In addition to the key efficacy endpoint, ESS, other efficacy endpoints have been selected, 
such as cognitive assessments including PVT and MoCA before and after each treatment period.  
A difference of 25% in ESS is considered clinically relevant. [26] Therefore responder rates will be 
analysed, with responders being defined as subjects with at least 25% improvement from baseline.  
1.3.2. Dose selection 
Based on the reported trial data with modafinil in PD subjects, a single morning dose of 200 mg was 
chosen, as it showed efficacy on EDS [3,5]. (Subjects aged above 65 years will be started on 100 mg 
during the first three days.) Trials using a higher dose (up to 400 mg) failed to show increased efficacy. 
[4] The flecainide doses were chosen based on preclinical pharmacological and exposure data as well as 
results of the phase Ib trial including healthy subjects after total sleep deprivation (THN102-102). 
1.4. Risk/Benefit Ratio 
1.4.1. Evaluation of risk 
It is anticipated that the safety and tolerance profile of THN102 is similar to that of modafinil given alone 
in a PD-EDS population, with frequent occurrence of headache, gastric pain, palpitation, tachycardia, 
dizziness, insomnia, anxiety, confusion, and blurred vision (see Table 1).  
For the treatment of tachyarrhythmias, flecainide is given at daily doses between 100 and 300 mg. In the 
present trial flecainide will be administered for EDS at two very low doses (2 mg, 18 mg as a single daily 
dose). In previous clinical studies with THN102 flecainide reached a mean (±SD) maximal concentration 
of 44.9±9.6 ng/mL when 50 mg were given as a single dose (study THN102-101), and of 19.5 ng/mL after 
27 mg (3 doses of 9 mg over 20 hours). The Cmax data appeared linear between flecainide doses of 3, 9, 
and 27 mg: 2.2±0.8 ng/mL, 6.4±2.2 ng/mL, and 19.5±4.5 ng/mL respectively. Extrapolating from steady 
state Cmax of 100 mg of flecainide [25] (173±46 ng/mL), one would expect a steady state Cmax for 18 mg/d, 
the maximal flecainide dose used in this trial, of about 30 ng/mL. This exposure level is well below 
exposure levels where cardiovascular AEs are expected for flecainide. [27] Flecainide does not trigger 
any significant cardiovascular effects below 100 ng/mL or even 200 ng/mL in plasma. [28,29,30]  
Thus, no cardiac effect is expected at the very low flecainide concentrations associated with the prescribed 
doses used in this trial and flecainide is not expected to raise any safety and tolerance issue in combination 
with THN102. As a precautionary measure cardiovascular exclusion criterion 3 has been included.  
In the two phase I trials with THN102 the adverse events’ profile did not significantly differ between 
THN102 and modafinil. A small but significant increase in blood pressure and heart rate was noted with 
both THN102 (400 mg/50 mg) and modafinil (400 mg/0 mg) in trial THN102-101 with 24-hour Holter 


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monitoring. No impact on cardiac conduction (QT, QRS) and no arrhythmia were seen (for more details, 
see the IB [31]). The lists of typical adverse events reported for modafinil and for flecainide are also listed 
in the IB and mentioned in the information for the subject.  
Risk will be minimised by regular contact between subject and investigator and by close safety monitoring.  
1.4.2. Evaluation of benefit 
These subjects have documented excessive daytime sleepiness (EDS) and it is expected that THN102 at 
one or both doses may significantly improve excessive daytime sleepiness, decreasing episodes of 
sleepiness and sleep attacks and may even improve night sleep in quantity and quality.  
This is a proof-of-concept trial in approximately 60 PD subjects with EDS treated with THN102 at two 
doses (200 mg/18 mg, 200 mg/2 mg) compared to placebo under a 3-way, double-blind, cross-over trial 
design. The exposure is thus limited (2 weeks at each dose). This design might contribute to a better 
understanding of the mode of action of THN102 in the target population, to define the profile for dose 
response and time response and to assess recovery after washout. If successful, a phase IIb-III trial could 
be initiated in the future.   
In summary, the risk/benefit ratio for this proof-of-concept trial is considered as satisfactory. 
 


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2. 
OBJECTIVES 
2.1. Primary Objective 
• 
To assess the safety profile of THN102 (modafinil/flecainide combination) at two doses 
(200 mg/18 mg and 200 mg/2 mg) versus placebo in subjects with excessive daytime sleepiness 
associated with Parkinson’s disease (PD). 
2.2. Secondary Objectives 
1. To quantify the efficacy of THN102 versus placebo in improving sleepiness. 
2. To quantify the efficacy of THN102 versus placebo in improving  
a. attention, vigilance 
b. cognition  
3. To determine the dose response profile of THN102 versus placebo on efficacy parameters. 
4. To determine the plasma levels of modafinil and flecainide at steady state. 
 


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3. 
TRIAL DESIGN 
3.1. Overall Trial Design and Plan 
This is a prospective, double-blind, randomised, controlled trial using a complete 3-way cross-over 
design. Subjects will attend the site for twelve visits. The seven trial periods are depicted in Table 2. 
Table 2: Trial design 
Screening 
Treatment I 
Washout I* 
Treatment II 
Washout II* 
Treatment III 
Follow-Up 
1-2 weeks 
2 weeks 
1(2) weeks 
2 weeks 
1(2) weeks 
2 weeks 
1 week 
No treatment 
A, B, or C 
No treatment 
A, B, or C 
No treatment 
A, B, or C 
No treatment 
(Dose A = placebo; Dose B = THN102 200 mg/2 mg; Dose C = THN102 200 mg/18 mg.) 
*Washout periods can be extended to up to 2 weeks, if this is more convenient for the subject. 
The trial procedures by visit are presented in the flow chart on Page 12. 
At visit VR the subjects will be equally randomised (1:1:1:1:1:1) double-blind to a treatment sequence 
containing three periods (shown in Table 3). 
Table 3: Treatment sequences 
Sequence 
Treatment period I 
Treatment period II 
Treatment period III 
1 
Dose A 
Dose B 
Dose C 
2 
Dose B 
Dose C 
Dose A 
3 
Dose C 
Dose A 
Dose B 
4 
Dose A 
Dose C 
Dose B 
5 
Dose C 
Dose B 
Dose A 
6 
Dose B 
Dose A 
Dose C 
The duration of each treatment period is 2 weeks, with a 1-week washout in between (to avoid carry-over 
effects) and 1-week follow-up period after the last treatment period. Washout periods can be extended up 
to two weeks. THN102 will be administered orally once daily. 
3.2. Trial Duration and Dates 
The expected duration of this clinical trial is approximately 7 months. For the individual subject the trial 
will last 11 – 13 weeks.  
First subject first visit: Q2/2018 
Last subject last visit: Q4/2018 


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4. 
TRIAL POPULATION 
4.1. Number of Subjects 
A total of 60 Parkinson’s disease subjects with excessive daytime sleepiness will be randomised. 
Recruitment will be competitive. Dropouts will not be replaced. The target figure is 54 subjects completing 
the trial as per protocol. To be eligible for inclusion into this trial, each subject must fulfill the following 
inclusion criteria and none of the exclusion criteria at visit VS1. For the sample size calculation refer to 
Section 8.5. 
4.2. Inclusion Criteria 
1. Subjects with a diagnosis of idiopathic Parkinson’s disease as defined by the Movement Disorders 
Society (MDS). 
2. Subjects with Hoehn and Yahr scale score ≤ 4. 
3. Males or females, aged between 18 and 80 years. 
4. Body mass index > 18 kg/m2 and < 35 kg/m2. 
5. Subjects should have a complaint of daytime sleepiness impacting their quality of life and/or daytime 
functioning (e.g. falling asleep while reading or watching TV, while eating or talking with other 
people). 
6. Epworth Sleepiness Scale (ESS) score ≥ 14. 
7. Women of childbearing potential (not surgically sterile or < 2 years postmenopausal), must use a 
highly effective method of contraception, and must continue for the duration of the trial (and for 2 
months after participation in the trial). Highly effective methods of contraception include hormonal 
contraception associated with inhibition of ovulation (combined estrogen/progestogen: oral, 
intravaginal, transdermal; progestogen-only: oral, implanted, and injected), in conjunction with a 
barrier method (preferably male condom). Highly effective methods further include intrauterine 
device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised 
partner (provided that the partner is the sole sexual partner of the subject and the vasectomised partner 
has received medical assessment of the surgical success) and sexual abstinence, i.e. when this is in 
line with the preferred and usual lifestyle of the subject. 
8. Subjects willing and able to follow trial procedures (including to swallow IMP capsules) and to 
regularly attend scheduled clinic visits as specified in the protocol, and who have signed the informed 
consent prior to any screening procedure. 
All above-mentioned inclusion criteria will be checked at VS1. 
At VR the following inclusion criteria will be re-checked: 5, 6, 7, 8. 
4.3. Exclusion Criteria 
1. Subjects with known or with a suspected sleep apnea syndrome or who have any other cause of 
excessive daytime sleepiness, such as shift work sleep disorder. 
2. Psychiatric and neurological disorders (other than Parkinson’s disease), such as idiopathic narcolepsy, 
Alzheimer’s disease, Huntington’s Chorea, multiple sclerosis, epilepsy, psychosis, bipolar disorder, 
severe clinical anxiety or depression, multiple system atrophy (Shy-Drager syndrome) or other 
problem that in the investigator’s opinion would preclude the subject’s participation and completion 
of this trial or comprise reliable representation of subjective symptoms. 
3. Cardiovascular disorders such as 
a. Uncontrolled moderate to severe hypertension 
b. ECG QTcF duration ≥ 450 ms (men) or ≥ 470 (women) 
c. ECG signs of left ventricular hypertrophy (exclusion if at least one of the three indices is 
abnormal): 
• 
Sokolow-Lyon voltage (sum of amplitude of the S wave in lead V1 and the R wave in lead 
V5 or V6 ≥ 3.5 mV), or 


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• 
Cornell voltage (S wave in V3 + R wave in aVL > 2.8 mV in men or > 2.0 mV in women), or 
• 
Modified Cornell (R wave in aVL > 1.1 mV) 
d. Recent (less than three months before screening visit VS1) myocardial infarction  
e. Stable or unstable angina pectoris 
f. Cardiac insufficiency 
g. Previous history of heart failure 
h. Previous history of cardiac valvular surgery 
i. 
Ventricular arrhythmias considered as clinically significant 
j. 
Atrial fibrillation unless it is stable and controlled by stable doses of amiodarone, calcium channel 
blocker or beta-blocker 
k. 2nd or 3rd grade atrioventricular block or chronic bifascicular block, unless an adequate 
pacemaker is present 
l. 
Sinus node dysfunction 
m. Documented Brugada syndrome 
4. Subjects with current impulse control disorder.  
5. Subjects showing dementia or with MoCA < 23. 
6. Subjects with current suicidal risk, based on investigator’s clinical judgement or with a “yes” answer 
to item 4 and/or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at VS1, referring to the 
last month before screening. 
7. Current or recent (within one year) history of substance abuse or dependence disorder as defined in 
Diagnostic and Statistical Manual of Mental Disorders (DSM-V), e. g. alcohol. Tobacco use is 
accepted. 
8. Other active clinically significant illness, including unstable cardiovascular or malignant pathology, 
significant abnormality in physical examination or clinical laboratory results at VS1, which could 
interfere with the trial conduct or counter-indicate the trial treatments or place the subject at risk during 
the trial or compromise the trial participation. 
9. Subjects with hepatic impairment (serum total bilirubin ≥ 2 mg/dL, except in patients diagnosed with 
Gilbert’s syndrome, or prothrombin time [PT] ≥ 13.7 s (except in patients on therapeutic anti-
coagulation), or serum albumin < 3.5 g/dL), or renal impairment (glomerular filtration rate [GFR] 
< 60 mL/min/1.73 m2, according to Kidney Disease Improving Global Outcomes (KDIGO, [32])). 
10. Known hypersensitivity to IMP (active ingredients or excipients of modafinil or flecainide capsules). 
11. Subjects currently (or within 6 weeks before VS1) under one of the following medications (isolated 
intake up to 1 week can be accepted):  
a. Neuroleptics, anxiolytics, anticonvulsants. Benzodiazepines and benzodiazepine-like drugs are 
only authorised if used regularly at stable indicated doses with an evening intake as sleep 
promoting agents. 
b. Flecainide or other class I antiarrhythmic drugs (see Section 14.3). 
c. Psychostimulants (except caffeine if no abuse and stable consumption) such as, but not limited to, 
modafinil, methylphenidate, amphetamine. 
d. Antidepressants except if maintained at stable dose for at least 6 weeks prior to VS1 and 
anticipated to remain stable during the trial in subjects with mild or moderate unipolar depression. 
e. Antiemetic medications (except domperidone), myo-relaxing drugs and opioids. 
f. Dopaminergic medications, unless they have been used at stable doses for at least 4 weeks before 
screening and it is anticipated that the doses will not be changed throughout the trial. Efficacious 
medication for Parkinson's disease should not be discontinued for the sole purpose of the subject's 
enrolment into this clinical trial but must be maintained at stable dosage levels. 
g. Centrally acting anti-obesity drugs. 
h. TNF-alpha inhibitors. 
12. Pregnancy or lactation. Women of childbearing potential who intend to be pregnant during the next 
few months.  
13. Subjects protected by the law (legal guardianship). 
14. Subjects participating in any other clinical trial within 60 days prior to entry in this trial or still in the 
protected period imposed by a previous trial. 
15. Subjects working in an occupation requiring variable shift work or routine night shifts. 


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16. Subjects who plan to travel involving time zone changes. 
All above-mentioned exclusion criteria will be checked at VS1. 
At VS2 it will be checked if laboratory results, new AEs or new concomitant medication conflict with any 
of the exclusion criteria. 
At VR the following exclusion criteria will be re-checked: 5, 11-12, 15, 16. 
4.4. Screening Failures and Withdrawals 
4.4.1. Screening failures 
Screening failures will be all subjects who have been enrolled in the trial (i.e. ICF signed), but discontinue 
the trial prior to randomisation (at visit VR) due to whatever reason (withdraw consent, do not fulfil 
criteria, by decision of investigator, etc.). 
All subjects pre-screened, but not enrolled (i.e. no ICF signed), and all subjects enrolled (i.e. ICF signed) 
will be recorded in respective log forms. 
4.4.2. Withdrawals 
Subjects will be informed that they have the right to withdraw from the trial at any time, without prejudice 
to their medical care, and without having to justify their reasons and decision. Additionally, the 
investigator may discontinue the treatment of a subject at any time if he/she considers this to be in the 
subject’s best interest or if lack of compliance with recommendations has been noted.  
The investigator will decide on trial continuation after consideration of all available clinical elements 
presumed to impact on the subject’s safety. 
Subjects may withdraw or may be withdrawn from the trial for the following reasons: 
• 
at their own request (withdrawal of consent) 
• 
if in the investigator’s opinion, for reasons of safety or ethics, continuation in the trial would be 
detrimental to the subject’s well-being 
• 
major protocol deviations 
• 
treatment incompliance 
• 
prohibited concomitant therapy  
• 
adverse event 
• 
pregnancy 
• 
if the subject answered “yes” to point 4 and/or 5 of the C-SSRS. In this case the subject must be sent 
for psychiatric consultation 
• 
elevation of liver enzymes ALT or AST ≥ 5 times the upper limit of normal, or ALT or AST ≥ 3 times 
the upper limit of normal together with increased (total or conjugated) bilirubin ≥ 2 times the upper 
limit of normal 
• 
ECG signs of left ventricular hypertrophy, showing abnormality of at least one of the three indices 
listed below, confirmed by a cardiologist: 
o Sokolow-Lyon voltage (sum of amplitude of the S wave in lead V1 and the R wave in lead V5 or 
V6 ≥ 3.5 mV), or 
o Cornell voltage (S wave in V3 + R wave in aVL > 2.8 mV in men or > 2.0 mV in women), or 
o Modified Cornell (R wave in aVL > 1.1 mV) 
In this case, the subject must be referred to a cardiologist for further examinations. 


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• 
at the specific request of the sponsor 
In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject's medical records. 
The subject must be followed up to establish whether the reason was an adverse event, and, if so, this must 
be reported in accordance with the procedures in this protocol. 
As far as possible, all examinations scheduled for visit V3B must be performed on all subjects who receive 
IMP but do not complete the trial according to protocol (early discontinuation visit, EDV). The 
investigator must make every effort to contact subjects lost to follow-up.  
In addition, visit V3C must be performed within 7 ±1 days after EDV. 
Efforts will be made to try maintaining all subjects in the trial until completion. 
4.5. Subject Identification 
A 6-digit number will be used to identify the subjects. The first 3 digits of the number will correspond to 
the site number. For example: Subject 101-001 will be the number given to the first subject who signed 
an ICF at site 101. 
The reference to the full names will be made in the subject’s identification list which must be kept strictly 
confidential. Only site number, subject number and randomisation number (if applicable) should appear 
in the eCRF and questionnaires. Age will be provided in eCRF for demographics. In the eCRF the 
randomisation number will be associated to the subject number in order to allocate the randomised 
sequence of treatment period. 
Subjects will wear a subject card during the trial, stating that they participate in a clinical trial and 
providing a contact name and telephone number of the investigator in case of need or of an emergency. 
 


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5. 
TREATMENTS 
5.1. Investigational Medicinal Product (IMP) 
5.1.1. Test drug formulations 
THN102 is a combination drug constituted by modafinil 100 mg tablets over-encapsulated and flecainide 
capsules of 1 mg or 9 mg. Daily dosages are: Modafinil 200 mg and flecainide: 2 or 18 mg. 
 
Drug code: 
Modafinil (Modiodal® Teva) 
Dosage form: 
1 tablet of 100 mg, over-encapsulated (orange capsule) 
Excipients: 
Tablet: Lactose monohydrate, pregelatinised starch (maize), microcrystalline 
cellulose, croscarmellose sodium, Povidone K29/32, magnesium stearate. 
Capsule, filler: Gelatine, Swedish Orange, microcrystalline cellulose. 
Vials: 
Capsules will be provided into HDPE snap-cap vials containing 18 capsules each. 
Storage: 
15-25 °C (avoid exposure >25°C) 
 
Route:  
Oral 
Dose: 
2 capsules containing 100 mg each, at 8:00 h (± 1:00 h) in the morning.  
A 24-hour (± 1:00 h) interval between two consecutive doses is required. 
 
For subjects aged above 65 years: 
On the first, second and third day of each treatment period, 1 capsule will be taken. 
From the fourth to the last day of each treatment period, the regimen will be as 
described above. 
 
Drug code: 
Flecainide (manufactured by PCA, Central Pharmacy of the French Army) 
Dosage form: 
1 or 9 mg of flecainide powder per capsule (white capsule) 
Excipients: 
Tablet: Microcrystalline cellulose (Avicel PH112), magnesium stearate. 
 
Capsules: Hypromellose (HPMC) 
Storage: 
15-25 °C  
Route:  
Oral 
Vial: 
Capsules will be provided in HDPE snap-cap vials containing 18 capsules each. 
Dose: 
2 capsules containing 1 or 9 mg each, in the morning at the same time as modafinil. 
 
For subjects aged above 65 years: 
On the first, second and third day of each treatment period, 1 capsule will be taken. 
From the fourth to the last day of each treatment period, the regimen will be as 
described above. 
5.1.2. Reference drug formulations 
THN102 Placebo is a combination drug constituted by modafinil 100 mg placebo tablets over-
encapsulated and by flecainide placebo capsules. Daily dosages are: Modafinil 0 mg and flecainide: 0 mg. 
 
Drug code: 
Modafinil placebo 
Dosage form: 
1 tablet of 0 mg, over-encapsulated (orange capsule) 
Excipients: 
Tablet: Lactose monohydrate, pregelatinised starch (maize), microcrystalline 
cellulose, croscarmellose sodium, Povidone K29/32, magnesium stearate. 
Capsule, filler: Gelatine, Swedish Orange, microcrystalline cellulose. 
Vials: 
Capsules will be provided into HDPE snap-cap vials containing 18 capsules each. 
Storage: 
15-25 °C (avoid exposure >25°C) 
 
Route:  
Oral 


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Dose: 
2 capsules containing 0 mg each, at 8:00 h (± 1:00 h) in the morning 
A 24-hour (± 1:00 h) interval between two consecutive doses is required. 
 
For subjects aged above 65 years: 
On the first, second and third day of each treatment period, 1 capsule will be taken. 
From the fourth to the last day of each treatment period, the regimen will be as 
described above. 
 
Drug code: 
Flecainide placebo 
Dosage form: 
0 mg of flecainide powder per capsule (white capsule) 
Excipients: 
Tablet: Microcrystalline cellulose (Avicel PH112), magnesium stearate. 
 
Capsules: Hypromellose (HPMC) 
Storage: 
15-25 °C  
Route:  
Oral 
Vial: 
Capsules will be provided in HDPE snap-cap vials containing 18 capsules each. 
Dose: 
2 capsules containing 0 mg each, in the morning at the same time as modafinil 
placebo. 
For subjects aged above 65 years: 
On the first, second and third day of each treatment period, 1 capsule will be taken. 
From the fourth to the last day of each treatment period, the regimen will be as 
described above. 
 
5.1.3. Timing of IMP doses and administration 
IMP will be administered only to subjects included in this trial, following the procedures set out in the 
trial protocol.  
IMP (2 capsules modafinil or placebo plus 2 capsules flecainide or placebo; 4 capsules in total) will be 
administered in the morning. IMP will be swallowed before meal with 150 mL tap water at 8:00 h (± 1 h).  
For subjects aged above 65 years: 
On the first, second and third day of each treatment period, 1 modafinil and 1 flecainide capsule will be 
taken. From the fourth to the last day of each treatment period, the regimen will be as described above. 
The time of IMP intake will be recorded in the subject diary daily. 
Dose adjustments will not be permitted. 
In each treatment period, first IMP intake will take place on the day after IMP dispensation, i.e. on the day 
after visit VR, V1C or V2C, respectively.  
In each treatment period, last IMP intake will take place on the day of visit V1B, V2B or V3B, 
respectively. 
5.1.4. Labelling and Packaging  
 (for contact details, see Section 14.1) will be in charge for over-encapsulation, labelling, preparation 
of treatment period kits and trial supply management in accordance with the randomisation list. 18 
capsules will be packed into a vial (sufficient for 1 week, with 4 capsules as reserve). Modafinil and 
flecainide capsules will be packed in separate vials. 
The IMP vials, boxes and kits will be labelled individually according to allocation schedule, site, subject 
number, trial period and content. All labels will be in the respective language of the country and will be 
in accordance with local regulations. (Multi-language label booklets will be used.) Label terminology may 
vary according to local regulations, and country-specific remarks will be added as needed. Sample labels 
will be filed in the TMF. 


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5.1.5. Drug storage and distribution  
Clinical supplies will be stored at trial site for subjects recruited if a locked, dedicated cupboard with 
temperature control and logging is available. If not, the clinical supply should be stored at the hospital 
pharmacy. 
For each treatment period, the box contains two vials with 18 capsules of modafinil 100 mg or its placebo 
and two vials of 18 capsules of flecainide of the corresponding assigned dosage or its placebo. The boxes 
will be kept under lock until treatment dispensation to the subject. The subjects will be provided with 
sufficient IMP for the next treatment period as defined by the randomisation scheme. Dispensations will 
be done at the end of VR, V1C and V2C. 
Subjects must be instructed to return all the dispensed medication vials, boxes and packaging material at 
the visit scheduled at the end of each period (V1B, V2B, V3B) whatever the state (intact, empty or partially 
used vials). Treatment medications accountability and compliance should be done at V1B, V2B and V3B 
by the investigators or their designee. 
5.2. Randomisation and Blinding 
5.2.1. Randomisation 
Subjects will be randomised to receive all three treatments, according to one of the six possible sequences 
(see Table 3).  
The statistics department of the clinical CRO will prepare the randomisation list using SAS® in the version 
specified in the data management plan (DMP). Randomisation data will be kept strictly confidential, 
accessible only to authorised persons, until the time of unblinding. The randomisation scheme will be 
included in the clinical trial report for this protocol. 
The procedure will be as follows: 
• 
After a subject's preliminary eligibility is confirmed, the site will enter the subject into the eCRF 
system.  
• 
The eCRF system will send a notification to the randomisation coordinator at the clinical CRO. 
• 
The randomisation coordinator will allocate the subject to the randomisation code as follows: 
o He/she will assign each screened subject to the next available randomisation number from the 
randomisation list until the first screening failure of a subject with an assigned randomisation 
code is documented.  
o After such a screening failure has occurred, the randomisation coordinator will assign 
randomisation numbers to subjects by taking into account the number of subjects allocated to 
each sequence, to ensure the balance (manual randomisation). 
o At sites with an unused kit from a previous screening failure, any new eligible subject will be 
assigned the randomisation number corresponding to the unused kit (forced randomisation). 
• 
The randomisation coordinator will enter the randomisation code into the eCRF system and request 
the warehouse to send the treatment kit (labelled with the randomisation code) and the emergency 
unblinding envelope to the respective site.  
• 
The randomisation coordinator will document the status of all screened subjects and kits and will keep 
track of the balance between treatment sequences and unused kits available at the sites.  
• 
A subject will only be considered randomised after his/her eligibility has been confirmed at VR. 
5.2.2. Blinding 
Modafinil 100 mg capsules and modafinil placebo capsules will be identical in size, colour and 
appearance. The packaging and labelling will not allow for any distinction between them. 
Likewise, flecainide 1 mg capsules, flecainide 9 mg capsules and flecainide placebo capsules will be 
identical in size, colour and appearance. The packaging and labelling will not allow for any distinction 
between them. 


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During the trial, the subject and all personnel involved with the conduct and the interpretation of the trial, 
including the investigators, site personnel, and the sponsor’s staff, will be blinded to the treatment 
assignment. The randomisation schedule will be filed securely by the clinical CRO, in a manner such that 
blinding is properly maintained throughout the trial. Treatment assignment will not be available until the 
completion of the trial and until after final data review (clinical data base lock), except in the case of 
emergency. 
Emergency unblinding will be done via sealed emergency code envelopes. Unblinding will not to be done 
unless an actual emergency occurs, and knowledge of the subject’s treatment assignment affects his/her 
medical treatment. If possible, before breaking the blind the investigator consults with the medical monitor 
to ascertain the necessity of breaking the code. A record will be made of the date, time and reason for 
breaking the blind. Subjects with SUSARs will be unblinded for regulatory reporting by the CRO 
pharmacovigilance representative. Other trial personnel and the investigators will receive blind 
information on the SUSAR until the trial has been unblinded. 
The principal investigator at each trial site and the pharmacovigilance representative will be provided with 
individual sealed emergency envelopes containing treatment assignment to be maintained in locked area 
and to be opened only in case of a medical emergency. The integrity of these sealed envelopes will be 
checked by the CRA at the end of the trial.  
The allocation schedule will be transmitted electronically to the CRO in charge of secondary packaging. 
A secrecy agreement will be signed by the PK analyst and no individual data will be distributed or 
discussed with any other party until the database has been frozen and the code has been released. The 
pharmacists at trial site are blinded to trial treatment.  
All other groups involved in trial support will only have access to treatment assignment after delivering 
data planned as per protocol and after data freezing. Electronic transfer of allocation schedule to 
investigators, sponsor, CRO's trial manager, and to other parties will be performed after freezing of the 
database. All documents for blinding and for signature of secrecy agreements will be filed in the TMF. 
The set of envelopes from principal investigators at each trial site and from pharmacovigilance will be 
recovered at trial completion, inspected for integrity and destroyed by the sponsor. The integrity 
statements will be stored in the TMF. 
5.3. Clinical Supplies Accountability 
The investigator or pharmacist will document IMP dispense and return on a drug accountability form. 
This will be verified by the CRA and documented on the same form. In addition, the investigator or 
pharmacist will maintain a site inventory. 
Drug dispensation logs will be maintained throughout the trial at each visit and for each subject by site 
staff. Comparison between capsules count and eCRF as well as comparison between capsules count and 
subject diaries will be performed to obtain information on compliance. The originals of these log forms, 
along with the filled drug accountability form will be filed in the ISF and copies will be collected for the 
TMF. 
After reconciliation at the end of the trial, all unused IMP will be returned to the warehouse. 
5.4. Treatment Compliance 
The trial medication will be administered at home by the subject and to ensure adequate drug compliance 
is consequently a key issue. Instructions will be provided to the subject on respecting time schedule trying 
to maintain same time schedule throughout the trial and a 24-hour interval (± 1 hour) between daily doses.  


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5.5. Prior and Concomitant medication 
Efficacious medication for Parkinson's disease should not be discontinued for the sole purpose of 
the subject's enrolment into this clinical trial but must be maintained at stable dosage levels 
(exclusion criterion no. 11f). 
The following concomitant medication is prohibited during the trial and within 6 weeks before VS1: 
1. Neuroleptics, anxiolytics, anticonvulsants. Benzodiazepines and benzodiazepine-like drugs are only 
authorised if used regularly at stable indicated doses with an evening intake as sleep promoting agents. 
2. Psychostimulants (except caffeine if no abuse and stable consumption) such as, but not limited to, 
modafinil, methylphenidate, amphetamine. 
3. Antidepressants except if maintained at stable dose for at least 6 weeks prior to VS1 and anticipated 
to remain stable during the trial in subjects with mild or moderate unipolar depression, providing the 
treatment is well tolerated and devoid of orthostatic hypotension and QT prolongation as documented 
at screening. 
4. Antiemetic medications (except domperidone), myo-relaxing drugs and opioids. 
5. Antiarrhythmic drugs class I (see Section 14.3). 
6. Dopaminergic medications, unless they have been used at stable doses for at least 4 weeks before 
screening and it is anticipated that the doses will not be changed throughout the trial. 
7. 
Centrally acting anti-obesity drugs. 
8. 
TNF-alpha inhibitors. 
Co-prescription of CYP2D6 inhibitors, CYP3A4,5 or CYP2C19 substrates has to be closely monitored. 
The doses of such co-prescribed drugs have to be decreased as appropriate. The decision will be made by 
the investigator after consulting with the medical monitor, if necessary. A list of the most important 
CYP2D6 inhibitors and of CYP3A4,5 and CYP2C19 substrates is provided in Section 14.4. 
 
Sexually active women of child-bearing potential must be established on a contraceptive programme (see 
inclusion criterion no. 7). Since the effectiveness of steroidal contraceptives may be reduced when used 
with IMP, alternative or concomitant methods of contraception are recommended during the trial, and for 
two months after discontinuation of IMP. 
For more information, please refer to the Investigator's Brochure (Section 5.3, Drug-drug interactions; 
Sections 7 and 12.3 of Modafinil SmPC, and Section 8.1 of Flecainide SmPC). 
5.6. Lifestyle and Diet 
Subjects should be advised that driving ability, operation of machinery and work without a secure fit may 
be affected by adverse reactions such as dizziness and visual disturbances. 
There are no trial restrictions with respect to smoking. Moderate consumption of caffeine (tea, coffee, 
cola, energy drinks etc.) and alcoholic beverages (such as 200 mL of beer or 100 mL wine per day) will 
be permitted. Grapefruit consumption and quinine-containing drinks should be avoided. 
Additional information regarding contraindications, precautions and warnings concerning IMP are 
provided in the current version of the IB. [31] 
5.7. Further Treatment after the End of the Trial 
After the end of the trial, the subjects will be treated according to local standard practice. 


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6. 
ASSESSMENTS 
The schedule of tests performed is described in the trial flow chart (Page 12).  
All measurements performed in this trial are recognised standard methods. Therefore, no further details 
concerning reliability or relevance will be discussed here. 
6.1. Description of Trial Visits 
Seven on-site visits and five phone call visits are planned.  
Due to the PVT and MoCA assessments on-site visits should always start in the morning. 
Unscheduled (on-site or phone) visits at additional time points may be performed, if required. An 
administrative/logistic phone contact or on-site presence will not be documented as unscheduled visit in 
the eCRF. 
6.1.1. Visit VS1  
This screening visit 1 is an on-site visit and will take place between Day -15 and Day -7. 
The following procedures will be performed: 
• 
Informed consent 
• 
Hand out subject card 
• 
Demography (incl. height measurement) 
• 
Medical history, prior medication 
• 
Concomitant medication 
• 
Hoehn & Yahr staging 
• 
Check for eligibility 
• 
Adverse event collection 
• 
Safety laboratory (blood [including serology and blood coagulation], urine) 
• 
Pregnancy test (urine), for women of childbearing potential only 
• 
Vital signs (after 5 minutes of supine rest and after 2 minutes in standing position, i.e. 1 set) 
• 
Weight 
• 
12-lead ECG (10 min supine) 
• 
C-SSRS Screening version 
• 
Physical examination 
• 
ESS 
• 
MoCA 
• 
Issue actigraphy device (fully charged) 
• 
Issue subject diary (screening phase diary) 
 
6.1.2. Visit VS2 
This screening visit 2 is a phone call visit and will take place on Day -5 ±1. 
The following procedures will be performed: 
• 
Concomitant medication 
• 
Check for eligibility 
• 
Adverse event collection 
• 
Remind subject to wear actigraphy device 
 


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6.1.3. Visit VR  
This randomisation/baseline visit is an on-site visit and will per definition take place on Day -1.  
(Please note that there is no Day 0. The day after Day -1 is Day 1. Day 1 is the day of first IMP intake.) 
The following procedures will be performed: 
• 
Concomitant medication 
• 
Check for eligibility 
• 
Randomisation 
• 
IMP dispensation 
• 
Adverse event collection 
• 
Safety laboratory (blood, urine) 
• 
Pregnancy test (urine), for women of childbearing potential only 
• 
Vital signs (3 sets of orthostatic vital signs 15-20 min apart) 
• 
Weight 
• 
12-lead ECG (10 min supine) 
• 
C-SSRS Since Last Visit version 
• 
MDS-UPDRS 
• 
QUIP-RS 
• 
Physical examination 
• 
ESS 
• 
PVT at 10:00 h, 12:00 h, 14:00 h and 16:00 h (± 0:15 h each). If this PVT assessment schedule 
is too burdensome for the subject, it may be individually adapted to at least 3 assessments, with 
a time window of not less than 1 h between two PVT assessments. Once chosen, the timeframe 
should remain constant during the trial for each subject. Upload data 
• 
MoCA 
• 
Collect and charge actigraphy device 
• 
Read out actigraphy device, upload data 
• 
Issue actigraphy device (fully charged) 
• 
Issue subject diary (treatment phase diary) 
• 
Check subject diary (screening phase diary) 
• 
Collect subject diary (screening phase diary) 
• 
PK blood sample 
 
6.1.4. Visits V1A, V2A and V3A  
These actigraphy sensor visits are phone call visits and will take place  
• 
on Day 10 ±1 (V1A) 
• 
on Day 31 ±1 (V2A) 
• 
on Day 52 ±1 (V3A) 
 
The following procedures will be performed: 
• 
Concomitant medication 
• 
Adverse event collection 
• 
Remind subject to wear actigraphy device 
 
6.1.5. Visits V1B, V2B and V3B  
These end-of-treatment period visits are on-site visits and will take place  


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• 
on Day 14 ±2 (V1B) 
• 
on Day 35 ±2 (V2B) 
• 
on Day 56 ±2 (V3B) 
 
The following procedures will be performed: 
• 
Concomitant medication 
• 
IMP accountability, compliance check, collect IMP 
• 
Adverse event collection 
• 
Safety laboratory (blood, urine) 
• 
Pregnancy test (urine), for women of childbearing potential only 
• 
Vital signs (after 5 minutes of supine rest and after 2 minutes in standing position, i.e. 1 set) 
• 
Weight 
• 
12-lead ECG (10 min supine) 
• 
C-SSRS Since Last Visit version 
• 
MDS-UPDRS 
• 
QUIP-RS 
• 
Physical examination 
• 
ESS 
• 
PVT at 10:00 h, 12:00 h, 14:00 h and 16:00 h (± 0:15 h each) or individually adapted PVT 
schedule with the same timeframe as at VR. Upload data 
• 
MoCA 
• 
Collect and charge actigraphy device 
• 
Read out actigraphy device, upload data  
• 
Check subject diary (treatment diary) 
• 
Collect subject diary (treatment phase diary, V3B only) 
• 
PK blood sample 
In case of early discontinuation, the same procedures as required for V3B will be performed. 
6.1.6. Visits V1C and V2C  
These end-of-washout visits are on-site visits and will take place  
• 
on Day 21-1/+7 (V1C) 
• 
on Day 42-1/+7 (V2C) 
The washout periods can be extended from 1 week to 2 weeks, if this is more convenient for the subject.  
 
The following procedures will be performed: 
• 
Concomitant medication 
• 
IMP dispensation 
• 
Adverse event collection 
• 
Vital signs (3 sets of orthostatic vital signs 15-20 min apart) 
• 
12-lead ECG (10 min supine) 
• 
C-SSRS Since Last Visit version 
• 
ESS 
• 
PVT at 10:00 h, 12:00 h, 14:00 h and 16:00 h (± 0:15 h each) or individually adapted PVT 
schedule with the same timeframe as at VR. Upload data 
• 
MoCA 
• 
Issue actigraphy device (fully charged) 
• 
Issue subject diary (treatment phase diary) 
• 
Check subject diary (treatment phase diary) 
• 
Collect subject diary (treatment phase diary) 


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• 
PK blood sample 
 
6.1.7. Visit V3C  
This follow-up visit is a phone call visit and will take place between Day 63 ±1 or 7 ±1 days after EDV 
(whatever comes first). This visit is also mandatory for subjects who discontinue early. 
 
The following procedures will be performed: 
• 
Concomitant medication 
• 
Adverse event collection 
 
6.2. Baseline Assessments 
6.2.1. Demography 
The investigator will record demographic data, including (but not limited to) age, gender, race, and will 
measure height (also used for BMI calculation). 
6.2.2. Medical history, concomitant diseases 
In an interview, medical history will be evaluated by the investigator in order to determine whether the 
subject fulfils the inclusion criteria and meets none of the exclusion criteria. Concomitant diseases that 
might be present at VS1 must be recorded in the eCRF.  
Medical conditions that are diagnosed at VS1 will only be documented as adverse events, if they are 
known to have started or are suspected to have started after the ICF has been signed. All other medical 
findings at the medical examination at VS1 will be documented as medical history. 
6.2.3. Prior and concomitant treatments and lifestyle 
Any treatment that was given in addition to IMP during the trial is regarded as a concomitant treatment 
and must be documented on the appropriate pages of the eCRF, specifying drug taken, dose, route, 
start/stop date and reason for use. 
Therapies administered within 3 months before VS1 will also be documented in the eCRF. 
All concomitant drugs must be known to and approved by the investigator and should be maintained stable 
during the trial unless mandatory to increase or decrease the dose to ensure a better efficacy or a better 
safety for the subjects. All changes in therapy or in doses must be documented in the eCRF. The subject 
should mention all other drugs, including over the counter medication such as acetylsalicylic acid. 
Consumption of alcohol will be recorded in the eCRF at VS1, consumption of grapefruit products and 
quinine-containing drinks not. 
6.2.4. Modified Hoehn & Yahr stage 
The investigator will assess the subject's Hoehn & Yahr stage as follows: 
0 
No signs of disease. 
1 
Unilateral disease. 
1.5 
Unilateral plus axial involvement. 


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2 
Bilateral disease, without impairment of balance. 
2.5 
Mild bilateral disease, with recovery on pull test. 
3 
Mild to moderate bilateral disease; some postural instability; physically independent. 
4 
Severe disability; still able to walk or stand unassisted. 
5 
Wheelchair bound or bedridden unless aided. 
6.2.5. Calculation of glomerular filtration rate 
For the verification of exclusion criterion no. 9, the glomerular filtration rate will be calculated based on 
2009 CKD-EPI creatinine equation [32] as follows: 
GFR [mL/min/1.73 m2] =  
141 x min(SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if Black] 
SCr = standardised serum creatinine [mg/dL] 
κ = 0.7 (females) or 0.9 (males) 
α = -0.329 (females) or -0.411 (males) 
min(SCr/κ, 1) = indicates the minimum of SCr/κ or 1 
max(SCr/κ, 1) = indicates the maximum of SCr/κ or 1 
age [years] 
6.3. Safety Assessments 
6.3.1. Adverse events 
For adverse events see Section 7. 
6.3.2. Safety laboratory and pregnancy tests 
Serology, haematology, blood coagulation and biochemistry analyses will be performed by a central 
laboratory. Urinalysis (dipstick) and urine pregnancy test (women of childbearing potential only) will be 
performed by trial site staff on-site. For the list of parameters, see Section 14.2. 
For safety laboratory tests, approximately 10 mL of blood will be collected at each blood withdrawal.  
Laboratory values outside the normal ranges have to be assessed by the investigators if clinically 
significant abnormal or not clinically significant abnormal. 
Each change to clinically significant abnormal laboratory value during the trial has to be documented as 
an AE in the eCRF unless the measurement is identified to be caused by a laboratory error and unless the 
underlying disease causing the change to laboratory abnormality is already documented. Clinically 
significant abnormal laboratory values at VS1 not related to any already documented underlying disease 
have to be documented as medical history. 
6.3.3. Vital signs and weight 
Vital signs (systolic and diastolic blood pressure as well as heart rate) will be measured twice: after 5 
minutes supine rest and after 2 minutes in standing position (one set of supine and standing vital signs).  


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At VR, V1C and V2C three sets of supine and standing vital signs will be measured with 15-20 min 
intervals between the sets.  
Weight will be measured in street clothes without shoes. 
6.3.4. Electrocardiogram (ECG) 
The sponsor will provide the investigator with the ECG device that shall be used in this trial. Twelve-lead 
ECG will be recorded after 10 minutes in supine position. ECG reading will be performed centrally by the 
provider specified in Section 14.1 and will include  
• 
ECG measured parameters as intervals (PR, QRS, QT)  
• 
Pattern of change for PR, QRS and QT versus ECG from baseline  
• 
Derived ECG parameters (QTcF, heart rate)  
ECG will be recorded at VS1, VR, V1B, V1C, V2B, V2C and V3B. 
6.3.5. Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a tool that was developed to facilitate a prospective, systematic monitoring for the 
emergence of suicidal tendencies in clinical studies. It is used to compare the occurrence, severity, and 
frequency of suicide-related thoughts and behaviours during treatment in a clinical trial.  
The C-SSRS Screening version will be used at VS1 to obtain baseline data. The recall period will be set 
to 12 months / 1 year. Exclusion criterion no.6 will be met if the subject answers “yes” to items 4 and/or 
5 of the C-SSRS only referring to the last month before VS1. 
The C-SSRS Since Last Visit version will be used to capture changes in the subject’s status at VR, V1B, 
V1C, V2B, V2C and V3B. 
Subjects who answer “yes” to point 4 and/or 5 of the C-SSRS will be withdrawn from the trial and will 
be sent for psychiatric consultation. 
6.3.6. Movement Disorder Society-Sponsored Version of Unified 
Parkinson's Disease Rating Scale (MDS-UPDRS) 
The MDS-UPDRS is a comprehensive assessment of both motor and non-motor symptoms associated 
with Parkinson's disease. [33] It has four parts: 
• 
Part I (non-motor experiences of daily living, 13 items), further divided into: 
o Part IA focuses on complex behaviors and is completed by the investigator, based on interview 
with the subject 
o Part IB focuses on non-motor experiences of daily living and is completed by the subject 
• 
Part II (motor experiences of daily living, 13 items), completed by the subject 
• 
Part III (motor examination, 33 items), completed by the investigator 
• 
Part IV (motor complications, 6 items) completed by the investigator, based on interview with the 
subject.  
The MDS-UPDRS rates 65 items on a 5-point scale: normal (0), slight (1), mild (2), moderate (3) and 
severe (4). 
The MDS-UPDRS will be completed at baseline and at the end of each treatment period, i.e. at visits: VR, 
V1B, V2B and V3B. 
 


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6.3.7. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease – Rating Scale (QUIP-RS) 
The QUIP-RS is a validated tool designed to measure the severity of symptoms of impulse control 
disorders (ICDs) and related disorders. [34] The QUIP-RS consists of four primary questions, each applied 
to four ICDs (compulsive gambling, buying, eating and sexual behaviour) and three related disorders 
(medication use, punding and hobbyism). The QUIP-RS uses a 5-point Likert scale (score 0-4 for each 
question) to rate the severity of each symptom based on its weekly frequency. To be applicable in this 
trial, the standard 4-week recall period will be reduced to one week. 
The total ICD score ranges from 0 to 64, and the total QUIP-RS score for all ICDs and related disorders 
ranges from 0 to 112. 
The QUIP-RS will be provided in a local language. The investigator will complete the scales based on 
interview with the subject.  
The QUIP-RS will be completed at baseline and at the end of each treatment period (visits: VR, V1B, 
V2B and V3B). 
6.3.8. Physical examination 
Physical examination includes an examination of the organ systems head, neck, eyes, ear-nose-throat, 
heart, respiratory, gastrointestinal, hepatic, urogenital, musculoskeletal, vascular, lymphatic, 
dermatologic, central-nervous system (CNS) and psychiatric. 
6.4. Efficacy Assessments 
6.4.1. Epworth Sleepiness Scale (ESS) 
The subject will complete the Epworth Sleepiness Scale (ESS, 1-week recall period). The questionnaire 
will be provided in local language. Site staff will enter ESS data into the eCRF. 
6.4.2. Psychomotor Vigilance Test (PVT) 
The psychomotor vigilance test is an objective tool used to measure the subject's behavioural alertness. 
[35] It is a visual test which involves measuring  
• 
Mean response time (ms) 
• 
Number of lapses 
• 
Number of total errors 
The PVT requires no training, only a brief explanation of the procedure to the subject prior to the start of 
the test. It will be performed in the 'on' state. 
PVT will be performed at 10:00 h, 12:00 h, 14:00 h and 16:00 h (± 0:15 h each). If this PVT assessment 
schedule is too burdensome for the subject, it may be individually adapted to at least 3 assessments, with 
a time window of not less than 1 h between two PVT assessments. Once chosen, the timeframe of PVT 
assessments should remain constant during the trial for each subject. 
The sponsor will provide the investigator with a PVT-192 device to perform a 3-minutes PVT and a 
notebook computer to read out data. 
6.4.3. Montreal Cognitive Assessment (MoCA) 
The MoCA is a brief screening instrument to detect mild cognitive impairment. It is a paper-and-pencil 
tool that requires approximately 10 minutes and will be administered by the investigator. It will be 


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performed in the 'on' state. The MoCA assesses multiple cognitive domains including attention, 
concentration, executive functions, memory, language, visuospatial skills, abstraction, calculation and 
orientation. One part of the paper questionnaire will be completed by the subject, another part will be 
completed by the investigator. Site staff will enter MoCA data into the eCRF. 
The MoCA questionnaire will be provided in local language. To decrease possible learning effects, the 
three (equivalent) versions 7.1, 7.2 and 7.3 will be used in alternation. 
MoCA should be performed in the morning. 
MoCA scores range between 0 and 30. A score of 26 or over is considered to be normal.  
6.4.4. Actigraphy assessment 
Actigraphy is a non-invasive method of monitoring a person's rest and activity cycles. The movements the 
actigraphy sensor undergoes are continually recorded.  
The sponsor will provide the investigator with actigraphy sensors for the trial subjects and a notebook 
computer to read out data. The actigraphy data will be transferred to 
 
), where they will be further processed and stored. 
Actigraphy assessments will be performed for 3 days prior to baseline and for 3 days at the end of each 
treatment period. At phone call visits VS2, V1A, V2A and V3A, trial staff will call the subjects and remind 
them to put on their actigraphy sensor bracelet and wear it until the next on-site visit. 
6.4.5. Subject diaries 
The paper-based subject diaries are intended for the daily documentation of 
• 
Get-up time  
• 
Total time (hours) slept last night 
• 
Wake-up periods during night sleep 
• 
Time of drug intake (except screening phase diary) 
• 
Number of capsules taken (except screening phase diary) 
• 
Somnolence episodes 
• 
Diurnal involuntary sleep attacks 
• 
Voluntary naps 
• 
Number of caffeinated drinks 
• 
Going-to-bed time 
The diaries will be translated in the local languages of the countries involved. Only the subject is allowed 
to make any entry in the diaries. In case of difficulties with writing, however, a caregiver may help. 
The subject will complete four paper diaries: One screening phase diary (started at VS1, without time of 
IMP intake and number of capsules taken) and treatment phase diaries (started at VR, V1C and V2C) for 
each treatment period. The subject has to bring the diaries for inspection by the investigator at all visits. 
The screening phase diary will be collected at VR, the treatment phase diaries will be collected at V1C, 
V2C and V3B. 
Thus, the diaries will be completed continuously from VS1 to V3B, i.e. also during the washout periods 
after treatment periods I and II. 


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6.5. Pharmacokinetics (PK) 
For PK laboratory tests, approximately 4.5 mL of blood will be collected at each blood withdrawal. The 
sample will be taken when the subject arrives on the site. The times of blood withdrawal must be recorded. 
Modafinil and flecainide concentrations in plasma will be measured by a central laboratory (for contact 
details, see Section 14.1) using a validated LC-MS/MS method.  
 


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7. 
ADVERSE EVENT, PREGNANCY AND EMERGENCY 
7.1. Adverse Event (AE)  
7.1.1. Definition of an adverse event 
An adverse event is any untoward medical occurrence in a clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
AEs can be symptoms, signs, or clinically relevant laboratory abnormalities occurring during the course 
of the trial. 
All other medical conditions, which are present at VS1, should not be considered as AEs unless a 
worsening in severity or frequency has occurred during the trial. These medical conditions should be 
adequately documented on the appropriate page of the eCRF. 
When reporting abnormal laboratory results on the AE pages of the eCRF, a clinical diagnosis should be 
recorded rather than the abnormal value itself if this is available (e.g. “anaemia” rather than “decreased 
red blood cell count” or “haemoglobin = 10.5 g/dL”). 
In case of surgical or diagnostic procedures, the condition/illness leading to such a procedure is considered 
as the AE rather than the procedure itself. 
7.1.2. Severity assessment 
The investigator must systematically assess the severity of adverse events according to the following 
definitions: 
• 
Mild: a type of adverse event that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily living. 
• 
Moderate: a type of adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research participant. 
• 
Severe: a type of adverse event that requires intensive therapeutic intervention. The event interrupts 
usual activities of daily living, or significantly affects clinical status. The event possesses a significant 
risk of harm to the research participant and hospitalisation may be required. 
Changes in the severity of an AE should be documented as a new AE. Adverse events characterised as 
intermittent requires documentation of the onset and duration of each episode. 
7.1.3. Relationship assessment 
The investigator must systematically assess the relationship of adverse events to the IMP using the 
following definitions: 
• 
Unrelated: A clinical event with no evidence of any causal relationship. 
• 
Unlikely: A clinical event, including laboratory test abnormality, with a temporal relationship to drug 
administration which makes a causal relationship improbable, and in which other drugs, chemicals or 
underlying disease provide plausible explanations. 
• 
Possible: A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the drug, but which could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear. 
• 
Probable: A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, 
and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required to fulfil this definition. 


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• 
Definite: A clinical event, including laboratory test abnormality, occurring in a plausible time 
relationship to drug administration, and which cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically 
plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory 
rechallenge procedure if necessary. 
The relationship to IMP can be modified during the trial or AE assessment. For example, although an AE 
may rate only as “possibly” related to IMP soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably”. Changes in the assessment of relationship to IMP should 
be clearly documented. 
Mapping to the two categories “related” and “unrelated”: The categories “unrelated” and “unlikely” will 
be mapped to “unrelated”, the categories “possible”, “probable” and “definite” will be mapped to 
“related”. 
7.1.4. Procedures for reporting of adverse events 
Assessing of adverse events 
Data on AEs will be obtained at scheduled or unscheduled trial visits, based on information spontaneously 
provided by the subject and/or through questioning of the subject. AE data may also be obtained from 
subject’s diary cards, but information thus collected must be reviewed and assessed medically before it is 
transcribed to the eCRF. 
If a subject is seen by a physician not involved in the trial because of an adverse event, the investigator 
should make every effort to contact the treating physician in a timely manner in order to obtain all 
information necessary to appropriate reporting of the event. 
Recording of adverse events 
Complete description of all adverse events must be available in the source documents. 
All AEs including local and systemic reactions should be captured on the appropriate pages of the eCRF.  
Information to be recorded, based on above assessment criteria, includes event description, its duration 
(time of onset and time of resolution), its severity, whether it is considered serious (and if so the criterion 
satisfied), its relationship to IMP, any action taken (concerning the IMP or other) and its outcome.  
Any AE that is still ongoing after final visit will be left as ongoing in the eCRF. However, the investigator 
will continue to follow up ongoing SAEs and record information in the source documents and on the 
Follow-Up SAE Form, until resolution or no further improvement can be expected. 
AEs must be recorded on the eCRF according to the following guidelines: 
• 
Whenever possible, recognised medical terms should be used to describe an AE rather than 
colloquialism (e.g. “influenza” rather than “flu”) and abbreviations should be avoided. 
• 
The description of an AE should use a specific clinical diagnosis, if this is available, rather than a 
list of component signs or symptoms (e.g. “congestive heart failure” rather than “dyspnea, rales 
and cyanosis”). 
• 
Signs and symptoms that are not linked to an identified disease or syndrome, or for which an 
overall diagnosis is not available, should be reported separately, as individual AEs. 
• 
Provisional diagnosis (e.g. “suspected myocardial infarction”) is acceptable but should be 
followed up to a definite diagnosis if finally available. 
Reporting of adverse events 
Complete and accurate data on all AEs experienced, for the duration of the reporting period, will be 
reported on an ongoing basis in the AE pages of the eCRF. 


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The period of observation for the collection of AEs extends from the time when the subject gives informed 
consent until the date of final visit.  
Serious adverse events occurring after a subject has taken the last dose of IMP will be collected until the 
date of final visit, regardless of the investigator's opinion of causation. Thereafter, SAEs are not required 
to be reported unless the investigator feels the events were related to either IMP administration or to a 
protocol procedure. 
All AEs with onset or worsening after first intake of IMP until 7 days after last intake of IMP are defined 
as treatment emergent. 
If a subject is documented as lost-to follow-up, ongoing/unknown outcome AEs will not be followed up. 
For screening failure subjects, new AEs and updates must be recorded in the source and trial documents 
until the date the subject is determined to be a screening failure. Beyond this date, only SAEs will be 
followed up by CRO’s pharmacovigilance representative.  
7.2. Serious Adverse Event (SAE) 
7.2.1. Definition of a serious adverse event  
A serious adverse event (SAE) is defined as an AE which at any dose meets one of the following 
conditions: 
• 
Death during the period of protocol defined surveillance, i.e. the AE causes or contributes to the 
death. In case of fatality, the cause of death is considered as the AE, and the death is its outcome. 
• 
Life threatening event (defined as a subject at immediate risk of death at the time of the event), 
i.e. the AE places the subject at immediate risk of death (the definition does not apply to an AE 
that hypothetically might cause death if it was more severe). 
• 
An event requiring inpatient hospitalisation or prolongation of existing hospitalisation during the 
period of protocol defined surveillance, i.e. the AE requires at inpatient hospitalisation or prolongs 
a hospitalisation beyond the expected length of stay.  
• 
Hospital admissions are not to be considered as SAE according to this criterion in the following 
purposes: surgery planned before trial entry, social reasons, normal disease management 
(including treatment adjustment), if the protocol procedures or the standard management of the 
disease under study requires planned hospitalisations.  
• 
Results in a persistent or significant disability/incapacity, i.e. the AE resulted in a substantial 
disruption of the subject’s ability to conduct normal activities. 
• 
Any other important medical condition, i.e. AE that may not immediately result in death, be life 
threatening, or require hospitalisation, but is clearly of major clinical significance. Based upon 
appropriate medical judgment, the event may jeopardise the subject or may require medical or 
surgical intervention to prevent one of the serious outcomes listed above. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasia or convulsions that do not result in inpatient hospitalisation, or 
the development of drug dependency or drug abuse.  
Any serious adverse event requires an expedited reporting to the pharmacovigilance delegate regardless 
of its relationship to the IMP. 
7.2.2. Definitions of Suspected Unexpected Serious Adverse Reactions 
(SUSAR) 
Suspected unexpected serious adverse reaction (SUSAR) is an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information (e.g. investigator’s brochure for an 
unauthorised investigational product or summary of product characteristics for an authorised product). 


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7.2.3. Procedures for reporting of SAEs and SUSARs 
All serious adverse events must be recorded on the SAE report form, followed through resolution by the 
investigator. 
The investigator must complete the SAE report form and notify the CRO’s pharmacovigilance delegate, 
be it a new SAE or new information on a previously reported SAE (i.e. so-called SAE follow-up), within 
the following timelines: 
• 
The investigator must report all SAEs to the CRO’s pharmacovigilance delegate within 24 hours 
of identifying the SAE. 
• 
Other supporting documentation of the event may be requested by CRO’s pharmacovigilance 
delegate and should be provided as soon as possible. 
• 
All reportable SAEs will be followed until satisfactory resolution or until the investigator deems 
the event to be chronic or the subject to be stable.  
The SAE report form must be sent directly to the CRO’s pharmacovigilance delegate by electronic 
mail or facsimile as specified below: 
 
 
 
 
  
 
 
For any new SAE, the following minimum information is required as initial notification: 
• 
Identification of the investigator, 
• 
Subject identification details (subject number) 
• 
IMP details (name, dose(s), route and date(s) of administration, indication) 
• 
Diagnosis of the event (or an outcome) with the description (or a brief description of signs/ 
symptoms/clinical course if the diagnosis is not available) and the date of onset 
• 
Reason(s) for considering the event as serious 
• 
Relationship of the event with the IMP or with the trial procedure (i.e. the causality according to 
the investigator). 
Information about SAEs and important medical conditions with any relevant ongoing/unknown outcomes 
will be followed-up until resolution, even if eCRFs and database will no longer be updated. SAEs 
occurring after a subject has taken the last dose of trial drug will be collected until final study visit, 
regardless of the investigator's opinion of causation. Thereafter, serious adverse events are not required to 
be reported unless the investigator feels the events were related to either IMP administration or a protocol 
procedure.  
7.2.4. Procedures for regulatory reporting of serious adverse events 
Following notification by the investigator, sponsor or designee will report events that are both serious and 
unexpected (i.e. using the current version of the THN102 IB at the time of SAE reporting as reference) 
and that are associated with IMP to the competent authorities (CAs) in expedited reporting. Unblinding 
will be performed as described in Section 5.2.2 by opening the individual sealed envelope for the involved 
subject. 
Moreover, any other new information that might influence the benefit-risk assessment of the IMP or that 
would be sufficient to consider changes in IMP administration or in the overall conduct of the clinical trial 
necessitate an expedited reporting to the CAs as well. 


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CAs should be notified of any expedited reporting within the required timelines as specified in ICH-E2A: 
fatal and life-threatening events within 7 calendar days (by phone/fax/writing/electronic communication) 
after first knowledge by CRO’s pharmacovigilance delegate who will issue a complete report within 8 
additional calendar days, with copy to investigator, CRA, CRO's trial manager, and sponsor. All other 
serious adverse events and SUSARs must be filed in writing within 15 calendar days after first knowledge 
by CRO’s pharmacovigilance delegate.   
All serious adverse events will be reported to the CAs in the development safety update report (DSUR) 
annually, if appropriate. 
In accordance with the ICH GCP guidelines, the responsible person for pharmacovigilance on behalf of 
the sponsor Theranexus will inform the investigators of findings that could affect adversely the safety of 
the subjects, impact the conduct of the trial, or alter the IEC/IRB’s approval/favourable opinion to continue 
the trial. 
In particular, sponsor or designee will inform the investigators of SUSARs and serious adverse events that 
are considered to be related to the administered IMP. The investigators will keep copies of these safety 
reports in the investigator site file (ISF). National regulations with regards to safety reports notifications 
to investigators will be taken into account.  
Unless clearly defined otherwise by national or site-specific regulations and duly documented, the clinical 
CRO will promptly notify the concerned IEC/IRB of any safety reports provided by the 
pharmacovigilance delegate and provide copies of all related correspondence to the CRA and the CRO's 
trial manager.  
7.3. Pregnancy 
Women of childbearing potential (defined as not surgically sterile or less than 2 years postmenopausal), 
must use a highly effective method of contraception, and must continue for the duration of the trial (and 
for 2 months after participation in the trial). Highly effective methods of contraception include: hormonal 
contraception associated with inhibition of ovulation (combined estrogen/progestogen: oral, intravaginal, 
transdermal; progestogen-only: oral, implanted, and injected) in conjunction with a barrier method 
(preferably male condom). Highly effective methods further include intrauterine device (IUD), 
intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner (provided 
that the partner is the sole sexual partner of the subject and the vasectomised partner has received medical 
assessment of the surgical success) and sexual abstinence, i.e. when this is in line with the preferred and 
usual lifestyle of the subject.  
Women of child-bearing potential will undergo sensitive urinary pregnancy tests (hCG, human chorionic 
gonadotropin). 
Pregnancy discovered during the clinical trial must lead immediately to exclusion (if at screening) or 
withdrawal of the subject. 
If the subject has already received IMP, the pregnancy will be documented on a pregnancy report form. 
The case must be reported within 24 hours of knowledge to the CRO’s pharmacovigilance delegate or the 
CRA. The subjects will be asked to report also pregnancies within 3 months after (regular or premature) 
termination of the trial to the investigator. 
The investigator must follow up on pregnancies discovered after IMP administration until the end of 
pregnancy to document the outcome on the pregnancy outcome report form. 
7.4. Emergency 
In case of emergency situations, the investigator should contact first his/her assigned CRA, and in case of 
no answer the CRO's trial manager and/or the sponsor's trial manager. 
Emergency identification of IMP:  


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Since this trial is blinded for treatment periods I, II, and III, two sets of individual sealed randomisation 
envelopes with treatment code (individual sealed envelopes with scratch labels for disclosure of treatment) 
will be prepared. One set will be delivered to the principal investigator at each site and one full set to the 
CRO's medical monitor prior to trial start.  
In case of urgent need during the trial, the envelope pertaining to the involved subject may be opened by 
the investigator in case of an SAE for which knowledge of exact treatment may be useful for medical 
decision or for treatment. Such an event must be documented by the investigator by signing and dating 
the envelope (including precise time) and indicating the reason for breaking the code on the appropriate 
form. Efforts must be made to reach the medical monitor before undertaking this step. All envelopes must 
be retrieved at trial completion from trial site by the CRA and inspected for integrity. All envelopes from 
investigator, intact or opened, will be filed in the TMF. 


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8. 
STATISTICAL PROCEDURES 
Prior to freezing the database, an overall Statistical Analysis Plan (SAP) will be prepared by the 
statistician. The SAP will be signed by the involved statistician and the sponsor prior to unblinding. 
8.1. Analysis Variables 
8.1.1. Safety variables 
1. Adverse events 
2. Safety laboratory 
3. Vital signs change 
4. Electrocardiogram assessments 
5. Columbia-Suicide Severity Rating Scale (C-SSRS) 
6. MDS-UPDRS 
7. QUIP-RS 
8.1.2. Efficacy variables 
Key Efficacy Endpoint 
8. Mean ESS score change from baseline at the end of each treatment period 
Secondary Efficacy Endpoints 
9. ESS score responder rate, defined as the proportion of patients with at least 25% ESS improvement 
from baseline, at the end of each treatment period 
10. Absence of residual somnolence, i.e. ESS < 11 at the end of each treatment period 
11. Psychomotor Vigilance Test (PVT) variables change from baseline at the end of each treatment period 
12. MoCA score change from baseline at the end of each treatment period 
13. Actimetry change (inactivity) from baseline at the end of each treatment period 
14. Number and duration of diurnal involuntary sleep attacks (subject diaries) change from baseline at the 
end of each treatment period 
15. Episodes of somnolence (subject diaries) change from baseline at the end of each treatment period 
8.1.3. Pharmacokinetic variables 
See Section 8.3.3. 
8.2. Trial Populations 
• 
The Safety Set (SS) includes all subjects who have received IMP at least once. 
• 
The Full Analysis Set (FAS) includes all randomised subjects with an evaluable ESS score at the end 
of at least one treatment period. The efficacy analyses will be conducted on the FAS. 
• 
The Per Protocol (PP) set includes all subjects who have completed the trial without major protocol 
deviation. Major and minor violations will be defined in the SAP. The main secondary endpoints 
(ESS, PVT and cognition) will be analysed with the PP set to demonstrate robustness of the primary 
analysis.  


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• 
The PK analysis set will include all subjects who have received treatment as per protocol (even if the 
trial was not completed) and who present no major protocol deviations with an impact on PK. 
 
8.3. Statistical Methods 
Details of the planned analyses will be described in the SAP. Some important features are listed below: 
• For all analyses, the results will be pooled and presented by treatment and over time. Graphical 
representations will be done for individual subject data and for treatment means ± SD over time. 
• Efficacy data will be analysed according to the treatment as randomised. Safety and pharmacokinetic 
data will be summarised according to the actual treatment received. 
• Continuous (quantitative) variables will be tabulated using standard descriptive statistics (number of 
observations, mean, standard deviation, median, minimum and maximum values, for efficacy and some 
safety parameters, with geometric mean and geometric CV) if appropriate. Continuous variables may 
be categorised into grouped intervals for analysis; in which case frequencies and percentages will also 
be presented.  
• Categorical (qualitative) variables will be tabulated using frequencies and percentages. 
 
8.3.1. Efficacy 
Continuous efficacy endpoints – the change from baseline at each key visit (end of treatment period I, II, 
and III) in ESS, PVT and MoCA - will be analysed using a mixed linear regression model. The model will 
include the treatment, period, treatment by period interaction, sequence, and baseline scores as fixed 
effects, and the subject nested within sequence as a random effect.  
Categorical efficacy endpoints – absence of residual somnolence and ESS responder status at each key 
visit – will be analysed using a mixed effects logistic regression model, with the treatment, period, 
treatment by period interaction, sequence, and baseline scores as fixed effects, and the subject nested 
within sequence as a random effect. 
Treatment least square means and mean differences will be reported with their standard errors and 95% 
confidence intervals. The significance of the differences between Treatment A (THN102 Placebo), 
Treatment B (THN102 200/2) and Treatment C (THN102 200/18) will be assessed with a contrast t-test 
at the two-sided 5% level. 
Handling of missing values/censoring/discontinuations: Subjects who misused their planned treatments 
or doses or have missing outcome measurements will not be excluded from the primary analysis in the 
FAS. Under the assumption that outcomes are missing at random, the mixed-model can propagate 
uncertainty due to missing data into estimates of treatment efficacy and other quantities of interest. Hence, 
missing data will not be imputed or replaced prior to the analysis. 
Supportive analysis: The same analysis will be repeated on the PP set, to assess robustness of the analysis 
of the variables from ESS and PVT and possibly on other efficacy results. Subgroup analyses may be 
performed to investigate the effect of the main demographics (age, gender) and disease characteristics (in 
term of daily sleepiness extent, and cognitive impairment) on the efficacy outcomes. 
The presence of a significant treatment by period interaction term in the main model may indicate a 
residual treatment (carryover) effect. In case of a significant treatment by period interaction, period I 
results will be analysed separately, and further analyses will be performed to explore the carry-over 
effects. The methods for evaluation of carryover effects will be defined in the SAP. 
8.3.2. Safety 
Safety parameters will be analysed as follows: 


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Vital signs: All vital signs data will be listed by treatment, subject, and visit/time and will be flagged vs. 
predefined clinical normal range. The mean value of vital sign parameter assessments during a visit will 
be summarized. Summary statistics will be provided by treatment and visit/time. Shift tables will be 
provided for vital sign abnormality change from baseline to endpoint within each treatment period. 
ECG parameters: All ECG parameters data will be listed by treatment, subject, and visit/time and 
abnormalities will be flagged vs. predefined clinical normal range. Summary statistics will be provided 
by treatment and visit/time.  
A shift table will be prepared to document QT change and distribution vs. baseline. 
C-SSRS: C-SSRS score data will be listed by treatment, subject, and visit/time. Summary statistics will 
be provided by treatment and visit/time.  
QUIP-RS: QUIP-RS score data will be listed by treatment, subject and visit/time. Summary statistics will 
be provided by treatment and visit/time. 
MDS-UPDRS: MDS-UPDRS score data will be listed by treatment, subject and visit/time. Summary 
statistics for each part of the MDS-UPDRS as well as the total score will be provided by treatment and 
visit/time. 
Clinical laboratory evaluations: All laboratory data will be listed by treatment, subject, and visit/time 
and abnormalities will be flagged vs. common normal range if considered by investigator as clinically 
relevant. Summary statistics will be provided by treatment and visit/time. Shift tables will be provided for 
clinical laboratory variables’ change from baseline to endpoint. 
Adverse events: All information obtained on adverse events will be displayed by treatment and subject 
after coding with pertinent MedDRA version. All adverse events and related adverse events will be 
presented. The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. An adverse event starting in one period and continuing 
into the next period is counted only in the onset period. A subject with multiple adverse events within a 
body system is only counted once towards the total of this body system. 
Concomitant medications / Significant non-drug therapies: All concomitant therapies will be coded 
by WHO version and listed by treatment group and subject. 
8.3.3. Pharmacokinetics 
As soon as they are available but only after database has been frozen, analytical determinations will be 
sent by e-mail (Microsoft Excel® file) by the bioanalytical center of 
 to the sponsor's 
PK expert (with copy to Theranexus, CRO's trial manager). All the transmission of data must be done in 
blinded condition up to the reception of the certificate of database lock by CRO. 
Subsequently, plasma concentrations will be processed for PK data generation.  
For the calculation of the PK parameters and characteristics the following rules are usually applied:  
• 
All the plasma concentrations validated by the bioanalytical laboratory and provided to the 
pharmacokineticist will be used for the PK analysis. 
• 
The actual blood sampling time points related to the preceding administration will be used. 
• 
At time points in the lag-time between time zero and the first concentration equal or above LLOQ 
(lower limit of quantification), concentrations below LLOQ will be set to zero. Concentrations 
below LLOQ between two concentrations equal or above LLOQ will be set to half the LLOQ. 
Trailing concentrations below LLOQ will not be used in calculations.  


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• 
For plasma concentration above the upper limit of quantification and reported as ALQ (above limit 
of quantification) in the final plasma concentration tables, ALQ will be replaced by the first 
measurement for the PK analysis. 
• 
Not reported concentration will be excluded from the PK analysis. 
Plasma concentrations reached at steady state will be presented for modafinil and for flecainide for each 
visit, considering time after last IMP intake. 
Concentration-time data will be listed per treatment and subject for modafinil and for flecainide. Plasma 
concentrations and time post IMP intake will also be plotted to assess range of exposure at steady state for 
each treatment and to assess reliability of prediction made by extrapolation from phase I studies for 
flecainide. 
Further details of the pharmacokinetic analyses will be defined in the SAP. 
8.4. Interim Analysis 
No formal interim analysis is planned. 
8.5. Sample Size Justification 
For the purpose of sample size planning ESS is considered to be the key efficacy endpoint. Solid 
information on the expected difference between placebo and THN102 dose and the associated intrasubject 
variance are not available. Using results reported in Adler et al. [5] as a rough orientation an effect size of 
0.40 may constitute a conservative estimation for the comparison of the high THN102 dose with placebo. 
A sample size of 54 subjects will have a power of 82% to detect this effect size based on a paired t-test 
with a 0.05 two-sided significance level. To account for drop outs 60 subjects will be randomised. 


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9. 
ETHICAL AND LEGAL ASPECTS  
9.1. Good Clinical Practice 
This trial will be conducted in compliance with the protocol, good clinical practice (GCP) and the 
applicable regulatory requirements. 
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and documentation of 
this trial, are designed to ensure that investigators, sponsor, CRO’s pharmacovigilance delegate, CRAs 
and CRO's trial manager all abide by the principles of GCP, ICH guidelines and all applicable international 
and local regulations as well as the ethical principles laid down in the current revision of the Declaration 
of Helsinki.  
9.2. Delegation of Investigator Responsibilities 
The investigator should ensure that all persons assisting with the trial are adequately informed about all 
relevant trial procedures and well-trained on the protocol, any amendments to the protocol, the trial 
treatments, and their trial-related duties and functions. 
Each investigator should maintain a list of sub-investigators and other appropriately qualified persons to 
whom he/she has delegated significant trial-related duties. 
9.3. Subject Information and Informed Consent 
Before being admitted to the clinical trial, the subject must consent to participate after the nature, scope, 
and possible consequences of the clinical trial have been explained in a form understandable to him/her. 
An informed consent document that includes both information about the trial and the consent form will 
be prepared and given to the subject. This document will contain all elements required by law and 
sponsor’s requirements. The document must be in a language understandable to the subject and must 
specify who informed the subject.  
After reading the informed consent document, the subject must give consent in writing. The subject's 
consent must be confirmed at the time of consent by the personally dated signature of the subject. It is not 
considered appropriate to allow a subject who is legally incompetent to enter this trial under the coverage 
of the subject's legally authorised representative. 
A copy of the signed informed consent document must be given to the subject.  
The investigator will not undertake any measures specifically required for the clinical trial purposes until 
valid consent has been obtained. 
9.4. Confidentiality 
Only the subject number will be recorded in the eCRF and transfer documents (no initials), and if the 
subject name appears on any other document (e.g. ECG, laboratory report, pathologist report), it must be 
obliterated before a copy of the document is supplied to other parties. The subjects will be told that 
principal investigator and his/her staff, CRO’s staff, IEC/IRB, regulatory authorities, and representatives 
of the sponsor may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in accordance with 
all applicable data protection laws. 
Biological samples collected during the trial will be used for assays specifically described in the protocol. 
The samples will be destroyed after approval of the clinical trial report (CTR) upon written request. 
The investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 


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9.5. Protocol Amendments 
No signee of this protocol (coordinating investigator, principal investigator, sponsor), nor the CRO's trial 
manager will alter this trial protocol without obtaining the written agreement of the other parties. Once 
the trial has started, amendments should be made only in exceptional cases. The changes then become part 
of the trial protocol and request a protocol amendment. 
9.6. Approval of the Trial Protocol and Amendments 
Before the start of the trial, the clinical CRO will submit to the IEC/IRBs and the competent authorities 
(CAs) all relevant trial documents. The trial will not start until authorisation by CAs and by IEC/IRBs 
have been received in writing and until the administrative requirements and workload (grid costs) have 
been discussed with the hospital administration and the agreements have been signed. 
Trial medication can only be supplied to the investigator after documentation on all ethical and legal 
requirements for starting the trial has been received by the trial CRA. This documentation must also 
include a list of the members of the IEC/IRB and their occupation and qualifications. The opinion given 
by the IEC/IRB should specify the trial title, trial code, trial site, amendment number if appropriate and 
any other documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. 
Before the first subject is enrolled in the trial, all ethical and legal requirements must be met. 
The IEC/IRB and, if applicable, the authorities must be informed of all subsequent protocol amendments, 
in accordance with legal requirements. Amendments must be evaluated to determine whether formal 
approval must be sought and whether the informed consent document should also be revised. 
The investigator must keep a record of all communication with the IEC/IRB. This also applies to any 
communication between the investigator and the authorities. 
9.7. Ongoing Information for the Independent Ethics Committee / 
Institutional Review Board 
The responsible IEC/IRB will be informed by the clinical CRO of all subsequent protocol amendments 
and of SUSARs occurring during the trial that are likely to affect the safety of the subjects or the conduct 
of the trial. 
Protocol amendments referring to logistical or administrative changes (non substantial) may be 
implemented with notification of the IEC/IRB and competent authority only. 
9.8. Premature Closure of the Trial 
The sponsor (Theranexus) has the right to close this trial under special considerations or events involving 
safety considerations or issues with recruitment. As far as possible, this should occur after mutual 
consultation and attempt of remedy with all trial sites. The IEC/IRB and the CA must be promptly 
informed. 
Should the trial be closed prematurely, all IMP must be returned to the warehouse, as if the trial had been 
completed. All other trial material (actigraphy sensors, PVT device, notebook, ECG device etc.) must also 
be returned. 
The sponsor reserves the right to close the trial at a site for one of the following (or other) reasons: 
• 
Non-compliance with GCP and/or regulatory requirements 
• 
Centre cannot recruit an adequate number of subjects 
• 
False documentation in the eCRF due to carelessness or deliberation 


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• 
Inadequate co-operation with the sponsor or its representatives 
If the trial is prematurely terminated at a trial site, all investigators at this trial site have to inform their 
subjects and take care of appropriate follow-up and further treatment of the subjects. IEC/IRBs and the 
CA will be informed according to the applicable laws and regulations. 
9.9. Regular Termination of the Trial 
The end of this trial is defined as the date of the last visit of the last subject undergoing this trial.  
Within 90 days of the end of the clinical trial, the clinical CRO will notify IECs/IRBs and regulatory 
authorities about the regular termination of the trial as required according to national laws and regulations.  
If the trial has to be terminated early, this period shall be reduced to 15 days and the reasons clearly 
explained. 
9.10. Archiving and Record Retention 
The following records must be retained by the principal investigator in the investigator site file (ISF) for 
a minimum of 15 years after the completion or termination of the trial: 
• 
Signed informed consent documents for all subjects 
• 
Subject identification list, subject non-eligibility log and subject enrolment log 
• 
Record of all communications between the investigator and the IEC/IRB 
• 
Composition of the IEC/IRB  
• 
Record of all relevant communications between the investigator and sponsor’s representatives 
• 
List of sub-investigators and other appropriately qualified persons to whom the investigator has 
delegated significant trial-related duties, together with their roles and their signatures 
• 
Copies of case report forms and of documentation of corrections for all subjects 
• 
Drug accountability records 
• 
Record of any body fluids or tissue samples retained 
• 
All other source documents (patient records, hospital records, laboratory records, worksheets etc.) 
• 
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP (Essential 
Documents for the Conduct of a Clinical Trial) 
However, because of international regulatory requirements, Theranexus may request retention for a longer 
period of time. The investigator must therefore obtain approval in writing from Theranexus or from the 
CRO's trial manager prior to destruction of any records. 
Normally, these records will be held in the investigator's archives. If the investigator is unable to meet this 
obligation, he must ask Theranexus for permission to make alternative arrangements. Details of these 
arrangements should be documented. 
9.11. Liability and Insurance 
In accordance with GCP and ICH guidelines, the clinical CRO (authorised by the sponsor) has subscribed 
to an insurance policy covering, in its terms and provisions, its legal liability for injuries caused to 
participating persons and arising out of this research performed strictly in accordance with the scientific 
protocol as well as with applicable law and professional standards. 
The insurance certificate will be submitted with the documents to the IEC/IRB. 


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10. TRIAL MONITORING AND AUDITING 
10.1. Trial Monitoring 
The CRO's CRAs will review the eCRFs and source documents, supported on occasions by the CRO's 
trial manager or the sponsor. By frequent communications (letter, e-mail, telephone and fax), the CRO's 
trial manager and the CRAs will ensure: 
• 
that the investigation is conducted according to protocol design and requirements, 
• 
that potential deviations are discussed and queries solved, always working according to regulatory 
guidelines. 
The sponsor, the CRO's trial manager and the CRAs may at any time demand information on the progress 
of the trial by phone or in writing, or may visit the trial centre in order to monitor trial procedures and to 
review the original trial documents and subject's data. 
After trial completion, used and unused IMP will be verified, reconciled with eCRF, diaries and log forms. 
Intact and used clinical supplies will be returned to the CRO involved with clinical packaging after 
reconciliation of clinical supplies by CRA and after written instruction.  
CRO’s standard operating procedures (SOPs) are available for all activities relevant to trial monitoring 
and to process at trial sites.  
10.2. Source Data Verification and On-Site Audits 
The local IEC/IRB, and/or a clinical quality assurance group delegated by the sponsor (Theranexus), or 
the CA acting on its own or at specific request of EMA or FDA may request access to all source 
documents, eCRF, and other trial documentation for on-site audit or inspection as may be indicated. Direct 
access to these documents must be guaranteed by the investigators, who must provide support at all times 
for these activities. 


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11. DATA HANDLING AND RECORD KEEPING 
11.1. Electronic CRF and Database 
An electronic case report form (eCRF) will be used. The clinical CRO will provide the system. 
Questionnaires filled by subject will be provided on paper. Trial staff will transfer the results into the 
eCRF.  
Electronic device for PVT tests and actigraphy will be provided by the CRO to each site. The 
questionnaires will be considered as source documents and filed in the ISF.  
The investigator or delegate must maintain adequate and precise source documents (safety laboratory test 
results, ECG, physical examination etc.), also including the diaries and the questionnaires filled by the 
subject. The trial data will be entered into the eCRF by dedicated site personnel.  
Medical history and AE data will be coded by system organ class and Lowest Level Term, using the 
current version of the MedDRA dictionary. Concomitant medication data will be coded by Drug Name, 
taking Preferred Name and ATC into account, using the World Health Organization Drug Dictionary 
Enhanced (WHO DDE), current version. 
Further details will be provided in the DMP and in the pertinent SAP. 
11.2. Documentation of Trial Findings 
Details on monitoring process by the CRA will be included in the monitoring plan. 
The plasma concentrations data will be transmitted by
 to data management for 
inclusion into the trial database. The format and the details however will be provided in the analytical 
protocol to be prepared by 
 and in the SAP. 
The investigator, or designated representative, should complete the source documents (including 
worksheet pages, if applicable) immediately after information is collected, when a trial subject is seen for 
an examination, treatment, or any other trial procedure. Any outstanding entries must be completed 
immediately after the final examination. An explanation should be provided for all missing data. 
A source data location list will be prepared and updated as required.  
The completed eCRF must be reviewed and signed by the principal investigator named in the trial protocol 
prior to transmission to the sponsor.  
11.3. Use of Trial Findings 
All information concerning the drug product, such as clinical indications for the drug, its formula, methods 
of manufacture and formulations and other scientific data relating to it, that have been provided to 
investigators and are unpublished, will be considered as confidential and must remain the sole property of 
Theranexus. The investigator agrees to use the information only for the purposes of carrying out this trial 
and for no other purpose unless prior written permission from Theranexus is obtained. 
By signing the trial protocol, the principal investigator agrees that the results of the trial may be used for 
the purposes of national and international registration, publication, and information for medical and 
pharmaceutical professionals. The principal investigator also agrees that one or more designated staff 
members will be responsible for maintaining the investigator site file (ISF). The trial master file (TMF) 
will be maintained by the clinical CRO and transferred to sponsor after trial completion. 
The sponsor or designee will be responsible for preparing the CTR. The coordinating investigator will be 
required to sign a statement that he has read the CTR and that he confirms that, to the best of his 
knowledge, it accurately describes the conduct and results of the trial. 


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Theranexus shall have the right to present and to publish the scientific findings from this phase II trial 
within reasonable time after termination of the trial and availability of the CTR, providing appropriate 
circulation of the manuscript among involved partners at least 60 days in advance. Co-authorship will 
reflect scientific involvement in trial design, trial performance, and/or analysis.  
Suggestions made by Theranexus shall be implemented as appropriate to ensure strict protection of its 
commercial knowhow, to enable a timely patent submission prior to disclosure, to protect its commercial 
and proprietary interests and/or to support its strategy, unless competing with scientific accuracy and 
objectivity. 
 


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12. DECLARATIONS OF SPONSOR AND INVESTIGATOR 
12.1. Declaration of Sponsor 
This trial protocol was subject to critical review and has been approved by the sponsor and its 
representatives. The information it contains is consistent with: 
• 
The current risk-benefit evaluation of the investigational product 
• 
The moral, ethical, and scientific principles governing clinical research as set out in the Declaration 
of Helsinki and the principles of GCP as described in the GCP and ICH guidelines.  
 
The investigator will be supplied with details of any significance or new findings, including adverse 
events, relating to treatment with the investigational product. 
 
 
 
 
 
 
 
Date:___________________________ 
_______________________________ 
 
 
 
Chief Medical Officer’s signature 
 
Theranexus S. A. 
 


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12.2. Declaration of Coordinating Investigator 
I have received the following: 
• 
The THN102 investigator brochure, Version 4.0, 24 January 2019. 
And I confirm that: 
• 
I have been adequately informed about the development of the investigational product to date. I will 
confirm the receipt of updated investigator brochures. 
• 
I have read this trial protocol and agree that it contains all the information required to conduct the 
trial. 
• 
I agree to conduct the trial as set out in this protocol and further written trial instructions (including, 
but not limited to, laboratory manual, CRF completion instructions, as well as instructions for PVT, 
AX3 and ECG assessments). 
• 
I will not enrol the first subject in the trial until I have received approval from the appropriate IEC/IRB 
and until all legal requirements in my country have been fulfilled. 
• 
The trial will be conducted in accordance with the moral, ethical, and scientific principles governing 
clinical research as set out in the Declaration of Helsinki and the GCP and ICH Guidelines. 
• 
I agree to obtain, in the manner described in this trial protocol, written informed consent to participate 
for all subjects enrolled in this trial. 
• 
I am aware of the requirements for the correct reporting of serious adverse events, and I undertake to 
document and to report such events as requested. 
• 
I agree with the use of results of the trial for the purposes of national and international registration, 
publication, and information for medical and pharmaceutical professionals. 
• 
I agree to keep all source documents and eCRF as specified in this protocol.  
• 
I will provide my curriculum vitae before the trial starts, which may be submitted to regulatory 
authorities and will request my collaborators to forward their curriculum vitae as appropriate. 
 
Site (name and address): 
 
 
 
 
  
 
 
 
 
 
 
 
Date:______________________________ 
____________________________________ 
 
Coordinating Investigator’s signature  
 
  
 
 


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12.3. Declaration of Principal Investigator 
I have received the following: 
• 
The THN102 investigator brochure, Version 4.0, 24 January 2019. 
And I confirm that: 
• 
I have been adequately informed about the development of the investigational product to date. I will 
confirm the receipt of updated investigator brochures. 
• 
I have read this trial protocol and agree that it contains all the information required to conduct the 
trial. 
• 
I agree to conduct the trial as set out in this protocol and further written trial instructions (including, 
but not limited to, laboratory manual, CRF completion instructions, as well as instructions for PVT, 
AX3 and ECG assessments). 
• 
I will not enrol the first subject in the trial until I have received approval from the appropriate IEC/IRB 
and until all legal requirements in my country have been fulfilled. 
• 
The trial will be conducted in accordance with the moral, ethical, and scientific principles governing 
clinical research as set out in the Declaration of Helsinki and the GCP and ICH Guidelines. 
• 
I agree to obtain, in the manner described in this trial protocol, written informed consent to participate 
for all subjects enrolled in this trial. 
• 
I am aware of the requirements for the correct reporting of serious adverse events, and I undertake to 
document and to report such events as requested. 
• 
I agree with the use of results of the trial for the purposes of national and international registration, 
publication, and information for medical and pharmaceutical professionals. 
• 
I agree to keep all source documents and eCRF as specified in this protocol.  
• 
I will provide my curriculum vitae before the trial starts, which may be submitted to regulatory 
authorities and will request my collaborators to forward their curriculum vitae as appropriate. 
 
Site (name and address): 
 
 
 
 
 
 
Date:______________________________ 
____________________________________ 
 
Principal Investigator’s signature  
 
 
 
 
 


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13. REFERENCES 
 
1. B. Knie, M.T. Mitra, K. Logishetty, K.R. Chaudhuri, Excessive daytime sleepiness in patients with 
Parkinson's disease, CNS drugs, 25 (2011) 203-212. 
2. T.M. Rodrigues, A. Castro Caldas, J.J. Ferreira, Pharmacological interventions for daytime sleepiness 
and sleep disorders in Parkinson's disease: Systematic review and meta-analysis, Parkinsonism & 
related disorders, 27 (2016) 25-34. 
3. B. Hogl, M. Saletu, E. Brandauer, S. Glatzl, B. Frauscher, K. Seppi, H. Ulmer, G. Wenning, W. 
Poewe, Modafinil for the treatment of daytime sleepiness in Parkinson's disease: a double-blind, 
randomized, crossover, placebo-controlled polygraphic trial, Sleep, 25 (2002) 905-909. 
4. W.G. Ondo, R. Fayle, F. Atassi, J. Jankovic, Modafinil for daytime somnolence in Parkinson's disease: 
double blind, placebo controlled parallel trial, Journal of neurology, neurosurgery, and psychiatry, 76 
(2005) 1636-1639. 
5. C.H. Adler, J.N. Caviness, J.G. Hentz, M. Lind, J. Tiede, Randomized trial of modafinil for treating 
subjective daytime sleepiness in patients with Parkinson's disease, Movement disorders: official 
journal of the Movement Disorder Society, 18 (2003) 287-293. 
6. R. Kumar, Approved and investigational uses of modafinil : an evidence-based review, Drugs, 68 
(2008) 1803-1839. 
7. L. Barateau, R. Lopez, Y. Dauvilliers, Treatment Options for Narcolepsy, CNS drugs, 30 (2016) 369-
379. 
8. M.J. Thorpy, Y. Dauvilliers, Clinical and practical considerations in the pharmacologic management 
of narcolepsy, Sleep medicine, 16 (2015) 9-18. 
9. J.S. Ballon, D. Feifel, A systematic review of modafinil: Potential clinical uses and mechanisms of 
action, The Journal of clinical psychiatry, 67 (2006) 554-566. 
10. J.E. Black, M. Hirshkowitz, Modafinil for treatment of residual excessive sleepiness in nasal 
continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome, Sleep, 28 
(2005) 464-471. 
11. D. Lagarde, D. Batejat, P. Van Beers, D. Sarafian, S. Pradella, Interest of modafinil, a new 
psychostimulant, during a sixty-hour sleep deprivation experiment, Fundamental & clinical 
pharmacology, 9 (1995) 271-279. 
12. N.J. Wesensten, W.D. Killgore, T.J. Balkin, Performance and alertness effects of caffeine, 
dextroamphetamine, and modafinil during sleep deprivation, Journal of sleep research, 14 (2005) 255-
266. 
13. N.J. Wesensten, G. Belenky, D.R. Thorne, M.A. Kautz, T.J. Balkin, Modafinil vs. caffeine: effects on 
fatigue during sleep deprivation, Aviation, space, and environmental medicine, 75 (2004) 520-525. 
14. N.J. Wesensten, G. Belenky, M.A. Kautz, D.R. Thorne, R.M. Reichardt, T.J. Balkin, Maintaining 
alertness and performance during sleep deprivation: modafinil versus caffeine, Psychopharmacology 
(Berl), 159 (2002) 238-247. 
15. W.D. Killgore, E.T. Kahn-Greene, N.L. Grugle, D.B. Killgore, T.J. Balkin, Sustaining executive 
functions during sleep deprivation: A comparison of caffeine, dextroamphetamine, and modafinil, 
Sleep, 32 (2009) 205-216. 
16. D.C. Turner, T.W. Robbins, L. Clark, A.R. Aron, J. Dowson, B.J. Sahakian, Cognitive enhancing 
effects of modafinil in healthy volunteers, Psychopharmacology (Berl), 165 (2003) 260-269. 
17. U. Muller, J.B. Rowe, T. Rittman, C. Lewis, T.W. Robbins, B.J. Sahakian, Effects of modafinil on 
non-verbal 
cognition, 
task 
enjoyment 
and 
creative 
thinking 
in 
healthy 
volunteers, 
Neuropharmacology, 64 (2013) 490-495. 
18. A. Duchêne, M. Perier, Y. Zhao, X. Liu, J. Thomasson, F. Chauveau, C. Pierard, D. Lagarde, C. Picoli, 
T. Jeanson, F. Mouthon, Y. Dauvilliers, C. Giaume, J.S. Lin, M. Charvériat, Impact of Astroglial 
Connexins on Modafinil Pharmacological Properties, Sleep, 39 (2016) 1283-1292. 
19.  B.H.e. al, Ventricular Tachycardia during Treatment with Modafinil for Narcolepsy: A Case Report 
International Journal of Clinical Medicine, 3 (2012) 513-517. 
20. B.M. Heath, Y. Cui, S. Worton, B. Lawton, G. Ward, E. Ballini, C.P. Doe, C. Ellis, B.A. Patel, N.C. 
McMahon, Translation of flecainide- and mexiletine-induced cardiac sodium channel inhibition and 


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ventricular conduction slowing from nonclinical models to clinical, Journal of pharmacological and 
toxicological methods, 63 (2011) 258-268. 
21. P. Robertson, Jr., E.T. Hellriegel, Clinical pharmacokinetic profile of modafinil, Clinical 
pharmacokinetics, 42 (2003) 123-137. 
22. T.B. Tjandra-Maga, R. Verbesselt, A. Van Hecken, A. Mullie, P.J. De Schepper, Flecainide: single 
and multiple oral dose kinetics, absolute bioavailability and effect of food and antacid in man, British 
journal of clinical pharmacology, 22 (1986) 309-316. 
23. G.J. Conard, R.E. Ober, Metabolism of flecainide, The American journal of cardiology, 53 (1984) 
41B-51B. 
24. P. Robertson, H.H. DeCory, A. Madan, A. Parkinson, In vitro inhibition and induction of human 
hepatic cytochrome P450 enzymes by modafinil, Drug metabolism and disposition: the biological fate 
of chemicals, 28 (2000) 664-671. 
25. L. Tenneze, E. Tarral, N. Ducloux, C. Funck-Brentano, Pharmacokinetics and electrocardiographic 
effects of a new controlled-release form of flecainide acetate: comparison with the standard form and 
influence of the CYP2D6 polymorphism, Clinical pharmacology and therapeutics, 72 (2002) 112-122. 
26. L. Scrima, et al. Identifying clinically important difference on the ESS, Sleep Medicine, 38 (2017) 
108-112. 
27. D. M. Salerno, G. Granrud, P. Sharkey et al, Pharmacodynamics and side effects of flecainide acetate, 
Clin Pharmacol Ther. 40 (1986) 101-107. 
28. E. L. C. Pritchett, S. D. DaTorre, M. L. Platt, et al. Flecainide acetate treatment of paroxysmal 
supraventricular tachycardia and paroxysmal atrial fibrillation: Dose-response studies, JACC, 17 
(1991) 297-303.  
29. C. Funck-Brentano, L. Becquemont, HK Kroemer, et al. Variable disposition kinetics and 
electrocardiographic effects of flecainide during repeated dosing in humans: Contribution of genetic 
factors, dose-dependent clearance, and interaction with amiodarone. Clin Pharmacol Ther, 55 (1994) 
256-269. 
30. J. Beckmann, R. Hertrampf, U. Gundert-Remy, et al. Is there a genetic factor in flecainide toxicity? 
BMJ 297 (1988) 1316. 
31. Theranexus S. A. Investigator Brochure for THN102. Version 4.0, 24 January 2019. 
32. KDIGO 2012 Clinical practice guideline for the evaluation and management of chronic kidney 
disease. Kidney International Supplements, 3 (2013) 136-150.  
https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf 
33. C. G. Goetz, B. C. Tilley, S. R. Shaftman, et all. For the Movement Disorder Society UPDRS Revision 
Task Force. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS): Scale presentation and clinimetric testing results, Mov Disord, 23 
(2008) 2129-2170. 
34. D. Weintraub, E. Mamikonyan, K. Papay, et al. Questionnaire for Impulsive-Compulsive disorders in 
Parkinson’s Disease-Rating Scale. Mov Disord. 27 (2012) 242-247.  
35. M. Basner, D. F. Dinges. Maximizing sensitivity of the psychomotor vigilance test (PVT) to sleep 
loss, Sleep 34 (2011) 581-591. 
36. Indiana University, School of Medicine, Department of Medicine, Clinical Pharmacology. Flockhart 
Table™, P450 Drug Interaction Table (2016). http://medicine.iupui.edu/clinpharm/ddis/main-table 
 


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14. APPENDICES 
14.1. Appendix A – Trial Administrative Structure 
This trial will be conducted in an estimated 28 centres located in Europe and the USA. A list of principal 
investigators and their affiliations will be kept in the trial master file (TMF). 
 
Sponsor 
Theranexus S. A. 
86, rue de Paris 
F-91400 Orsay 
France 
Tel. +33 6 80 02 67 79 
www.theranexus.com 
 
Trial manager: 
 
Medical expert: 
 
 
The sponsor will contract planning, conduct, data management, statistical analysis, safety management, 
medical writing and medical monitoring in Europe to the contract research organisation (CRO) given 
below. 
 
Contract research organisation 
 
 
  
 
 
 
 
 
 
 
 
Coordinating investigator 
 
 
 
 
  
 
 
 
 
 
 
Electronic data capture (EDC) system provider (electronic case report form) 
 
 
 
 
 
 


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Laboratories 
Safety laboratory assessments (haematology, biochemistry, blood coagulation and serology) will be 
performed by 
Central laboratory 
 
 
 
 
 
 
 
 
 
 
Urinalyses and pregnancy tests will be performed on-site. 
 
Pharmacokinetic analyses will be performed by 
 
 
 
 
 
 
 
 
 
 
Processing of actigraphy data 
 
  
 
 
 
 
 
Contract research organisation for clinical trial supply management / warehouse 
 
 
 
  
 
 
   
 
 
 
For sites in the USA this will be done by a local warehouse. 
 
Central ECG reading 
 
  
  
  
  
  
  
  
  


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Medical monitoring in the USA: 
 
 
 
 
 
 
 
All other trial personnel not included in this section is identified in a separate personnel list as appropriate. 
This list will be regularly updated as needed. Its most current version will be available in each centre’s 
investigator site file (ISF) and/or in the TMF. 
 
 


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14.2. Appendix B – Safety Laboratory Parameters 
Serology (at VS1 only) 
Hepatitis A antibody IgM 
Hepatitis B surface antigen  
Hepatitis C virus antibody 
HIV antibodies (dual screen, HIV1, HIV2) 
Blood coagulation (at VS1 only) 
Prothrombin time 
Haematology 
Haemoglobin total 
Haematocrit 
Red blood cells (RBC)  
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular volume (MCV) 
White blood cells (WBC) differential count (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) 
Platelet count 
 
Biochemistry 
Fasting glucose (may not be fasting) 
Total protein 
Albumin 
Creatinine 
GFR (at VS1 only) 
Urea 
Uric acid 
Sodium, potassium 
Cholesterol, triglycerides 
AST, ALT 
Alkaline phosphatase 
Total bilirubin, conjugated bilirubin 
 
Urinalysis (performed at trial site on fresh urine) 
• 
Dipstick for pH, protein, glucose, blood, ketones, leukocytes, urobilinogen, bilirubin 
• 
Pregnancy test (hCG) for women of child-bearing potential 
 


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14.3. Appendix C – Most Common Antiarrhythmic Drugs Class I 
 
Ajmaline 
Disopyramide 
Flecainide 
Hydroquinidine (dihydroquinidine) 
Lidocaine 
Mexiletine 
Prajmaline (prajmalium) 
Procainamide 
Propafenone 
Quinidine 
Tocainide 
 
This list is not complete. In case of doubt, please contact the medical monitor. 


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14.4. Appendix D – CYP2D6 Inhibitors and CYP3A4,5 and 
CYP2C19 Substrates 
CYP2D6 inhibitors [36] 
Strong: 
Bupropion 
Cinacalcet 
Fluoxetine 
Paroxetine 
Quinidine 
Moderate: 
Duloxetine 
Sertraline 
Terbinafine 
Weak: 
Amiodarone 
Cimetidine 
CYP3A4,5 substrates [36] 
Macrolide antibiotics: 
Clarithromycin 
Erythromycin 
NOT: Azithromycin 
Telithromycin 
Anti-arrhythmics: 
Quinidine 
Benzodiazepines: 
Alprazolam 
Diazepam 
Midazolam 
Triazolam 
Immune modulators: 
Cyclosporine 
Tacrolimus (FK506) 
HIV antivirals: 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir 
Prokinetics: 
Cisapride 
Antihistamines: 
Astemizole 
Chlorpheniramine 


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Terfenadine 
Calcium channel blockers: 
Amlodipine 
Ditiazem 
Felodipine 
Lercanidipine 
Nifedipine 
Nisoldipine 
Nitrendipine 
Verapamil 
HMG COA reductase inhibitors: 
Atorvastatin 
Cerivastatin 
Lovastatin 
NOT: Pravastatin 
NOT: Rosuvastatin 
Simvastatin 
Steroid 6β-OH: 
Estradiol 
Hydrocortisone 
Progesterone 
Testosterone 
Miscellaneous: 
Alfentanil 
Aprepitant 
Aripiprazole 
Boceprevir 
Buspirone 
Carbamazepine 
Cafergot 
Caffeine 
Cilostazol 
Cocaine 
Codeine-n-demethylation 
Dapsone 
Dexamethasone 
Dextromethorphan 
Docetaxel 
Domperidone 
Eplerenone 
Fentanyl 
Finasteride 
Gleevec 
Haloperidol 
Irinotecan 
Levo-alpha-acetylmethadol 


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Lidocaine 
Methadone 
Nateglinide 
Nevirapine 
Ondansetron 
Pimozide 
Propranolol 
Quetiapine 
Quinine 
Risperidone 
Romidepsin 
Salmeterol 
Sildenafil 
Sirolimus 
Sorafenib 
Sunitinib 
Tamoxifen 
Taxol 
Telaprevir 
Terfenadine 
Torisel 
Trazodone 
Vemurafenib 
Vincristine 
Zaleplon 
Ziprasidone 
Zolpidem 
 
CYP2C19 Substrates [36] 
Proton pump inhibitors: 
Esomeprazole 
Lansoprazole 
Omeprazole 
Pantoprazole 
Anti-epileptics: 
Diazepam 
Phenytoin 
S-mephenytoin 
Phenobarbitone 
Amitriptyline 
Carisoprodol 
Citalopram 
Chloramphenicol 
Clomipramide 
Clopidogrel 
Cyclophosphamide 
Hexobarbital 


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Imipramine N-DeMe 
Indomethacin 
Labetalol 
R-Mephobarbital 
Moclobemide 
Nelfinavir 
Nilutamide 
Primidone 
Progesterone 
Proguanil 
Propanolol 
Teniposide 
R-Warfarin 
Voriconazole 
 
The lists are not complete. In case of doubt, please contact the medical monitor. 
 

SAP_001.pdf: 
Randomised, double-blind, placebo-controlled, complete 3-way cross-over phase IIa trial to 
investigate safety and efficacy of two THN102 doses in subjects with excessive daytime 
sleepiness associated with Parkinson’s disease 
 
 
 
 
Sponsor Project Code: THN102-202 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Sponsor:  
Theranexus S.A. 
86, rue de Paris 
F-91400 Orsay, France 
Phone: +33 6 80 02 67 79 
www.theranexus.com 
 
Author: 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version: 
Final 1.0 (21-FEB-2020) 
 
 
 
The information provided in this document is strictly confidential. No part of this document may be reproduced, 
transmitted or copied in any form nor its contents disclosed to the third parties without prior written consent of 
Theranexus S.A. or a nominated representative. 
 


Sponsor: Theranexus S.A. 
Protocol no. THN102-202 
Statistical Analysis Plan, Version Final 1.0 
21-FEB-2020 
I-DM-011-06-A1(SAP_template).docx 
Page 2 of 59 
SOP effective date: 18.04.2016 
Version 6 
DOCUMENT REVISION HISTORY 
 
Version Draft 0.1 (10-DEC-2018): Document was created. 
Version Draft 0.2 (22-MAY-2019): The following changes were made: 
• 
Incorporated Protocol versions Final 6.0/Final 8.0 France 
• 
Added description of objective activity measure analysis in Section 5.6.7 
• 
Added description of pharmacokinetic analysis to Section 5.7 
• 
Compliance now calculated for modafinil and flecainide tablets separately and overall 
• 
Subject diary data now summarised using the last 3 days before visit (from 7) 
• 
Added adjusted total time slept (hours) to the analysis of diary data 
• 
Statistical output has been re-numbered 
Version Draft 0.3 (16-JAN-2020): The following changes were made: 
• 
Added definition of treatment duration based on IMP exposure data 
• 
Re-evaluated the severity of some protocol deviations and added 2 new protocol deviations 
• 
Added the ‘ethnicity’ demographics variable (previously missed) 
• 
Added rule that PK samples below the LLOQ will be set to 0 for summaries. 
• 
Adjusted the statistics displayed in the pharmacokinetics summaries 
Version Draft 0.4 (31-JAN-2020): Updated analysis of activity measures (Section 5.6.7): 
• 
Added AX3 Analysis Plan to the list of appendices 
• 
Changed the list of activity variables included in the efficacy analysis 
• 
The mean value corresponding to the collection visit will be used in summaries and analyses 
Version Draft 0.5 (20-FEB-2020): The following changes were made after the BDRM: 
• 
Changed the definition of the Per Protocol set to include all subjects in the FAS with at least 
one treatment period not affected by a major protocol deviation 
• 
Protocol deviations #11, #18, #20 changed to “case by case” according to Sponsor’s 
comments on 06-FEB-2020 (before the blind data review meeting held on 10-FEB-2020). 
• 
Decisions made during the BDRM regarding protocol deviations affecting efficacy and 
pharmacokinetic analyses are described in Sections 5.1.2, 5.6, 5.7. 
• 
Tables and listings for protocol deviations now show the trial periods affected by the major 
protocol deviations 
• 
Added Table 15.1.4.1 Number of Subjects by Country and Site – Enrolled 
• 
Compliance is now calculated using the treatment duration rather than the treatment period 
duration 
Version Final 1.0 (21-FEB-2020): The following changes were made: 
• 
Added the titles and filenames of all TLFs to Appendices 
• 
Removed the estimation of carryover effects in Section 5.6.2 
 


Sponsor: Theranexus S.A. 
Protocol no. THN102-202 
Statistical Analysis Plan, Version Final 1.0 
21-FEB-2020 
 
I-DM-011-06-A1(SAP_template).docx 
Page 3 of 59 
SOP effective date: 18.04.2016 
Version 6 
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Sponsor: Theranexus S.A. 
Protocol no. THN102-202 
Statistical Analysis Plan, Version Final 1.0 
21-FEB-2020 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND KEY TERMS ............................................................................ 6 
INTRODUCTION ................................................................................................................................. 8 
1. 
FLOW CHART AND VISIT SCHEDULE ................................................................................ 9 
2. 
OBJECTIVES AND DESIGN................................................................................................... 12 
2.1 
TRIAL OBJECTIVES .............................................................................................................. 12 
2.1.1 
Primary Objective ....................................................................................................... 12 
2.1.2 
Secondary Objectives .................................................................................................. 12 
2.2 
TRIAL ENDPOINTS ................................................................................................................ 12 
2.2.1 
Safety Endpoints ......................................................................................................... 12 
2.2.2 
Key Efficacy Endpoint ................................................................................................ 12 
2.2.3 
Secondary Efficacy Endpoints .................................................................................... 12 
2.3 
OVERALL TRIAL DESIGN ..................................................................................................... 13 
2.4 
RANDOMISATION ................................................................................................................. 13 
2.5 
TREATMENTS ....................................................................................................................... 14 
2.5.1 
Test drug formulations ................................................................................................ 14 
2.5.2 
Reference drug formulations....................................................................................... 14 
2.6 
SAMPLE SIZE ........................................................................................................................ 15 
2.7 
BLINDING ............................................................................................................................. 15 
3. 
ANALYSIS SETS AND SUBGROUPS .................................................................................... 15 
3.1 
ANALYSIS SETS .................................................................................................................... 15 
3.2 
SUBGROUPS ......................................................................................................................... 16 
4. 
GENERAL DEFINITIONS AND NAMING CONVENTIONS ............................................ 17 
4.1 
GENERAL METHODOLOGY AND PRESENTATION OF THE RESULTS...................................... 17 
4.2 
STATISTICAL OUTPUT LAYOUT ........................................................................................... 17 
4.3 
TREATMENT GROUP NAMES AND LABELS .......................................................................... 18 
4.4 
VISIT NUMBERING AND LABELS .......................................................................................... 18 
4.5 
TREATMENT DAY NUMBERING ........................................................................................... 19 
4.6 
TRIAL PERIODS .................................................................................................................... 19 
4.7 
BASELINE AND ENDPOINT VALUES ..................................................................................... 20 
4.8 
TREATMENT ASSIGNMENT .................................................................................................. 20 
4.9 
CODING SYSTEMS AND CONVENTIONS ................................................................................ 21 
4.9.1 
Coding of adverse events and medical history............................................................ 21 
4.9.2 
Coding of medications ................................................................................................ 21 
4.10 
HANDLING OF MISSING DATA ............................................................................................. 21 
5. 
STATISTICAL ANALYSIS: DEFINITIONS, DERIVATIONS, CALCULATIONS AND 
METHODOLOGY ..................................................................................................................... 22 
5.1 
SUBJECTS DISPOSITION ........................................................................................................ 22 
5.1.1 
Disposition and Withdrawals ...................................................................................... 22 
5.1.2 
Protocol Deviations .................................................................................................... 23 
5.1.3 
Inclusion/Exclusion ..................................................................................................... 28 
5.2 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................................ 28 
5.2.1 
Demographics ............................................................................................................. 28 
5.2.2 
Baseline Disease Stage ............................................................................................... 28 
5.2.3 
Medical History .......................................................................................................... 29 
5.3 
PRIOR AND CONCOMITANT MEDICATIONS .......................................................................... 30 
5.4 
EXPOSURE TO IMP AND COMPLIANCE ................................................................................ 31 
5.4.1 
Exposure to IMP ......................................................................................................... 31 
5.4.2 
Compliance ................................................................................................................. 31 


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5.5 
SAFETY ANALYSIS ............................................................................................................... 32 
5.5.1 
Adverse Events ............................................................................................................ 32 
5.5.2 
Clinical Laboratory Evaluation .................................................................................. 34 
5.5.3 
Vital Signs ................................................................................................................... 35 
5.5.4 
12-Lead Electrocardiogram (ECG) Data ................................................................... 36 
5.5.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................................... 37 
5.5.6 
Movement Disorder Society-Sponsored Version of Unified Parkinson's Disease Rating 
Scale (MDS-UPDRS) ......................................................................................... 37 
5.5.7 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating 
Scale (QUIP-RS) ................................................................................................ 37 
5.5.8 
Physical Examination Findings .................................................................................. 38 
5.5.9 
Other Safety-Related Observations ............................................................................. 39 
5.6 
EFFICACY ANALYSIS ........................................................................................................... 40 
5.6.1 
Key Efficacy Analysis .................................................................................................. 40 
5.6.2 
Key Efficacy Endpoint Carryover Effect Estimation .................................................. 42 
5.6.3 
ESS Responder Rate .................................................................................................... 43 
5.6.4 
Absence of Residual Somnolence ................................................................................ 44 
5.6.5 
Psychomotor Vigilance Test (PVT) ............................................................................. 44 
5.6.6 
Montreal Cognitive Assessment (MoCA) .................................................................... 45 
5.6.7 
Actigraphy (Inactivity) Evaluation ............................................................................. 46 
5.6.8 
Subject Diary Data ..................................................................................................... 47 
5.6.8.1 
Diurnal Involuntary Sleep Attacks .............................................................................. 48 
5.6.8.2 
Somnolence Episodes .................................................................................................. 48 
5.6.8.3 
Other Efficacy-Related Variables ............................................................................... 48 
5.7 
PHARMACOKINETIC ANALYSIS ............................................................................................ 49 
6. 
INTERIM ANALYSIS ............................................................................................................... 49 
7. 
CHANGES TO THE ANALYSIS AS LAID DOWN IN THE PROTOCOL AND 
AMENDMENTS ........................................................................................................................ 50 
8. 
REFERENCES ........................................................................................................................... 51 
9. 
APPENDICES ............................................................................................................................ 52 
9.1 
TABLES ................................................................................................................................ 52 
9.2 
LISTINGS .............................................................................................................................. 57 
9.3 
FIGURES ............................................................................................................................... 59 
 


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Statistical Analysis Plan, Version Final 1.0 
21-FEB-2020 
 
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LIST OF ABBREVIATIONS AND KEY TERMS 
 
Abbreviations 
Description of abbreviations 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
AST 
Aspartate aminotransferase (SGOT) 
ATC 
Anatomical Therapeutic Chemical 
BDR 
Blind Data Review 
BMI 
Body mass index = body weight (kg) / height2 (m2) 
CNS 
Central nervous system 
CRO 
Contract research organisation 
CS 
Clinically significant 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of variation 
DMP 
Data management plan 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDV 
Early discontinuation visit 
EOT 
End-of-treatment 
ESS 
Epworth Sleepiness Scale 
FAS 
Full Analysis Set 
GFR 
Glomerular filtration rate 
GLM 
Generalised linear model 
GLMM 
Generalised linear mixed model 
HDPE 
High-density polyethylene 
HIV 
Human immunodeficiency virus 
HLGT 
High level group term 
HLT 
High level term 
ICD 
Impulse control disorder 
IMP 
Investigational medicinal product 
IS 
Interdaily Stability 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intradaily Variability 
KDIGO 
Kidney Disease Improving Outcomes 
LLT 
Lowest level term 
LNH 
Lower than (L), within (N) or higher than (H) the reference range 
MAR 
Missing at random 
MCH 
Mean corpuscular haemoglobin 
MCV 
Mean corpuscular volume 
MDS-UPDRS 
Movement Disorder Society-sponsored version of Unified Parkinson's 
Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed models for repeated measures 
MoCA 
Montreal Cognitive Assessment 
n 
Number of observations/ frequency count 
PCA 
Pharmacie Centrale des Armées (Central Army Pharmacy) 
PD 
Parkinson's disease 
PK 
Pharmacokinetics 
PP set 
Per Protocol set 
PT 
Preferred term 
PT 
Prothrombin time 


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PVT 
Psychomotor Vigilance Test 
RA 
Relative Amplitude 
Q1 
First quartile 
Q3 
Third quartile 
QRS 
Combination of three of the graphical deflections on an electrocardiogram 
QT 
Duration between Q wave and T wave on the ECG (expressed in ms) 
QTcF 
Corrected QT-interval (Fridericia’s formula) in ECG (expressed in ms) 
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease 
– Rating Scale 
REML 
Restricted maximum likelihood 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SOP 
Standard operating procedure 
SS 
Safety Set 
THN102 
Theranexus internal code for the combination modafinil and flecainide 
TLF 
Tables, listings, figures 
TNF 
Tumour Necrosis Factor 
WHO 
World Health Organization 
WHO-DDE 
World Health Organization-Drug Dictionary Enhanced 
 


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INTRODUCTION 
This statistical analysis plan (SAP) contains a more technical and detailed elaboration of the principal 
features of the statistical analyses as described in the clinical trial protocol versions: 
Document, Version 
Date 
Protocol, Final 1.0 
11-JAN-2018 
Protocol, Final 4.0 
30-MAY-2018 
Erratum to Protocol Final 4.0, Final 1.0 
14-JUN-2018 
Protocol, Final 5.0 France 
16-JUL-2018 
Protocol, Final 5.0 
19-OCT-2018 
Protocol, Final 6.0 France 
19-OCT-2018 
Protocol, Final 6.0 
27-FEB-2019 
Protocol, Final 8.0 France 
12-APR-2019 
Due to non-substantial changes in the data collected and no changes in the statistical methodology 
described by the protocol, this SAP is written assuming the latest protocol version (Final 6.0 or 
Final 8.0 France). Differences between the protocol versions will be listed in the relevant subsections 
of the SAP. 
The SAP includes detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data, and it is structured according to different data types. The SAP is finalised and 
signed-off prior to unblinding the trial. 
Actigraphy data collected over the course of the trial will be evaluated by a research team from 
 The corresponding AX3 Analysis Plan is included as an appendix (see Section 9). The 
resulting derived data will be transferred to 
 for efficacy analysis, which is described in Section 
5.6.7. 
All analysis data sets and statistical output will be produced by the statistics department at
 
using the SAS system version 9.4 for Windows (SAS 
Institute Inc., Cary, NC, USA) [1]. 






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4. Vital signs: Systolic and diastolic blood pressure as well as heart rate will be measured twice: after 5 minutes of supine rest and after 2 minutes in standing position (one 
set). At VR, V1C and V2C three sets of supine and standing vital signs will be measured 15-20 min apart.  
5. Weight will be measured in street clothes without shoes. 
6. At VS1 the C-SSRS Screening version will be completed. At other visits, the C-SSRS Since Last Visit version will be completed. 
7. PVT will be done at 10:00 h, 12:00 h, 14:00 h and 16:00 h (± 0:15 h each). If this PVT assessment schedule is too burdensome for the subject, it may be individually 
adapted to at least 3 assessments, with a time window of not less than 1 h between two PVT assessments. Once chosen, the timeframe should remain constant during the 
trial for each subject. 
8. The subject diary will be used continuously (i.e. also during washout periods) to record get-up time, total time (hours) slept last night, wake-up periods during night sleep, 
time of drug intake and number of capsules taken (except screening phase diary issued at VS1), somnolence episodes, diurnal involuntary sleep attacks, voluntary naps, 
number of caffeinated drinks and going-to-bed time.  
9. Visits V1A and V1B should be scheduled so that 3 days of actigraphy data can be collected. (The same for VS2 and VR, V2A and V2B, as well as V3A and V3B.) 
Actigraphy will be assessed using an actigraphy wrist band. 
10. MoCA should be performed in the morning. 
11. In case of early discontinuation, the same procedures as required for V3B will be performed.  
12. One PK blood sample will be taken when the subject arrives on the site. The times of blood withdrawal must be recorded. 
13. Starting from Day 21, the visit day numbers are theoretical, as the washout period is flexible and can be extended to up to 14 days. The 2-week duration of the treatment 
period is fixed. 
 
 
 
 


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2. OBJECTIVES AND DESIGN 
2.1 
Trial Objectives 
2.1.1 
Primary Objective 
The primary objective of this trial is to assess the safety profile of THN102 (modafinil/flecainide 
combination) at two doses (200 mg/18 mg and 200 mg/2 mg) versus placebo in subjects with excessive 
daytime sleepiness associated with Parkinson’s disease (PD). 
2.1.2 
Secondary Objectives 
The secondary objectives of this trial are 
1. To quantify the efficacy of THN102 versus placebo in improving sleepiness. 
2. To quantify the efficacy of THN102 versus placebo in improving 
a. attention, vigilance 
b. cognition 
3. To determine the dose response profile of THN102 versus placebo on efficacy parameters. 
4. To determine the plasma levels of modafinil and flecainide at steady state. 
2.2 
Trial Endpoints 
2.2.1 
Safety Endpoints 
The safety endpoints of this trial are 
1. Adverse events 
2. Safety laboratory 
3. Vital signs change 
4. Electrocardiogram assessments 
5. Columbia-Suicide Severity Rating Scale (C-SSRS) 
6. MDS-UPDRS 
7. QUIP-RS 
2.2.2 
Key Efficacy Endpoint 
The key efficacy endpoint for this trial is 
8. Mean ESS score change from baseline at the end of each treatment period 
2.2.3 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this trial are 
9. ESS score responder rate, defined as the proportion of subjects with at least 25% ESS 
improvement from baseline, at the end of each treatment period 
10. Absence of residual somnolence, i.e. ESS < 11 at the end of each treatment period 
11. Psychomotor Vigilance Test (PVT) variables change from baseline at the end of each treatment 
period 
12. MoCA score change from baseline at the end of each treatment period 
13. Actimetry change (inactivity) from baseline at the end of each treatment period 
14. Number and duration of diurnal involuntary sleep attacks (subject diaries) change from baseline 
at the end of each treatment period 
15. Episodes of somnolence (subject diaries) change from baseline at the end of each treatment 
period 


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2.3 
Overall Trial Design 
This is a prospective, double-blind, randomised, placebo-controlled trial using a complete 3-way 
cross-over design. Subjects will be assessed during  twelve visits (seven on site and five by phone 
call). The seven trial periods are depicted in Table 1. 
Table 1: Trial design 
Screening 
Treatment I 
Washout I* 
Treatment II 
Washout II* 
Treatment III 
Follow-Up 
1-2 weeks 
2 weeks 
1(2) weeks 
2 weeks 
1(2) weeks 
2 weeks 
1 week 
No treatment 
A, B, or C 
No treatment 
A, B, or C 
No treatment 
A, B, or C 
No treatment 
(Dose A = placebo; Dose B = THN102 200 mg/2 mg; Dose C = THN102 200 mg/18 mg.) 
* Washout periods can be extended to up to 2 weeks, if this is more convenient for the subject. 
 
The trial procedures by visit are presented in the flow chart in Section 1. 
At visit VR the subjects will be equally randomised (1:1:1:1:1:1) double-blind to a treatment sequence 
containing three periods (shown in Table 2). 
Table 2: Treatment sequences 
Sequence 
Treatment period I 
Treatment period II 
Treatment period III 
1 
Dose A 
Dose B 
Dose C 
2 
Dose B 
Dose C 
Dose A 
3 
Dose C 
Dose A 
Dose B 
4 
Dose A 
Dose C 
Dose B 
5 
Dose C 
Dose B 
Dose A 
6 
Dose B 
Dose A 
Dose C 
The duration of each treatment period is 2 weeks, with a 1-week washout in between (to avoid carry-
over effects) and 1-week follow-up period after the last treatment period. Washout periods can be 
extended up to two weeks. THN102 will be administered orally once daily. 
2.4 
Randomisation 
The statistics department of the clinical CRO will prepare the randomisation list using SAS® in the 
version specified in the data management plan (DMP). Randomisation data will be kept strictly 
confidential, accessible only to authorised persons, until the time of unblinding. The randomisation 
scheme will be included in the clinical trial report for this protocol. 
The procedure will be as follows: 
• 
After a subject's preliminary eligibility is confirmed, the site will enter the subject into the eCRF 
system.  
• 
The eCRF system will send a notification to the randomisation coordinator at the clinical CRO. 
• 
The randomisation coordinator will allocate the subject to the randomisation code as follows: 
o He/she will assign each screened subject to the next available randomisation number from 
the randomisation list until the first screening failure of a subject with an assigned 
randomisation code is documented.  
o After such a screening failure has occurred, the randomisation coordinator will assign 
randomisation numbers to subjects by taking into account the number of subjects allocated 
to each sequence, to ensure the balance (manual randomisation). 
o At sites with an unused kit from a previous screening failure, any new eligible subject will 
be assigned the randomisation number corresponding to the unused kit (forced 
randomisation). 
• 
The randomisation coordinator will enter the randomisation code into the eCRF system and request 
the warehouse to send the treatment kit (labelled with the randomisation code) and the emergency 
unblinding envelope to the respective site.  
• 
The randomisation coordinator will document the status of all screened subjects and kits and will 
keep track of the balance between treatment sequences and unused kits available at the sites.  
• 
A subject will only be considered randomised after his/her eligibility has been confirmed at VR. 


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2.5 
Treatments  
2.5.1 
Test drug formulations 
THN102 is a combination drug constituted by modafinil 100 mg tablets over-encapsulated and 
flecainide capsules of 1 mg or 9 mg. Daily dosages are: Modafinil 200 mg and flecainide: 2 or 18 mg. 
 
Drug code: 
Modafinil (Modiodal® Teva) 
Dosage form: 
1 tablet of 100 mg, over-encapsulated (orange capsule) 
Excipients: 
Tablet: Lactose monohydrate, pregelatinised starch (maize), microcrystalline 
cellulose, croscarmellose sodium, Povidone K29/32, magnesium stearate. 
Capsule, filler: Gelatine, Swedish Orange, microcrystalline cellulose. 
Vials: 
Capsules will be provided into HDPE snap-cap vials containing 18 capsules each. 
Storage: 
15-25 °C (avoid exposure >25°C) 
 
Route:  
Oral 
Dose: 
2 capsules containing 100 mg each, at 8:00 h (± 1:00 h) in the morning.  
A 24-hour (± 1:00 h) interval between two consecutive doses is required. 
 
For subjects aged above 65 years: 
On the first, second and third day of each treatment period, 1 capsule will be taken. 
From the fourth to the last day of each treatment period, the regimen will be as 
described above. 
 
Drug code: 
Flecainide (manufactured by PCA, Central Pharmacy of the French Army) 
Dosage form: 
1 or 9 mg of flecainide powder per capsule (white capsule) 
Excipients: 
Tablet: Microcrystalline cellulose (Avicel PH112), magnesium stearate. 
 
Capsules: Hypromellose (HPMC) 
Storage: 
15-25 °C  
Route:  
Oral 
Vial: 
Capsules will be provided in HDPE snap-cap vials containing 18 capsules each. 
Dose: 
2 capsules containing 1 or 9 mg each, in the morning at the same time as 
modafinil. 
 
For subjects aged above 65 years: 
On the first, second and third day of each treatment period, 1 capsule will be taken. 
From the fourth to the last day of each treatment period, the regimen will be as 
described above. 
 
2.5.2 
Reference drug formulations 
THN102 Placebo is a combination drug constituted by modafinil 100 mg placebo tablets over-
encapsulated and by flecainide placebo capsules. Daily dosages are: Modafinil 0 mg and flecainide: 0 
mg. 
 
Drug code: 
Modafinil placebo 
Dosage form: 
1 tablet of 0 mg, over-encapsulated (orange capsule) 
Excipients: 
Tablet: Lactose monohydrate, pregelatinised starch (maize), microcrystalline 
cellulose, croscarmellose sodium, Povidone K29/32, magnesium stearate. 
Capsule, filler: Gelatine, Swedish Orange, microcrystalline cellulose. 
Vials: 
Capsules will be provided into HDPE snap-cap vials containing 18 capsules each. 
Storage: 
15-25 °C (avoid exposure >25°C) 
 
Route:  
Oral 
Dose: 
2 capsules containing 0 mg each, at 8:00 h (± 1:00 h) in the morning 
A 24-hour (± 1:00 h) interval between two consecutive doses is required. 


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For subjects aged above 65 years: 
On the first, second and third day of each treatment period, 1 capsule will be taken. 
From the fourth to the last day of each treatment period, the regimen will be as 
described above. 
 
Drug code: 
Flecainide placebo 
Dosage form: 
0 mg of flecainide powder per capsule (white capsule) 
Excipients: 
Tablet: Microcrystalline cellulose (Avicel PH112), magnesium stearate. 
 
Capsules: Hypromellose (HPMC) 
Storage: 
15-25 °C  
Route:  
Oral 
Vial: 
Capsules will be provided in HDPE snap-cap vials containing 18 capsules each. 
Dose: 
2 capsules containing 0 mg each, in the morning at the same time as modafinil 
placebo. 
For subjects aged above 65 years: 
On the first, second and third day of each treatment period, 1 capsule will be taken. 
From the fourth to the last day of each treatment period, the regimen will be as 
described above. 
 
2.6 
Sample Size 
For sample size planning ESS was considered to be the key efficacy endpoint. Solid information on 
the expected difference between placebo and THN102 dose and the associated intrasubject variance 
were not available. Using results reported in Adler et al. [4] as a rough orientation an effect size of 
0.40 may constitute a conservative estimation for the comparison of the high THN102 dose with 
placebo. A sample size of 54 subjects will have a power of 82% to detect this effect size based on a 
paired t-test with a 0.05 two-sided significance level. To account for drop outs 60 subjects will be 
randomised. 
 
In this exploratory phase 2a study, no adjustment for multiple testing will be applied. 
2.7 
Blinding 
Modafinil 100 mg capsules and modafinil placebo capsules are identical in size, colour and 
appearance. The packaging and labelling will not allow for any distinction between them. 
Likewise, flecainide 1 mg capsules, flecainide 9 mg capsules and flecainide placebo capsules are 
identical in size, colour and appearance. The packaging and labelling will not allow for any distinction 
between them. 
During the trial, the subject and all personnel involved with the conduct and the interpretation of the 
trial, including the investigators, site personnel, and the sponsor’s staff, are blinded to the treatment 
assignment. The randomisation schedule is filed securely by the clinical CRO, in a manner such that 
blinding is properly maintained throughout the trial. Treatment assignment will not be available until 
the completion of the trial and until after final data review (clinical data base lock), except in the case 
of emergency. 
3. ANALYSIS SETS AND SUBGROUPS 
3.1 
Analysis sets 
The Enrolled Set (ES) includes all subjects who have signed the informed consent form. 
The Randomised Set (RS) includes all subjects randomised at visit VR. 
The Safety Set (SS) includes all subjects with at least one IMP administration. 


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The Full Analysis Set (FAS) includes all randomised subjects with an evaluable ESS score at the end 
of at least one treatment period. Evaluability of treatment periods is described in Section 5.6. The 
efficacy analyses will be conducted on the FAS. 
The Per Protocol (PP) set includes all subjects in the FAS who have at least one treatment period 
without a major protocol deviation. Major and minor violations are defined in Sections 5.1.2 and 5.6. 
The main secondary endpoints (ESS, PVT and cognition) will be analysed with the PP set to 
demonstrate robustness of the primary analysis. 
The PK analysis set will include all subjects who have received treatment as per protocol (even if the 
trial was not completed) and who present no major protocol deviations with an impact on PK. 
3.2 
Subgroups 
No subgroups are defined for the primary analysis of this study. 
 


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4. GENERAL DEFINITIONS AND NAMING CONVENTIONS   
To avoid ambiguity during the analysis, a number of definitions and conventions for data handling are 
described here. 
4.1 
General Methodology and Presentation of the Results 
The default summary statistics for quantitative (continuous) variables will be  
- 
the number of subjects (n),  
- 
mean,  
- 
standard deviation (SD),  
- 
median,  
- 
first quartile (Q1) and third quartile (Q3) 
- 
minimum (min) and maximum (max)  
for subjects with data. Additionally, the geometric mean (GeoMean), geometric standard deviation 
(GSD), and geometric coefficient of variation (GCV) will be displayed for certain variables. Values of 
‘0’ will be removed from the calculation of the geometric mean, GSD, and GCV. 
Mean, geometric mean, median, and the quartiles will be presented to one more decimal place than the 
raw value. The minimum and maximum values will be presented with the same decimal precision as 
the raw value. SD, GSD, and GCV will be reported to two decimal places greater than the original 
value. 
For qualitative (categorical) variables, the frequency count (n) and percentage (%) of subjects with non-
missing data per category will be the default frequency tabulations. Where appropriate and present, the 
number of missing values will be displayed as “Missing” category. 
Percentage values are to be presented to one decimal place, for example, 52.3%. 
The denominator used for calculation of the percentages will be specified in a footnote to the tables for 
clarification. 
4.2 
Statistical Output Layout 
All titles and column headers (consisting of one or several words) will be capitalised; articles, 
prepositions, and conjunctions, and “To” in infinitives will not be capitalised, except they are at the 
beginning of titles or headers. 
All pages will be numbered according to the table/listing/figure to which the page belongs to. Every 
table/listing/figure will be numbered from page 1, “Page X of Y” at the bottom of each page. 
The definition of baseline and endpoint value will be described in a footnote in every TLF where 
applicable. Other important definitions will also be presented if necessary. 
Dates will be listed in the format: yyyy-mm-dd (e.g. 2003-11-20). Times will be listed in the format: 
hh:mm (e.g. 09:15) or in the format hh:mm:ss if seconds are collected. When the date and time are 
collected, these are listed in the format: yyyy-mm-ddThh:mm (e.g. 2003-11-20T09:15), 
yyyy-mm-ddThh, or yyyy-mm-ddThh:mm:ss.  
Partially missing dates will be listed in the format yyyy-mm (e.g. 2013-11) if only day is missing or in 
the format yyyy (e.g. 2013) if month and day are missing. 
Missing data including missing dates or times will be displayed in listings as blank fields, unless 
otherwise specified. 
Listings will be sorted by subject’s number and visit number where applicable, unless specified 
otherwise. 
 
 


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4.3 
Treatment Group Names and Labels 
Statistical output will be presented by treatment sequence or treatment. Tables and figures that are 
displayed by treatment sequence or by treatment will be labelled with an S or T respectively. The labels 
used for treatment sequences and pooled treatment groups can be seen below (Table 3 and Table 4 
respectively). For more details data pooling by treatment, see Sections 4.6-4.8. 
Table 3: Sequence Labels 
Description 
Label in Statistical Output 
Sequence 1: Dose A – Dose B – Dose C 
ABC 
Sequence 2: Dose B – Dose C – Dose A 
BCA 
Sequence 3: Dose C – Dose A – Dose B 
CAB 
Sequence 4: Dose A – Dose C – Dose B 
ACB 
Sequence 5: Dose C – Dose B – Dose A 
CBA 
Sequence 6: Dose B – Dose A – Dose C 
BAC 
 
Table 4: Treatment Labels 
Description 
Label in Statistical Output 
Placebo 
Placebo or A 
THN102 200 mg/2 mg 
Test 200/2 or B 
THN102 200 mg/18 mg 
Test 200/18 or C 
 
4.4 
Visit Numbering and Labels 
The numbers to be used in the analysis datasets and the labels to be used in the tables, listings and 
figures for the different trial visits are defined in Table 5. 
Table 5: Visit Numbering and Labels 
Visit number 
Visit name 
Label in Statistical Output 
10 
Screening – VS1 
VS1 
20 
Actigraphy – VS2 
VS2 
30 
Baseline – VR 
VR 
40 
Actigraphy – V1A 
V1A 
50 
End of treatment I – V1B 
V1B 
60 
End of washout I – V1C 
V1C 
70 
Actigraphy – V2A 
V2A 
80 
End of treatment II – V2B 
V2B 
90 
End of washout II – V2C 
V2C 
100 
Actigraphy – V3A 
V3A 
110 
End of treatment III – V3B 
V3B 
120 
Early Discontinuation Visit – EDV 
EDV 
130 
Follow-up – V3C 
V3C 
The values collected at the EDV will be slotted according to date of EDV occurrence (see 
Section 4.6). 
 
 


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4.5 
Treatment Day Numbering 
All assessment dates will be related to the first day of IMP intake during the first treatment period. This 
first day of IMP intake is referred to as Day 1. Day –1 is the day that is preceding Day 1 and Day 0 will 
not be defined. 
Treatment days may alternatively be numbered in listings with reference to the ongoing treatment period 
using the following rules: 
- 
Dates prior to or during the first treatment period will be numbered with reference to the date 
of first IMP intake as described above. 
- 
Dates belonging to the second and third treatment periods will be numbered with reference to 
the day after visit V1C or V2C respectively. 
- 
Treatment days during any treatment period will be labelled according to the planned treatment 
sequence of the subject (e.g. A-11 for day 11 of the first treatment period in the sequence ABC). 
Treatment days prior up to visit VR will be labelled without reference to treatment sequence. 
4.6 
Trial Periods 
Baseline period 
The baseline period will be defined as the period from informed consent signature date to the date of 
visit VR. 
Treatment periods 
The periods from the day after visits VR, V1C, and V2C, to the dates of visits V1B, V2B, and V3B 
respectively, will be defined as the three treatment periods of this trial. 
Data collected at visits V1B, V2B, and V3B will be considered as end-of-treatment values for their 
respective treatment periods. 
If an early discontinuation visit (EDV) occurs after 7 or more IMP intakes, and not more than 3 days 
after the last IMP intake, the data collected at the EDV will be assigned to the end of the ongoing 
treatment period for statistical analyses. 
 
Washout periods 
The periods from the day after visits V1B and V2B, to the dates of visits V1C and V2C respectively 
will be defined as the two washout periods of this trial. 
Data collected at visits V1C and V2C will be considered as end-of-washout values for the first and 
second treatment periods respectively and will be summarised within the same treatment as the end-of-
treatment values of the respective treatment period. 
If an EDV occurs 6 or more days after the last IMP intake of the preceding treatment period, the data 
collected at the EDV will be assigned to the end of the ongoing washout period for statistical analyses. 
Follow-up period 
The follow-up period is a trial period starting with the day after visit V3B/EDV until the trial termination 
date. 
 
 


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4.7 
Baseline and Endpoint Values 
Baseline value 
The baseline value for a variable is defined as the last non-missing value collected before or during visit 
VR. 
For diary data, the baseline value will be the value standardised as described in Section 5.6.8 over the 
baseline period. 
Endpoint value 
The endpoint value for a variable is defined as the last non-missing value collected during any 
end-of-treatment visit (V1B, V2B, or V3B). 
For diary data, the endpoint value will be the value standardized as described in Section 5.6.8 over any 
treatment period corresponding to a given treatment. 
Absolute change from baseline will be calculated as 
𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝐶ℎ𝑎𝑛𝑔𝑒 𝑓𝑟𝑜𝑚 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑎𝑡 𝑉𝑖𝑠𝑖𝑡 𝑋= 𝑉𝑎𝑙𝑢𝑒 𝑎𝑡 𝑉𝑖𝑠𝑖𝑡 𝑋−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑎𝑙𝑢𝑒 
Relative change from baseline (%) will be calculated as 
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐶ℎ𝑎𝑛𝑔𝑒 𝑓𝑟𝑜𝑚 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑎𝑡 𝑉𝑖𝑠𝑖𝑡 𝑋= 𝑉𝑎𝑙𝑢𝑒 𝑎𝑡 𝑉𝑖𝑠𝑖𝑡 𝑋−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑎𝑙𝑢𝑒
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑎𝑙𝑢𝑒
× 100 
Note: Subjects with a baseline value of ‘0’ will be excluded from the calculation of relative change. 
 
4.8 
Treatment Assignment 
In summaries and analyses where data is pooled by treatment, assignment to treatments will be 
performed as follows: 
• 
Data collected up to and including visit VR (baseline) will be assigned to all treatments. 
• 
Data collected at visits V1A-V1C, V2A-V2C, V3A-V3B, will be assigned to the treatment 
corresponding to the first, second and third treatment period respectively 
• 
Data collected at the EDV visit will be assigned to treatment periods according to the rules in 
Section 4.6 
• 
Efficacy analyses will be performed according to treatment as randomised. Data will be assigned 
to treatments based on the combination of planned treatment sequence and treatment period. 
• 
Safety analyses will be performed according to treatment as treated. Data will be assigned to 
treatments based on the treatment actually received during the corresponding treatment period. 
Other features of or deviations from the rules of treatment assignment are discussed in the relevant 
sub-sections of Section 5. 
 
 


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4.9 
Coding Systems and Conventions 
4.9.1 
Coding of adverse events and medical history 
Adverse event and medical history investigator terms are assigned to a lowest level term (LLT) and a 
preferred term (PT) and will be classified by high level term (HLT), high level group term (HLGT) and 
system organ class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 21.0 [2]. 
4.9.2 
Coding of medications 
Medications are classified according to active drug substance using the World Health Organization-
Drug Dictionary Enhanced (WHO-DDE), 2018 March version [3]. The WHO drug code has 11 digits. 
The generic name is defined by the first 6 of the 11 digits. In addition, the Anatomical Therapeutic 
Chemical (ATC) classes are assigned to the drug code. In this trial, ATC codes are defined to the 4th 
level. 
4.10 Handling of Missing Data 
Data imputation methods will not be used in the analysis of efficacy or safety data. Efficacy data will 
be assumed to be missing at random (MAR), and likelihood-based estimation methods robust to this 
form of missingness will be used in efficacy analysis. Other details of handling of missing data, where 
applicable, are discussed in the relevant sub-sections of Section 5 (STATISTICAL ANALYSIS: 
DEFINITIONS, DERIVATIONS, CALCULATIONS AND METHODOLOGY). 
 


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5. STATISTICAL ANALYSIS: DEFINITIONS, DERIVATIONS, CALCULATIONS AND 
METHODOLOGY 
5.1 
Subjects Disposition  
5.1.1 
Disposition and Withdrawals 
The following disposition data will be collected: 
- 
date of informed consent 
- 
date of trial termination 
- 
did the subject complete the trial as scheduled (yes, no) 
- 
reason for premature trial termination (at their own request (specified), investigator’s 
opinion, major protocol deviations, treatment incompliance, prohibited concomitant 
therapy, adverse event, at the specific request of the sponsor, other (specified)) 
Screening failures will be all subjects discontinuing the trial due to any reason prior to randomisation 
at visit VR. 
Withdrawals will be all subjects randomised at visit VR who do not complete the trial (visits V1A-
V3B) as scheduled. 
The following tables and listings will be presented: 
Table 15.1.1.1.S Analysis Sets – Enrolled 
Table 15.1.1.2.T Analysis Sets – Enrolled 
Number and percentage of subjects included into the enrolled, randomised, safety, full analysis, per 
protocol, and PK analysis sets will be provided. Percentage will be based on the number of subjects in 
the enrolled set. 
Table 15.1.1.3 Reasons for Exclusions from Analysis Sets – Enrolled 
Number and percentage of subjects excluded from the randomised, safety, full analysis, per protocol, 
and PK analysis sets will be provided. Percentage will be based on the number of subjects in the enrolled 
set. The reasons of exclusion from the analysis sets will be incorporated into the table. 
Table 15.1.2 Screening Failures – Enrolled 
Counts and percentages of subjects who discontinued the trial prior to randomisation at visit VR will 
be summarised by reasons associated with the discontinuation. Percentage will be based on the number 
of subjects in the enrolled set. 
Table 15.1.3.1.S Subject Disposition – Randomised 
Table 15.1.3.2.S Subject Disposition – Safety 
Counts and percentages of subjects who completed the treatment phase as scheduled, drop-outs during 
the treatment phase will be summarised separately in each period and overall. Reasons associated with 
the termination will be included. Percentage will be based on the number of subjects in the safety set. 
Table 15.1.4.1 Number of Subjects by Country and Site – Enrolled 
Table 15.1.4.2 Number of Subjects by Country and Site – Randomised 
Table 15.1.4.3 Number of Subjects by Country and Site – Safety 
Counts and percentages of subjects will be presented by site. Percentage will be based on the number 
of subjects in the safety set. 
Table 15.1.5.S Number of Subjects by Visit – Safety 
Counts and percentages of subjects who continue in the trial will be presented by visit. Percentage will 
be based on the number of subjects in the safety set. 
Listing 16.2.1.1 Screening Failures – Enrolled 
Subjects who discontinued the trial prior to randomisation at visit VR will be listed. Reasons associated 
with the discontinuation will be displayed. 


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Listing 16.2.1.2 Subject Disposition – Randomised 
Listing 16.2.1.3 Subject Disposition – Safety 
Subjects who complete the trial as scheduled or as withdrawals will be listed. Reasons for premature 
trial termination will be displayed for drop-outs. 
Listing 16.2.1.4 Subject Visits – Enrolled 
All visits’ dates will be listed by subject. 
Listing 16.2.3 Exclusions from Analysis Sets – Enrolled 
Subjects excluded from any analysis set and corresponding reasons for exclusion will be listed. 
Figure 15.1.1.S Flow Chart of Subject Disposition – Enrolled 
Figure 15.1.2 Flow Chart of Analysis Sets – Enrolled 
5.1.2 
Protocol Deviations 
All analysis sets are defined in Section Error! Reference source not found.. The per protocol (PP) set 
is defined as all subjects who have completed the trial without major protocol deviation. 
During the Blind Data Review (BDR) the eligibility of subjects for the PP set will be assessed. The 
BDR will be performed after data entry, prior to locking the database. All decisions made during the 
BDR will be documented in the BDR report before the closure of the database. 
Protocol deviations are deviations from the procedures outlined in the clinical trial protocol or from 
subsequent protocol-related instructions like missed evaluations, incorrect timing of evaluations, 
non-compliance with the IMP, intake of prohibited medications or any non-adherence to the clinical 
trial protocol that impacts subject’s rights, safety or welfare. Protocol deviations that may affect the 
efficacy or PK outcome will be discussed during the BDR. 
An appropriate clinical trial team, including a physician, will review potential protocol deviations and 
relevant information regarding those deviations to determine a possible impact on safety or efficacy 
endpoints. A decision will be made as to the effect of the possible deviations to determine if it is 
considered major or minor. The status, major or minor, of each protocol deviation will be documented 
in the BDR report. A subject may have one or more major protocol deviations resulting in the exclusion 
of that subject from the per protocol analysis set. 
Reference listings will also be made available to help with the review of the protocol deviations. 
Note: Protocol deviations will, if possible, be validated against data recorded in the eCRF. Note where 
an answer for an inclusion/exclusion tick box differs from the algorithmic check of the criteria, the 
algorithmic check will overrule the tick box. 
Protocol deviations of the following categories and respective data listings will be reviewed during the 
BDR. 
Inclusion Criteria 
No. 
Inclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#01.  1. Subjects with a diagnosis of idiopathic Parkinson’s disease as defined 
by the Movement Disorders Society (MDS). 
major 
PD#02.  2. Subjects with Hoehn and Yahr scale score ≤ 4. 
case by case 
PD#03.  3. Males or females, aged between 18 and 75 years. 
 
Since Protocol Version 6.0 (or 8.0 France): 
3. Males or females, aged between 18 and 80 years. 
case by case 


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No. 
Inclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#04.  4. Body mass index > 18 kg/m2 and < 30 kg/m2. 
 
Since Protocol Version 6.0: 
4. Body mass index > 18 kg/m2 and < 35 kg/m2. 
 
For Protocol Version 8.0 France: 
4. Body mass index > 18 kg/m2 and < 30 kg/m2. 
case by case 
PD#05.  5. Subjects should have a complaint of daytime sleepiness impacting their 
quality of life and/or daytime functioning (e.g. falling asleep while 
reading or watching TV, while eating or talking with other people). 
major 
PD#06.  6. Epworth Sleepiness Scale (ESS) score ≥ 14. 
major 
PD#07.  7. Women of childbearing potential (not surgically sterile or < 2 years 
postmenopausal), must use a highly effective method of contraception, 
and must continue for the duration of the trial (and for 2 months after 
participation in the trial). Highly effective methods of contraception 
include hormonal contraception associated with inhibition of ovulation 
(combined estrogen/progestogen: oral, intravaginal, transdermal; 
progestogen-only: oral, implanted, and injected) in conjunction with a 
barrier method (preferably male condom). Highly effective methods 
further include intrauterine device (IUD), intrauterine hormone-releasing 
system (IUS), bilateral tubal occlusion, vasectomised partner (provided 
that the partner is the sole sexual partner of the subject and the 
vasectomised partner has received medical assessment of the surgical 
success) and sexual abstinence, i.e. when this is in line with the preferred 
and usual lifestyle of the subject. 
minor 
PD#08.  8. Subjects willing and able to follow trial procedures (including to 
swallow IMP capsules) and to regularly attend scheduled clinic visits as 
specified in the protocol, and who have signed the informed consent prior 
to any screening procedure.  
minor 
 
Exclusion Criteria 
No. 
Exclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#09.  1. Subjects with known or with a suspected sleep apnea syndrome or who 
have any other cause of excessive daytime sleepiness, such as shift work 
sleep disorder. 
major 
PD#10.  2. Psychiatric and neurological disorders (other than Parkinson’s disease), 
such as idiopathic narcolepsy, Alzheimer’s disease, Huntington’s Chorea, 
multiple sclerosis, epilepsy, psychosis, bipolar disorder, severe clinical 
anxiety or depression, multiple system atrophy (Shy-Drager syndrome) or 
other problem that in the investigator’s opinion would preclude the 
subject’s participation and completion of this trial or comprise reliable 
representation of subjective symptoms. 
case by case 
PD#11.  3. Cardiovascular disorders such as 
a. Uncontrolled moderate to severe hypertension 
b. ECG QTcF duration ≥ 450 ms (men) or ≥ 470 (women) 
case by case 


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No. 
Exclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
c. ECG signs of left ventricular hypertrophy (exclusion if at least 
one of the three indices is abnormal): 
• 
Sokolow-Lyon voltage (sum of amplitude of the S wave in 
lead V1 and the R wave in lead V5 or V6 ≥ 3.5 mV), or 
• 
Cornell voltage (S wave in V3 + R wave in aVL > 2.8 mV in 
men or > 2.0 mV in women), or 
• 
Modified Cornell (R wave in aVL > 1.1 mV) 
d. Recent (less than three months before screening visit VS1) 
myocardial infarction  
e. Stable or unstable angina pectoris 
f. Cardiac insufficiency 
g. Previous history of heart failure 
h. Previous history of cardiac valvular surgery 
i. 
Ventricular arrhythmias considered as clinically significant 
j. 
Atrial fibrillation unless it is stable and controlled by stable doses 
of amiodarone, calcium channel blocker or beta-blocker 
k. 2nd or 3rd grade atrioventricular block or chronic bifascicular 
block, unless an adequate pacemaker is present 
l. 
Sinus node dysfunction 
m. Documented Brugada syndrome 
 
For France only: 
3. Cardiovascular disorders such as 
a. Uncontrolled moderate to severe hypertension 
b. ECG QTcF duration ≥ 450 ms (men) or ≥ 470 (women) 
c. ECG signs of left ventricular hypertrophy (exclusion if at least 
one of the three indices is abnormal): 
• 
Sokolow-Lyon voltage (sum of amplitude of the S wave in 
lead V1 and the R wave in lead V5 or V6 ≥ 3.5 mV), or 
• 
Cornell voltage (S wave in V3 + R wave in aVL > 2.8 mV in 
men or > 2.0 mV in women), or 
• 
Modified Cornell (R wave in aVL > 1.1 mV) 
d. Recent (less than three months before screening visit VS1) 
myocardial infarction  
e. Stable or unstable angina pectoris 
f. Cardiac insufficiency 
g. Previous history of heart failure 
h. Previous history of cardiac valvular surgery 
i. 
Ventricular arrhythmias 
j. 
Atrial fibrillation unless it is stable and controlled by stable doses 
of amiodarone, calcium channel blocker or beta-blocker 
k. 2nd or 3rd grade atrioventricular block or chronic bifascicular 
block, unless an adequate pacemaker is present 
l. 
Sinus node dysfunction 
m. Documented Brugada syndrome 
n. Cardiogenic shock, severe bradycardia (less than 50 bpm), severe 
hypotension, hemodynamically significant valvular heart disease 


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No. 
Exclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
o. Mitral valve prolapse in subjects who have experienced the mitral 
valve prolapse syndrome when previously receiving CNS 
stimulants. 
PD#12.  4. Subjects with current impulse control disorder. 
minor 
PD#13.  5. Subjects showing dementia or with MoCA < 23. 
case by case  
PD#14.  6. Subjects with current suicidal risk, based on investigator’s clinical 
judgement or with a “yes” answer to item 4 and/or 5 of the Columbia-
Suicide Severity Rating Scale (C-SSRS) at VS1, referring to the last 
month before screening. 
minor 
PD#15.  7. Current or recent (within one year) history of substance abuse or 
dependence disorder as defined in Diagnostic and Statistical Manual of 
Mental Disorders (DSM-V), e. g. alcohol. Tobacco use is accepted. 
case by case  
PD#16.  8. Other active clinically significant illness, including unstable 
cardiovascular or malignant pathology, significant abnormality in physical 
examination or clinical laboratory results at VS1, which could interfere 
with the trial conduct or counter-indicate the trial treatments or place the 
subject at risk during the trial or compromise the trial participation. 
case by case  
PD#17.  9. Subjects with hepatic impairment (serum total bilirubin ≥ 2 mg/dL, 
except in patients diagnosed with Gilbert’s syndrome, or prothrombin time 
[PT] ≥ 13.7 s (except in patients on therapeutic anticoagulation), or serum 
albumin < 3.5 g/dL), or renal impairment (glomerular filtration rate [GFR] 
< 60 mL/min/1.73 m2, according to Kidney Disease Improving Global 
Outcomes (KDIGO)). 
case by case  
PD#18.  10. Known hypersensitivity to IMP (active ingredients or excipients of 
modafinil or flecainide capsules). 
case by case 
PD#19.  11. Subjects currently (or within 6 weeks before VS1) under one of the 
following medications (isolated intake up to 1 week can be accepted):  
a. Neuroleptics, anxiolytics, anticonvulsants. Benzodiazepines and 
benzodiazepine-like drugs are only authorised if used regularly at 
stable indicated doses with an evening intake as sleep promoting 
agents. 
b. Flecainide or other class I antiarrhythmic drugs. 
c. Psychostimulants (except caffeine if no abuse and stable 
consumption) such as, but not limited to, modafinil, methylphenidate, 
amphetamine. 
d. Antidepressants except if maintained at stable dose for at least 6 
weeks before visit VS1 and anticipated to remain stable during the 
trial in subjects with mild or moderate unipolar depression. 
e. Antiemetic medications (except domperidone), myo-relaxing 
drugs and opioids. 
f. Dopaminergic medications, unless they have been used at stable 
doses for at least 4 weeks before screening and it is anticipated that 
the doses will not be changed throughout the trial. Efficacious 
medication for Parkinson's disease should not be discontinued for the 
sole purpose of the subject's enrolment into this clinical trial but must 
be maintained at stable dosage levels. 
g. Centrally acting anti-obesity drugs. 
h. TNF-alpha inhibitors. 
case by case  


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No. 
Exclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#20.  12. Pregnancy or lactation. Women of childbearing potential who intend 
to be pregnant during the next few months. 
case by case 
PD#21.  13. Subjects protected by the law (legal guardianship). 
minor 
PD#22.  14. Subjects participating in any other clinical trial within 60 days prior to 
visit VS1 in this trial or still in the protected period imposed by a previous 
trial. 
case by case  
PD#23.  15. Subjects working in an occupation requiring variable shift work or 
routine night shifts. 
major 
PD#24.  16. Subjects who plan to travel involving time zone changes. 
case by case  
 
Additional trial conduct deviations 
No. 
Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#25.  IMP treatment compliance according to eCRF or diary <80% or >120%, 
by treatment period and overall 
case by case 
PD#26.  IMP repeatedly taken not according to schedule (earlier than 7:00 or later 
than 9:00) 
case by case 
PD#27.  Duration of treatment and washout periods 
case by case 
PD#28.  IMP intake deviations related to PK analysis 
case by case 
PD#29.  Intake of prohibited medications 
case by case 
PD#30.  Adverse events that may significantly affect the key efficacy or PK trial 
endpoints 
case by case 
PD#31.  PDs from the global Protocol deviations log that may significantly affect 
the key efficacy or PK endpoints and are not covered by other listings 
case by case 
The specific content and format of listings to be reviewed during the BDR meeting (including any 
additional requirements that may be necessary to aid in review) will be determined outside the scope of 
this SAP. 
Additional protocol deviation criteria were defined during the BDR meeting held on 10-FEB-2020. 
These deviations are described in full in the BDRM report (version Final 1.0, 20-FEB-2020). For a 
description of the rules and how they apply to efficacy and pharmacokinetic analysis, see Section 5.6 
and Section 5.7 respectively. 
The following tables and listing will be provided: 
Table 15.1.6.1.S Major Protocol Deviations – Safety 
Table 15.1.6.2.S Major Protocol Deviations – Full Analysis 
Number and percentage of subjects with major protocol deviations will be summarised by affected trial 
period and overall. The categories of major protocol deviations will be included. Percentage will be 
based on the number of subjects in the respective analysis set. 
Listing 16.2.2.1 Major Protocol Deviations – Safety 
Major protocol deviations will be listed including the affected trial periods. 


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5.1.3 
Inclusion/Exclusion 
The trial specific inclusion/exclusion criteria are presented in Section 4.2 and 4.3 of the Clinical Trial 
Protocol. For each criterion, as appropriate, a response of “Yes/No” is to be obtained at VS1, VS2, and 
checked again prior to confirmation of eligibility at Visit VR. 
The following listing will be provided: 
Listing 16.2.2.2 Inclusion Criteria Not Met and Exclusion Criteria Met – Enrolled 
Listing of inclusion criteria which were not met and exclusion criteria which were met will be presented 
per subject. 
5.2 
Demographic and Other Baseline Characteristics 
5.2.1 
Demographics 
The following demographic characteristics will be presented: 
- 
Age (years) 
- 
Gender 
- 
Race 
- 
Ethnicity 
- 
Alcohol consumption (≤ 200 mL beer or 100 mL wine per day, > 200 mL beer or 100 mL 
wine per day) 
- 
Education (12 years or less, more than 12 years) 
The following baseline characteristics will be presented: 
- 
Height (cm) 
- 
Weight (kg) 
- 
BMI (kg/m2) 
Subject alcohol consumption status at baseline will be presented in listings only. 
The following tables will be presented: 
Table 15.1.7.1.1.S Demographics – Safety 
Table 15.1.7.1.2.S Demographics – Full Analysis 
Table 15.1.7.1.3.S Demographics – Per Protocol 
Demographic data will be summarised using standard summary statistics or frequency tabulations as 
appropriate. Percentage for categorical variables will be based on the number of subjects in the 
respective analysis set. 
Table 15.1.7.2.1.S Baseline Characteristics – Safety 
Table 15.1.7.2.2.S Baseline Characteristics – Full Analysis 
Table 15.1.7.2.3.S Baseline Characteristics – Per Protocol 
Weight, height and BMI data at baseline will be summarised using standard summary statistics. 
Listing 16.2.4.1 Demographics and Baseline Characteristics – Enrolled 
Demographic and baseline characteristics’ data will be listed for the subjects in the enrolled set. 
5.2.2 
Baseline Disease Stage 
At visit VS1, the onset date of Parkinson’s disease and excessive daytime sleepiness as well as 
medication for these indications will be collected. 
Additionally, the stage of Parkinson’s disease at visit VS1 will be assessed using the modified Hoehn 
& Yahr scale. The scale contains 8 progression levels (0, 1, 1.5, 2, 2.5, 3, 4, 5). 
The following table and listing will be presented: 
Table 15.1.7.3.1.S Baseline Disease Stage – Safety 
Table 15.1.7.3.2.S Baseline Disease Stage – Full Analysis 
Table 15.1.7.3.3.S Baseline Disease Stage – Per Protocol 


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Hoehn & Yahr score will be summarised at baseline using standard frequency tabulations. 
Listing 16.2.4.2 Baseline Disease Stage – Enrolled 
Subjects’ neurological history will be listed. The substance names of medications taken for Parkinson’s 
disease and excessive daytime sleepiness at the date of visit VS1 will also be displayed. 
5.2.3 
Medical History  
Medical history encompasses relevant prior or ongoing relevant diseases, conditions, hospitalisation, 
and surgical procedures. Medical history records are collected at Visit VS1. 
Medical history of the subjects includes: 
- Diagnosis 
- Start date  
- Stop date (or ongoing) 
- Medication taken (yes, no) 
Medical history is classified as: 
- Prior medical conditions are the conditions which started and ended prior to Visit VS1. 
- Ongoing medical conditions are the conditions which are ongoing at Visit VS1 and include 
conditions with a stop date after Visit VS1. 
The following tables and listings will be provided:  
Table 15.1.8.1.1.S Prior Medical Conditions – Safety 
Table 15.1.8.1.2.S Prior Medical Conditions – Full Analysis 
Table 15.1.8.2.1.S Ongoing Medical Conditions – Safety 
Table 15.1.8.2.2.S Ongoing Medical Conditions – Full Analysis 
Medical history will be summarised displaying counts and percentages of subjects having at least one 
medical condition and will be presented by MedDRA SOC and by PT within the SOC. SOCs and PTs 
within the SOC are to be sorted by descending order of overall incidence. Subjects with two or more 
occurrences of the same condition (as qualified by its PTs) will be counted only once for the respective 
PT. Percentage will be based on the number of subjects in the respective set. 
Listing 16.2.4.3 Medical History – Enrolled 
Medical history conditions will be listed for the subjects from the enrolled set. 
 
 


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5.3 
Prior and Concomitant Medications 
Prior and concomitant medications and therapies are documented in the eCRF. 
The following information is collected: 
- Medication / therapy name 
- Indication (Parkinson’s disease, excessive daytime sleepiness, medical history diagnosis – 
specified, adverse event – specified, other) 
- Route 
- Total daily dose (units) 
- Frequency 
- Start date 
- Stop date (or ongoing) 
Medications and therapies will be classified as ‘prior’, ‘concomitant’ or ‘post-treatment’ based on 
start/stop dates: 
- Prior medications/therapies are defined as those medications/therapies starting and ending 
prior to the first IMP intake as recorded in the eCRF. 
- Concomitant medications/therapies are defined as medications/therapies started at or after 
the first IMP intake as recorded in the eCRF and include medications/therapies started prior 
to the first IMP intake but continued during the trial. 
- Post-treatment medications/therapies are defined as medications/therapies which started 
after the last IMP intake as recorded in the eCRF. 
If the start date of medication/therapy is incomplete or missing, it will be assumed to be concomitant 
except if the incomplete start date or the stop date indicates that the medication/therapy started prior 
to the first IMP intake or after the last IMP intake. 
Concomitant medications will be assigned to treatments based on the preceding IMP intake. 
Medications taken during a washout period will be assigned to the treatment of the IMP taken in the 
preceding treatment period. If the start or end date indicates that the medication was taken concurrently 
with multiple treatments, it will be assigned to every corresponding treatment. If the start or end date is 
incomplete such that it could belong to more than one treatment, the concomitant medication will be 
assigned to all such treatments. 
The following tables and listings will be provided:  
Table 15.1.9.1.1.S Prior Medications – Safety 
Table 15.1.9.1.2.S Prior Medications – Full Analysis 
Table 15.1.9.2.1.T Concomitant Medications – Safety 
Table 15.1.9.2.2.T Concomitant Medications – Full Analysis 
The number and percentage of subjects with at least one medication within each ATC 2nd level 
subgroup and substance name will be presented for the respective set. The ATC 2nd level subgroups 
and substance name within ATC 2nd level subgroup will be ordered by descending overall incidence. 
Listing 16.2.4.4 Medications and Therapies – Enrolled 
All medications, prior, concomitant and post-treatment, will be listed for the subjects from the enrolled 
set. 
 
 


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5.4 
Exposure to IMP and Compliance 
5.4.1 
Exposure to IMP 
Exposure data from eCRF includes: 
- 
date of first IMP intake  
- 
date of last IMP intake 
- 
date of IMP dispensed 
- 
number of capsules dispensed (modafinil and flecainide) 
- 
date of IMP returned 
- 
number of capsules returned (modafinil and flecainide) 
Exposure data from the subject treatment diaries includes: 
- 
date 
- 
number of capsules taken (modafinil and flecainide) 
The date of first IMP intake is the intake of the first morning dose as recorded in the eCRF. If the date 
of first intake as recorded in the eCRF is missing, the first IMP intake recorded in the subjects’ diaries 
will be used. 
The date of last IMP intake is the date of last IMP intake recorded at trial termination page. If the date 
of last intake of the last evaluated dose is missing, the last IMP intake recorded in the subject diaries 
will be used. 
The treatment period duration will be calculated in days as follows:  
𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑑𝑎𝑦𝑠) = 𝑒𝑛𝑑-𝑜𝑓-𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑣𝑖𝑠𝑖𝑡 𝑑𝑎𝑡𝑒−𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑖𝑠𝑖𝑡 𝑑𝑎𝑡𝑒 
For the purposes of treatment period duration calculation, visit VR as well as end-of-washout visits 
V1C and V2C are considered as baseline visits. 
Treatment duration based on IMP exposure data will be calculated for each treatment period as:  
𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑑𝑎𝑦𝑠) = 𝑙𝑎𝑠𝑡 𝐼𝑀𝑃 𝑖𝑛𝑡𝑎𝑘𝑒 𝑑𝑎𝑡𝑒 −𝑓𝑖𝑟𝑠𝑡 𝐼𝑀𝑃 𝑖𝑛𝑡𝑎𝑘𝑒 𝑑𝑎𝑡𝑒 + 1 
within the respective treatment period. The overall treatment and treatment period durations will be 
calculated as the sum of corresponding individual durations. 
The following will be provided: 
Table 15.1.10.1.1.T Treatment Duration (days) – Safety 
Table 15.1.10.1.2.T Treatment Duration (days) – Full Analysis 
Table 15.1.10.1.3.T Treatment Duration (days) – Per Protocol 
The default summary statistics of treatment period duration and treatment duration will be presented by 
period and overall. 
5.4.2 
Compliance 
Compliance based on the eCRF and subject diaries will be calculated as follows: 
𝑒𝐶𝑅𝐹 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%) = 100 ∗(𝑁 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑁 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑)
𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛∗𝑁 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑝𝑟𝑒𝑠𝑐𝑟𝑖𝑏𝑒𝑑 𝑝𝑒𝑟 𝑑𝑎𝑦 
𝑑𝑖𝑎𝑟𝑦 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%) =
100 ∗𝑁 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑡𝑎𝑘𝑒𝑛 
𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛∗𝑁 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑝𝑟𝑒𝑠𝑐𝑟𝑖𝑏𝑒𝑑 𝑝𝑒𝑟 𝑑𝑎𝑦 
The default number of tablets prescribed per day is 2 tablets of modafinil and flecainide, for a total of 
4 tablets per day. For subjects older than 65 years of age at visit VS1, on the first three days of each 
treatment period the dosage is halved, resulting in one tablet of modafinil and flecainide scheduled to 
be taken for a total of 2 tablets per day. 


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Compliance will be calculated for modafinil and flecainide tablets as well as overall. The overall 
compliance will be calculated via the sum of modafinil and flecainide tablets dispensed, returned or 
taken at the corresponding timepoint. 
Compliance will be calculated for each treatment period and overall. The individual treatment 
duration or overall treatment duration (see Section 5.4.1) will be used respectively. 
Compliance will be summarised as follows: 
Table 15.1.10.2.1.T Treatment Compliance (eCRF) – Safety 
Table 15.1.10.2.2.T Treatment Compliance (eCRF) – Full Analysis 
Table 15.1.10.2.3.T Treatment Compliance (eCRF) – Per Protocol 
The default summary statistics of compliance based on the eCRF within each treatment period and 
overall will be presented. Number and percentage of subjects will also be summarised by compliance 
categories (< 80%, ≥ 80% and ≤ 120%, >120%) for the respective analysis set. Compliance for 
modafinil and flecainide tablets will be displayed in addition to the overall compliance. 
Table 15.1.11.2.1.T Treatment Compliance (Diary) – Safety 
Table 15.1.11.2.2.T Treatment Compliance (Diary) – Full Analysis 
Table 15.1.11.2.3.T Treatment Compliance (Diary) – Per Protocol 
The default summary statistics of compliance based on the subject diaries within each treatment period 
and overall will be presented. Number and percentage of subjects will also be summarised by 
compliance categories (< 80%, ≥ 80% and ≤ 120%, >120%) for the respective analysis set. Compliance 
for modafinil and flecainide tablets will be displayed in addition to the overall compliance. 
Listing 16.2.5.1 Exposure to IMP and Compliance – Safety 
 
5.5 
Safety Analysis 
Safety will be assessed by evaluation of the following variables: 
- Adverse events 
- Safety laboratory (haematology, biochemistry, urinalysis) 
- Vital signs (blood pressure, heart rate) 
- 12-lead electrocardiogram (ECG) 
- Columbia-Suicide Severity Rating Scale (C-SSRS) 
- Movement Disorder Society-sponsored version of Unified Parkinson's Disease Rating 
Scale (MDS-UPDRS) 
- Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating Scale 
(QUIP RS) 
The safety set will be used for the analysis of the safety data. 
5.5.1 
Adverse Events 
AEs will be coded according to MedDRA Version 21.0. 
Adverse event data includes:  
- adverse event name 
- start date 
- stop date or ongoing 
- severity (mild, moderate, severe) 
- relationship to the IMP (unrelated, unlikely, possible, probable, definite) 
- action taken with IMP (no action, drug interrupted, drug withdrawn, unknown) 
- other actions (none, medication required, tests required, hospitalisation required or prolonged, 
other) 


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- outcome (recovered/resolved, recovered/resolved with sequelae, recovering/resolving, not 
recovered/not resolved, fatal, unknown) and date of outcome 
- serious (yes or no) 
All AEs will be presented in listings. 
Adverse event summaries will focus on treatment-emergent adverse events (TEAEs), defined as AEs 
with an onset or worsening after the first IMP intake and not more than 7 days after the last IMP intake. 
If the start date of an AE is incomplete or missing, it will be assumed to be treatment-emergent except 
if the stop date or the incomplete start date indicates that the event started prior to the first IMP intake 
or later than 7 days after the last IMP intake. 
Treatment-emergent adverse events will be assigned to treatments based on the treatment period 
containing the AE onset date. If the onset date of an adverse event is during a washout period, it will be 
assigned to the preceding treatment period. If the AE onset date is incomplete such that it could belong 
to more than one treatment period, the AE will be assigned to all treatments corresponding to such 
treatment periods. 
Based on collected data the following will be determined and will be used in addition to AEs overall 
for presentation in the applicable tables and listings: 
- Serious Adverse Events (SAEs): defined as AEs considered by the investigator as serious. 
- Related TEAEs: defined as AEs with relationships to the IMP assessed as being “possible”, 
“probable” or “definite” and include AEs with missing IMP relationship assessments. 
- Unrelated TEAEs: defined as AEs with relationships to the IMP assessed as being “unlikely” 
or “unrelated”.  
- Severe TEAEs: defined as AEs assessed as being “severe” in intensity and include the events 
with missing severity assessment. 
- TEAEs leading to discontinuation: defined AEs whose action taken with IMP is “drug 
withdrawn” or other action taken is “withdrawal from trial”. 
- TEAEs leading to death: selected as those events where outcome of event is indicated as 
“fatal”. 
The duration of the AE will be calculated using the following formula: 
𝐴𝐸 𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑑𝑎𝑦𝑠) = 𝐴𝐸 𝑠𝑡𝑜𝑝 𝑑𝑎𝑡𝑒−𝐴𝐸 𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒+ 1 
If the start or stop dates of the AE are incomplete or AE is still ongoing at the end of the trial, the 
duration will not be calculated. 
The following tables and listings will be provided:  
Table 15.2.1.1.1.S Overall Summary of TEAEs – Safety 
Table 15.2.1.1.2.T Overall Summary of TEAEs – Safety 
An overview of TEAEs:  
- TEAE  
- Non-Serious TEAE  
- Serious TEAE  
- Related TEAE 
- Related Serious TEAE 
- Severe TEAE 
- TEAE leading to discontinuation 
- Serious TEAE leading to discontinuation 
- Related TEAE leading to discontinuation 
- TEAE leading to death  
will be displayed for the subjects in the safety set. 


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Table 15.2.1.2.T Incidence of TEAEs – Safety 
Table 15.2.1.3.T Incidence of Non-Serious TEAEs – Safety 
Table 15.2.1.4.T Incidence of Serious TEAEs – Safety 
Table 15.2.1.5.T Incidence of Related TEAEs – Safety 
Table 15.2.1.6.T Incidence of Related Serious TEAEs – Safety 
Table 15.2.1.7.T Incidence of TEAEs Leading to Discontinuation – Safety 
Table 15.2.1.8.T Incidence of TEAEs Leading to Death – Safety 
TEAEs will be summarised by displaying the numbers of adverse events, as well as counts and 
percentages of subjects having experienced adverse events. Percentages will be based on the number of 
subjects in the safety set. SOCs and PTs within each SOC will be ordered by descending overall 
incidence. 
Table 15.2.1.9.T Incidence of TEAEs by Severity – Safety 
TEAEs will be summarised similarly as above within each adverse event severity level. 
All adverse event data will be listed as follows: 
Listing 16.2.6.1 Adverse Events: MedDRA Coding 
Listing 16.2.6.2 Adverse Events: General – Enrolled 
Listing 16.2.6.3 Serious Adverse Events – Safety 
Listing 16.2.6.4 AEs Leading to Discontinuation – Safety 
Listing 16.2.6.5 AEs Leading to Death – Safety 
All AEs will be displayed by subject including the PT of an AE, start and stop dates, duration and other 
characteristics of AEs. 
5.5.2 
Clinical Laboratory Evaluation 
Clinical laboratory values (haematology, biochemistry, and urinalysis) are collected at visit VS1, VR, 
V1B, V2B, and V3B/EDV for each laboratory parameter. 
The following parameters are collected:  
Haematology: Leukocytes, erythrocytes, haemoglobin, haematocrit, MCV, MCH, platelets, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils (%), lymphocytes (%), 
monocytes (%), eosinophils (%), basophils (%). 
Biochemistry: sodium, potassium, urea, creatinine, total protein, albumin, total bilirubin, direct 
bilirubin, AST (GOT), ALT (GPT), alkaline phosphatase, uric acid, glucose (fasting and non-fasting), 
cholesterol, triglycerides. 
Urinalysis: Leukocytes, nitrites, pH, protein, glucose, ketones, urobilinogen, bilirubin, blood, 
haemoglobin. 
Haematology and biochemistry test results are assigned an LNH classification according to whether the 
value is lower than (L), within (N) or higher than (H) the reference range for that parameter as provided 
by the corresponding laboratory. 
Clinical significance of laboratory values is evaluated by the investigator. 
Range values of laboratory results will be set to ½ of the specified threshold for analysis (e.g. a result 
of “<0.03” will be considered as 0.015 in summaries). 
The following tables and listings will be provided:  
Table 15.2.4.1.1.T Summary of Clinical Laboratory Tests: Haematology – Safety 
Table 15.2.4.1.2.T Summary of Clinical Laboratory Tests: Biochemistry – Safety 
Table 15.2.4.1.3.T Summary of Clinical Laboratory Tests: Urinalysis – Safety 
The default summary statistics of clinical laboratory test results will be presented at each visit. The 
absolute change from baseline will be presented for haematology and biochemistry findings. 


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Table 15.2.4.2.1.T Clinical Laboratory Tests: Incidence of Haematology Abnormalities – Safety 
Table 15.2.4.2.2.T Clinical Laboratory Tests: Incidence of Biochemistry Abnormalities – Safety 
Number and percentage of subjects for each laboratory parameter will be displayed in CS Low, Low, 
Normal, High, and CS High categories. Percentage will be based on the number of subjects at specified 
visit. 
Table 15.2.4.2.3.T Clinical Laboratory Tests: Incidence of Urinalysis Abnormalities – Safety 
Number and percentage of subjects with abnormal values of urinalysis parameters will be displayed in 
normal/abnormal/CS abnormal categories. Percentage will be based on the number of subjects at 
specified visit. 
Table 15.2.4.3.1.T Clinical Laboratory Tests: Shift Table of Haematology Results – Safety 
Table 15.2.4.3.2.T Clinical Laboratory Tests: Shift Table of Biochemistry Results – Safety 
Table 15.2.4.3.3.T Clinical Laboratory Tests: Shift Table of Urinalysis Results – Safety 
Shift tables showing changes in the number and frequency of subjects with respect to the normal range 
between baseline and endpoint will be provided. Subjects with missing data will be presented as part of 
a “missing” category. 
Listing 16.2.7.1 Laboratory Data – Haematology – Enrolled 
Listing 16.2.7.2 Laboratory Data – Biochemistry – Enrolled 
Values of laboratory tests will be listed. 
Listing 16.2.7.3 Laboratory Data – Urinalysis – Enrolled 
All urinalysis data will be listed.  
5.5.3 
Vital Signs 
Vital signs (systolic and diastolic blood pressure as well as heart rate) will be measured twice: after 5 
minutes supine rest and after 2 minutes in standing position (one set of supine and standing vital signs) 
at visits VS1, VR, V1B, V1C, V2B, V2C, and V3B/EDV. 
At VR, V1C and V2C three sets of supine and standing vital signs will be measured with 15-20 min 
intervals between the sets.  
Vital signs’ parameters will be summarised using the mean value at each visit. The mean will be 
calculated if there is at least one non-missing value for a given parameter. 
Results for systolic blood pressure, diastolic blood pressure, and heart rate will be classified according 
to whether the value was lower than (L), within (N) or higher than (H) the reference range for that 
parameter. The normal ranges are provided in Table .  
Table 6: Normal Ranges for Vital Signs 
Parameter 
Lower Reference 
Range 
Upper Reference 
Range 
Systolic blood pressure – Supine [mmHg] 
90 
140 
Diastolic blood pressure – Supine [mmHg] 
60 
90 
Systolic blood pressure – Standing [mmHg] 
80 
140 
Diastolic blood pressure – Standing [mmHg] 
60 
90 
Heart rate [bpm] 
50 
100 
The following tables and listings will be provided:  
Table 15.2.5.1.T Summary of Vital Signs – Safety 
Vital signs’ parameters will be summarised including change from baseline at each visit. 
Table 15.2.5.2.T Incidence of Vital Signs Abnormalities – Safety 
Number and percentage of subjects will be displayed in Low, Normal and High categories for every 
vital signs’ parameter. Percentage will be based on the number of subjects at specified visit. 


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Table 15.2.5.3.T Shift Table of Vital Signs Abnormalities – Safety 
Shift tables showing changes in the number and frequency of subjects with respect to the normal range 
between baseline and endpoint will be provided. Subjects with missing data will be presented as part of 
a “missing” category. 
Listing 16.2.8.1 Vital Signs – Enrolled 
5.5.4 
12-Lead Electrocardiogram (ECG) Data 
A 12-lead electrocardiogram (ECG) will be recorded after 10 minutes in supine position at visits VS1, 
VR, V1B, V1C, V2B, V2C, and V3B/EDV. The following ECG parameters will be collected: 
- 
Heart rate (bpm) 
- 
R-R interval (ms) 
- 
PR interval (ms) 
- 
QRS duration (ms) 
- 
QT interval (ms) 
- 
QT interval – Bazett correction (ms) 
- 
QT interval – Fridericia correction (ms) 
- 
Mean electrical axis (degrees) 
- 
ECG diagnosis 
- 
ECG abnormality assessment 
- 
Comparison to baseline 
ECG abnormality assessments of “Incomplete Analysis” and “Uninterpretable” will be considered as 
part of the “Not Applicable” category in summaries. 
The central ECG reading provider will also assess the ECG results against baseline, using the following 
categories: 
- 
Improved 
- 
Unchanged 
- 
Worsened 
- 
Not Applicable 
- 
Not compared 
The clinical significance of ECG abnormalities will be additionally assessed by the investigator. If the 
assessment of clinical significance differs between the investigator and the ECG reading provider, the 
investigator’s assessment will be used in the analysis. 
The following tables and listing will be presented: 
Table 15.2.6.1.T Summary of ECG Parameters – Safety 
ECG parameters will be summarised using default summary statistics including change from baseline 
at each visit. 
Table 15.2.6.2.T Summary of ECG Diagnoses – Safety 
The number and percentage of subjects with each ECG diagnosis will be displayed at each visit. 
Percentage will be based on the number of subjects at specified visit. 
Table 15.2.6.3.T Summary of ECG Abnormality Assessments – Safety 
Number and percentage of subjects with normal, abnormal, and CS abnormal ECG assessments will be 
displayed. Percentage will be based on the number of subjects at specified visit. 
Table 15.2.6.4.T Shift Table of ECG Abnormality Assessments – Safety 
Number and percentage of subjects with normal, abnormal, and CS abnormal ECG assessments will be 
displayed. Percentage will be based on the number of subjects at specified visit. 
Listing 16.2.8.2 Electrocardiogram – Enrolled 


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5.5.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a tool that was developed to facilitate a prospective, systematic monitoring for the 
emergence of suicidal tendencies in clinical studies. It is used to compare the occurrence, severity, and 
frequency of suicide-related thoughts and behaviours during treatment in a clinical trial.  
The C-SSRS Screening version will be used at VS1 to obtain baseline data, and the C-SSRS Since Last 
Visit version will be used to capture changes in the subject’s status at visits VR, V1B, V1C, V2B, V2C, 
and V3B/EDV. 
The following table and listing will be presented: 
Table 15.2.7.T Summary of Columbia-Suicide Severity Rating Scale – Safety 
Number and percentage of subjects with suicidal ideation and suicidal behaviour will be summarised 
using standard frequency tabulations at every visit. Percentage will be based on the number of subjects 
at specified visit. 
Listing 16.2.8.3 Columbia-Suicide Severity Rating Scale – Enrolled 
5.5.6 
Movement Disorder Society-Sponsored Version of Unified Parkinson's Disease Rating 
Scale (MDS-UPDRS) 
An MDS-UPDRS questionnaire is administered on visits VR, V1B, V2B, and V3B/EDV. The MDS-
UPDRS consists of four parts: 
1. Non-motor aspects of experiences of daily living (13 items) 
2. Motor aspects of experiences of daily living (13 items) 
3. Motor examination (33 scores based on 18 items) 
4. Motor complications (6 items) 
with each item being scored using an integer rating of 0 to 4.  
A score will be calculated for each part of the MDS-UPDRS as the sum of all items in that part of the 
questionnaire. According to Goetz et al. [5], a valid score for the MDS-UPDRS parts can be calculated 
if the respective part contains a number of missing values less than or equal to the following: 
- 
Non-motor aspects of experiences of daily living – 1 
- 
Motor aspects of experiences of daily living – 1 
- 
Motor examination – 3 
- 
Motor complications – 0 
For subjects with partially missing data, a prorated score will be calculated by taking the sum of all non-
missing items, dividing it by the number of non-missing items, and multiplying it by the total number 
of items in each part. The prorated score will be rounded to the nearest whole number. 
The total MDS-UPDRS score will be calculated as the sum of the scores of each part. The total score 
will not be calculated if the score for any part of the MDS-UPDRS is missing. 
The following table and listing will be presented: 
Table 15.2.8.T Summary of MDS-UPDRS – Safety 
Each part of the MDS-UPDRS as well as the total score will be summarised at baseline, and at the end 
of each treatment period using default summary statistics. 
Listing 16.2.8.4 MDS-UPDRS Questionnaire – Enrolled 
5.5.7 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating 
Scale (QUIP-RS) 
The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating Scale 
(QUIP-RS) is a tool designed to measure the severity of symptoms of impulse control disorders (ICDs) 
and related disorders. Subjects will complete the QUIP-RS at baseline (visit VR) and at the end of each 
treatment period (V1B, V2B, V3B/EDV). 


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The QUIP-RS consists of four primary questions, each applied to four ICDs (compulsive gambling, 
buying, eating and sexual behaviour) and three related disorders (medication use, punding and 
hobbyism). The QUIP-RS uses a 5-point scale (score 0-4 for each question) to rate the severity of each 
symptom based on its weekly frequency. The total ICD score ranges from 0 to 64, and the total 
QUIP-RS score for all ICDs and related disorders ranges from 0 to 112. 
The following tables and listing will be presented: 
Table 15.2.9.1.T Summary of QUIP-RS Items – Safety 
Each part of the QUIP-RS will be summarised at baseline and at the end of each treatment period using 
default frequency tabulations. 
Table 15.2.9.2.T Summary of QUIP-RS Scores – Safety 
The total ICD score and total QUIP-RS score will be summarised at baseline and at the end of each 
treatment period using default summary statistics. 
Listing 16.2.8.5 QUIP-RS Questionnaire – Enrolled 
5.5.8 
Physical Examination Findings 
Physical examinations will be performed at visits VS1, VR, V1B, V2B, and V3B/EDV on the following 
body systems: 
- 
Head 
- 
Neck 
- 
Eyes 
- 
Ear-nose-throat 
- 
Heart 
- 
Respiratory 
- 
Gastrointestinal 
- 
Hepatic 
- 
Urogenital 
- 
Musculoskeletal 
- 
Vascular 
- 
Lymphatic 
- 
Dermatologic 
- 
Central-nervous system (CNS) 
- 
Psychiatric 
Clinical significance (yes/no) of any abnormal physical examination findings will be assessed by the 
investigator. 
Physical measurements (height, weight, and BMI) of subjects will be performed at VS1. In addition, 
weight and BMI will be repeatedly assessed at visits VR, V1B, V2B, and V3B/EDV. 
The following tables and listings will be presented: 
Table 15.2.10.1.T Summary of Physical Measurements – Safety 
Physical measurement parameters will be summarised using standard summary statistics including 
change from baseline at each visit. 
Table 15.2.10.2.T Summary of Physical Examination Findings – Safety 
Number and percentage of subjects with normal, abnormal, and CS abnormal physical examinations 
findings will be displayed at each visit. Percentage will be based on the number of subjects at specified 
visit. 
Listing 16.2.8.6 Physical Measurements – Enrolled 
Listing 16.2.8.7 Physical Examinations – Enrolled 


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5.5.9 
Other Safety-Related Observations 
5.5.9.1 
Pregnancy Testing 
On visits VS1, VR, V1B, V2B, and V3B/EDV, female subjects of childbearing potential will undergo 
urine pregnancy testing. Pregnancy test results will be assessed as “positive” or “negative” by the 
investigator. 
The following listing will be provided: 
Listing 16.2.8.8 Pregnancy Testing – Enrolled 
Childbearing potential and pregnancy test data will be listed for each female in the enrolled analysis 
set. 
 
5.5.9.2 
Safety Laboratory Screening 
During VS1, certain safety laboratory parameters will be assessed for the purposes of subject eligibility 
screening. The following serology parameters will be collected: 
• 
HAV-AB (IgM) (Hepatitis A) 
• 
HBsAg (Hepatitis B) 
• 
HCV-AB (Hepatitis C) 
• 
HIV-Ag/Ab (HIV) 
Each serology parameter will be assessed as positive or negative. 
Additionally, blood coagulation will be assessed using prothrombin time (PT), and renal impairment 
will be assessed using glomerular filtration rate (GFR). 
The following listing will be provided: 
Listing 16.2.8.9 Safety Laboratory Screening – Enrolled 
Safety laboratory data collected for screening purposes will be listed for subjects in the enrolled 
analysis set. 
 
 


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5.6 
Efficacy Analysis 
Efficacy will be assessed by evaluation of the following variables: 
- Epworth Sleepiness Scale (ESS) score change from baseline at the end of each treatment 
period 
- ESS score responder rate at the end of each treatment period 
- Absence of residual somnolence at the end of each treatment period 
- Psychomotor Vigilance Test (PVT) variable change from baseline at the end of each 
treatment period 
- Montreal Cognitive Assessment (MoCA) score change from baseline at the end of each 
treatment period 
- Actimetry change from baseline at the end of each treatment period 
- Number and duration of diurnal involuntary sleep attacks (subject diaries) change from 
baseline at the end of each treatment period 
- Episodes of somnolence (subject diaries) change from baseline at the end of each 
treatment period 
The Full Analysis set as well as the Per Protocol set will be used for the analysis of efficacy data.  
Treatment periods will be considered as evaluable for efficacy analysis only if the following rules 
are satisfied: 
• 
IMP is taken for at least 7 days during the treatment period 
• 
Last IMP intake is at most 3 days before the corresponding end-of-treatment visit, i.e. a 
maximum of 3 IMP intakes can be missed leading up to the end-of-treatment visit. 
Washout periods will be considered as evaluable for efficacy analysis only if the preceding treatment 
period is evaluable and the last IMP intake is 6 or more days before the corresponding end-of-washout 
visit. 
For the purposes of these rules, EDVs are considered as end-of-treatment (if the preceding scheduled 
visit was VR/V1C/V2C) or end-of-washout (if the preceding scheduled visit was V1B/V2B) visits. 
A trial period not being evaluable for efficacy analysis according to these rules is considered a major 
protocol deviation. 
Efficacy analyses for the FAS will be performed using data available from all scheduled visits, as well 
as EDV visits satisfying the above criteria. Efficacy analyses for the PP will be performed using only 
data from trial periods unaffected by major protocol deviations. 
5.6.1 
Key Efficacy Analysis 
On visits VS1, VR, V1B, V1C, V2B, V2C, and V3B/EDV subjects will fill out the Epworth 
Sleepiness Scale (ESS) questionnaire. The ESS consists of 8 questions with the answers on the scale 
of 0-3. The ESS score is the sum of the 8 items and has a range of 0-24. The key efficacy variable in 
this trial is the change from baseline of the ESS score at the end of each treatment period (visits V1B, 
V2B, and V3B/EDV). 
The ESS score change from baseline will be analysed using a mixed linear regression model with the 
fixed effects of treatment, period, treatment by period interaction, sequence, and baseline score, and 
subject nested within sequence as a random effect. The model will be estimated using the restricted 
maximum likelihood method (REML). Degrees of freedom for the fixed effects will be estimated 
using the Kenward-Roger approximation. 


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The following SAS code will be used in mixed linear regression modelling: 
PROC MIXED DATA=<Dataset> METHOD=REML; 
 
CLASS <Subject> <Treatment> <Period> <Sequence>; 
 
MODEL <Change from Baseline> = <Treatment> | <Period>  
 <Sequence> <Baseline> 
/ DDFM = KENROG; 
 
RANDOM int / SUBJECT=<Subject>(<Sequence>); 
 
LSMEANS <Treatment> / PDIFF CL;  
RUN; 
A statistically significant (p-value < 0.05) treatment by period interaction may indicate the presence of 
residual treatment (carryover) effects, which may bias the estimates of treatment effects. For this 
reason, if a statistically significant treatment by period interaction is found in the analysis of the key 
efficacy endpoint, the key efficacy analyses will be performed using data from the first period only. In 
such an event, the key efficacy endpoint will be modelled using an analysis of covariance (ANCOVA) 
model with the fixed effect of treatment and baseline score as a covariate. 
The following SAS code will be used in the analysis of first-period data: 
PROC MIXED DATA=<Dataset> METHOD=REML; 
 
CLASS <Treatment>; 
 
MODEL <Change from Baseline> = <Treatment> <Baseline> 
/ DDFM = KENROG; 
 
LSMEANS <Treatment> / PDIFF CL;  
RUN; 
 
Additional exploratory analysis of the carryover effect is defined in section 5.6.2. 
The following tables, listings and figures will be provided:  
Table 15.3.1.1.1.S Summary of Epworth Sleepiness Scale Score – Full Analysis 
Table 15.3.1.1.2.S Summary of Epworth Sleepiness Scale Score – Per Protocol 
Table 15.3.1.2.1.T Summary of Epworth Sleepiness Scale Score – Full Analysis 
Table 15.3.1.2.2.T Summary of Epworth Sleepiness Scale Score – Per Protocol 
The Epworth sleepiness scale score will be summarised using default summary statistics at each visit. 
The ESS change from baseline will be summarised at each post-baseline visit. 
Table 15.3.2.1.1 Analysis of Epworth Sleepiness Scale Score – Full Analysis 
Table 15.3.2.1.2 Analysis of Epworth Sleepiness Scale Score – Per Protocol 
Table 15.3.2.2.1 Analysis of Epworth Sleepiness Scale Score (First Period) – Full Analysis 
Table 15.3.2.2.2 Analysis of Epworth Sleepiness Scale Score (First Period) – Per Protocol 
Estimates of each modelled effect will be displayed with standard errors, t-values and p-values. Contrast 
estimates will be displayed for the difference between each pair of treatments. 
Figure 15.3.1.1.S Subject-Level ESS Score Change from Baseline – Full Analysis 
Figure 15.3.1.2.S Subject-Level ESS Score Change from Baseline – Per Protocol 
ESS score change from baseline at the end of every treatment period will be displayed for each subject 
stratified by treatment sequence. 
Figure 15.3.2.1.T Mean ESS Score Change from Baseline by Period – Full Analysis 
Figure 15.3.2.2.T Mean ESS Score Change from Baseline by Period – Per Protocol 
The mean and standard deviation of ESS score change from baseline pooled by treatment at the end of 
every treatment period will be displayed using a scatter plot with error bars. 
Listing 16.2.9.1 Epworth Sleepiness Scale – Enrolled 
Epworth sleepiness scale results will be listed for each subject in the enrolled analysis set. 


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5.6.2 
Key Efficacy Endpoint Carryover Effect Estimation 
If the key efficacy endpoint analysis shows a statistically significant treatment by period interaction (p-
value < 0.05), modified key efficacy analyses will be performed to adjust for potential first-order 
carryover effects on the ESS score. For these analyses, the treatment of the previous treatment period 
will be assigned to each observation. The treatment by period interaction in the original efficacy model 
will not be included. 
The treatment effects at end-of-treatment visits V1B, V2B and V3B will be estimated using a mixed 
linear regression model with the fixed effects of treatment, period, sequence, and residual treatment, 
baseline score as a covariate, and the random effect of subject nested within sequence. The carryover 
effect estimation will be performed using the following SAS code: 
PROC MIXED DATA=<Dataset> METHOD=REML; 
 
CLASS <Subject> <Treatment> <Period> <Sequence> <LagTreatment>; 
 
MODEL <Change from Baseline> = <Treatment> <Period> <Sequence>  
 
 
 
 
 
 
 <Baseline> <LagTreatment> 
/ DDFM = KENROG; 
 
RANDOM int / SUBJECT=<Subject>(<Sequence>); 
 
LSMEANS <Treatment> / PDIFF CL;  
RUN; 
 
The following tables will be presented: 
Table 15.3.2.3.1 Analysis of Epworth Sleepiness Scale Score Adjusted for Carryover – Full Analysis 
Table 15.3.2.3.2 Analysis of Epworth Sleepiness Scale Score Adjusted for Carryover – Per Protocol 
Estimates of each modelled effect will be displayed with standard errors, t-values and p-values. Contrast 
estimates will be displayed for the difference between each pair of direct treatment effects. 
 
 


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5.6.3 
ESS Responder Rate 
The Epworth Sleepiness Scale (ESS) responder rate is defined as the proportion of subjects with a 
relative ESS score change from baseline of at least -25% after each treatment period. 
The treatment differences in the ESS responder rate will be assessed using a generalised linear mixed 
regression model (GLMM) with the fixed effects of treatment, period, treatment by period interaction, 
sequence, and baseline score, and subject nested within sequence as a random effect. The logit link 
function will be used to model the binary response data. The model will be estimated using the default 
RSPL method. Degrees of freedom for the fixed effects will be estimated using the Kenward-Roger 
approximation. 
The following SAS code will be used in GLMM estimation: 
PROC GLIMMIX DATA=<Dataset> METHOD=RSPL; 
 
CLASS <Subject> <Treatment> <Period> <Sequence>; 
 
MODEL <Responder Status> = <Treatment> | <Period>  
 <Sequence> <Baseline> 
/ DIST=BINARY LINK=LOGIT DDFM = KENROG; 
 
RANDOM int / SUBJECT=<Subject>(<Sequence>); 
 
LSMEANS <Treatment> / PDIFF ODDSRATIO ILINK CL;  
RUN; 
The treatment least-squares means of the log-odds will be reported as well as their standard errors and 
95% confidence intervals. Also, the odds ratios between each treatment will be displayed with 95% 
confidence intervals. 
In case of model non-convergence, the treatment by period interaction will be removed from the 
model. If the simplified model fails to converge, the difference in response rate between treatments 
will be evaluated using an exact McNemar’s test. Response at endpoint will be compared between 
each treatment at the two-sided 5% level. 
McNemar’s test will be performed using the following SAS code: 
PROC FREQ DATA=<Dataset>; 
 
TABLES <Treatment 1 Response>*<Treatment 2 Response>; 
 
EXACT MCNEM; 
RUN; 
If a statistically significant (p-value < 0.05) treatment by period interaction is found in the analysis of 
the ESS responder rate, an additional analysis will be performed using only data collected during the 
first treatment period. If the full GLMM specification was not used due to model non-convergence, 
this additional analysis will be performed in case of a statistically significant treatment by period 
interaction in the key efficacy model (Section 5.6.1). 
Model-based analysis of first-period data will be based on a generalised linear model (GLM) with the 
fixed effect of treatment and baseline as a covariate. The following SAS code will be used: 
PROC GLIMMIX DATA=<Dataset>; 
 
CLASS <Treatment>; 
 
MODEL <Responder Status> = <Treatment> <Baseline> 
 
 
 
 
 
 
/ DIST=BINARY LINK=LOGIT; 
 
LSMEANS <Treatment> / PDIFF CL;  
RUN; 
 


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The following table and listing will be presented: 
Table 15.3.3.1.1.S Summary of Epworth Sleepiness Scale Responder Rate – Full Analysis 
Table 15.3.3.1.2.S Summary of Epworth Sleepiness Scale Responder Rate – Per Protocol 
Table 15.3.3.2.1.T Summary of Epworth Sleepiness Scale Responder Rate – Full Analysis 
Table 15.3.3.2.2.T Summary of Epworth Sleepiness Scale Responder Rate – Per Protocol 
Epworth sleepiness scale responder rate at each post-baseline visit will be summarised using default 
frequency tabulations. Percentage will be based on number of subjects with data available at each 
timepoint. 
Table 15.3.4.1.1 Analysis of Epworth Sleepiness Scale Responder Rate – Full Analysis 
Table 15.3.4.1.2 Analysis of Epworth Sleepiness Scale Responder Rate – Per Protocol 
Table 15.3.4.2.1 Analysis of Epworth Sleepiness Scale Responder Rate (First Period) – Full Analysis 
Table 15.3.4.2.2 Analysis of Epworth Sleepiness Scale Responder Rate (First Period) – Per Protocol 
Estimates of each modelled effect will be displayed with standard errors, t-values and p-value. Log-
odds contrast estimates will be displayed for the difference between each pair of treatments. 
5.6.4 
Absence of Residual Somnolence 
Residual somnolence is defined as an ESS score of 11 or more at the end of a treatment period. The 
rate of subjects with an absence of residual somnolence (i.e. ESS score < 11) at the end of each 
treatment period will be analysed using statistical methods described in Section 5.6.3.  
In the case that a statistically significant (p-value < 0.05) treatment by period interaction is found in 
the model-based analysis of residual somnolence, an additional analysis will be performed using only 
data collected during the first treatment period. The statistical methods will be adjusted as described 
in Section 5.6.3. 
The following tables will be presented: 
Table 15.3.5.1.1.S Summary of Absence of Residual Somnolence – Full Analysis 
Table 15.3.5.1.2.S Summary of Absence of Residual Somnolence – Per Protocol 
Table 15.3.5.2.1.T Summary of Absence of Residual Somnolence – Full Analysis 
Table 15.3.5.2.2.T Summary of Absence of Residual Somnolence – Per Protocol 
Absence of residual somnolence at each post-baseline visit will be summarised using default frequency 
tabulations. Percentage will be based on number of subjects with data available at each timepoint. 
Table 15.3.6.1.1 Analysis of Absence of Residual Somnolence – Full Analysis 
Table 15.3.6.1.2 Analysis of Absence of Residual Somnolence – Per Protocol 
Table 15.3.6.2.1 Analysis of Absence of Residual Somnolence (First Period) – Full Analysis 
Table 15.3.6.2.2 Analysis of Absence of Residual Somnolence (First Period) – Per Protocol 
Estimates of each modelled effect will be displayed with standard errors, t-values and p-value. Log-
odds contrast estimates will be displayed for the difference between each pair of treatments. 
5.6.5 
Psychomotor Vigilance Test (PVT) 
On visits VR, V1B, V1C, V2B, V2C, and V3B/EDV subjects will undergo 3-minute Psychomotor 
Vigilance Task evaluations. PVT will be performed up to four times during each visit: at 10:00 h, 
12:00 h, 14:00 h, and 16:00 h (±15 minutes each) by default. If the default PVT schedule is too 
burdensome for a particular subject, it may be individually adapted to at least 3 assessments with a 
time window of at least 1 hour between each PVT assessment. The actual time of each PVT 
assessment will be collected in the eCRF. 
The following PVT variables will be collected at every visit and timepoint: 
- 
Mean response time (ms) 
- 
Number of lapses 
- 
Number of total errors 


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A failure to react or any reaction exceeding 500 ms is considered a lapse. A reaction without stimulus 
or under 100 ms is considered a false start. Lapses and false starts are counted towards total errors. 
For each PVT variable, the mean value during a visit will be used for analysis. 
The PVT mean response time will be analysed using a mixed linear regression model as described in 
Section 5.6.1. 
In the case that a statistically significant (p-value < 0.05) treatment by period interaction is found in 
the analysis of the PVT mean response time, an additional analysis will be performed using only data 
collected during the first treatment period. The statistical model will be adjusted as described in 
Section 5.6.1. 
The following tables, listing, and figures will be presented: 
Table 15.3.7.1.1.S Summary of PVT Mean Response Time – Full Analysis 
Table 15.3.7.1.2.S Summary of PVT Mean Response Time – Per Protocol 
Table 15.3.7.2.1.T Summary of PVT Mean Response Time – Full Analysis 
Table 15.3.7.2.2.T Summary of PVT Mean Response Time – Per Protocol 
PVT mean response time will be summarised using default summary statistics at each visit. The change 
from baseline will be summarised at each post-baseline visit. 
Table 15.3.8.1.1.S Summary of PVT Errors – Full Analysis 
Table 15.3.8.1.2.S Summary of PVT Errors – Per Protocol 
Table 15.3.8.2.1.T Summary of PVT Errors – Full Analysis 
Table 15.3.8.2.2.T Summary of PVT Errors – Per Protocol 
The number of lapses and number of total errors during PVT evaluation will be summarised using 
default summary statistics at each visit. The change from baseline will be summarised at each post-
baseline visit. 
Table 15.3.9.1.1 Analysis of PVT Mean Response Time – Full Analysis 
Table 15.3.9.1.2 Analysis of PVT Mean Response Time – Per Protocol 
Table 15.3.9.2.1 Analysis of PVT Mean Response Time (First Period) – Full Analysis 
Table 15.3.9.2.2 Analysis of PVT Mean Response Time (First Period) – Per Protocol 
Estimates of each modelled effect will be displayed with standard errors, t-values and p-values. Contrast 
estimates will be displayed for the difference between each pair of treatments. 
Figure 15.3.3.1.S Subject-Level PVT Performance Change from Baseline – Full Analysis 
Figure 15.3.3.2.S Subject-Level PVT Performance Change from Baseline – Per Protocol 
PVT mean response time change from baseline at the end of every treatment period will be displayed 
for each subject stratified by treatment sequence. 
Figure 15.3.4.1.T Mean PVT Performance Change from Baseline by Period – Full Analysis 
Figure 15.3.4.2.T Mean PVT Performance Change from Baseline by Period – Per Protocol 
The mean and standard deviation of PVT mean response time change from baseline pooled by treatment 
at the end of every treatment period will be displayed using a scatter plot with error bars. 
Listing 16.2.9.2 Psychomotor Vigilance Test – Enrolled 
PVT variable data will be listed for each subject in the enrolled analysis set. 
 
5.6.6 
Montreal Cognitive Assessment (MoCA) 
The Montreal Cognitive Assessment (MoCA) is a brief screening instrument to detect mild cognitive 
impairment. The MoCA assesses multiple cognitive domains including attention, concentration, 
executive functions, memory, language, visuospatial skills, abstraction, calculation and orientation. 
Subjects will complete the MoCA during the screening and washout visits VS1, VR, V1C, and V2C, 
and on end-of-treatment visits V1B, V2B, and V3B/EDV. 
To decrease possible learning effects, the three (equivalent) versions 7.1, 7.2, and 7.3 will be used in 
alternation. MoCA scores range between 0 and 30. A score of 26 or over is considered to be normal. 


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For subjects with an education of 12 years or fewer, the MoCA score will be increased by 1. MoCA 
scores of 30 will not be increased. 
MoCA scores will be analysed using a mixed linear regression model as described in Section 5.6.1. 
In the case that a statistically significant (p-value < 0.05) treatment by period interaction is found in 
the analysis of the MoCA score, an additional analysis will be performed using only data collected 
during the first treatment period. The statistical model will be adjusted as described in Section 5.6.1. 
The following tables and listing will be presented: 
Table 15.3.10.1.1.S Summary of Montreal Cognitive Assessment Scores – Full Analysis 
Table 15.3.10.1.2.S Summary of Montreal Cognitive Assessment Scores – Per Protocol 
Table 15.3.10.2.1.T Summary of Montreal Cognitive Assessment Scores – Full Analysis 
Table 15.3.10.2.2.T Summary of Montreal Cognitive Assessment Scores – Per Protocol 
The Montreal Cognitive Assessment score will be summarised using default summary statistics at each 
visit. The change from baseline will be summarised at each post-baseline visit. 
Table 15.3.11.1.1 Analysis of Montreal Cognitive Assessment Scores – Full Analysis 
Table 15.3.11.1.2 Analysis of Montreal Cognitive Assessment Scores – Per Protocol 
Table 15.3.11.2.1 Analysis of Montreal Cognitive Assessment Scores (First Period) – Full Analysis 
Table 15.3.11.2.2 Analysis of Montreal Cognitive Assessment Scores (First Period) – Per Protocol 
Estimates of each modelled effect will be displayed with standard errors, t-values and p-values. Contrast 
estimates will be displayed for the difference between each pair of treatments. 
Listing 16.2.9.3 Montreal Cognitive Assessment– Enrolled 
5.6.7 
Actigraphy (Inactivity) Evaluation 
Actigraphy is a non-invasive method of monitoring a person's rest and activity cycles. The movements 
the actigraphy sensor undergoes are continually recorded.  
Actigraphy measurements will be collected for 3 days prior to visit VR and for 3 days at the end of each 
treatment period. Charged actigraphy devices will be handed out to subjects at visits VS1, VR, V1C, 
and V2C, and actigraphy data will be collected during visits VR, V1B, V2B, and V3B/EDV. 
Objective activity measures will be estimated from the raw activity data by a research team from 
 and provided to
 for efficacy analysis. A description of this process and each 
evaluated objective activity measure is provided in the AX3 Analysis Plan, attached as an appendix to 
this SAP (see Section 9). 
The following objective activity measures will be estimated for each day prior to the collection visit: 
- Night Time Immobility Duration (minutes) (NTID) 
- Night Time Mobility Periods (NTMP) 
- Night Time Mobility Duration (minutes) (NTMD) 
- Diurnal Immobility Periods (DIP) 
- Diurnal Immobility Duration (minutes) (DID) 
- Daily Physical Activity (g) (DPA) 
- Nightly Physical Activity (g) (NPA) 
- Daily Jerk (g/s) (DJ) 
The following activity ratios will be estimated once per collection visit: 
- Intradaily Variability (IV) 
- Interdaily Stability (IS) 
- Relative Amplitude (RA) 
The results of each activity measure will be summarised at each visit. The mean value of assessments 
corresponding to the collection visit will be used for analysis. All values will be listed. 


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Activity ratios (IV, IS, RA) and physical activity variables (DPA, DJ) will additionally be analysed 
using a mixed linear regression model as described in Section 5.6.1. 
In the case that a statistically significant (p-value < 0.05) treatment by period interaction is found in 
the analysis of an objective actigraphy measure, an additional analysis will be performed for that 
activity measure using only data collected during the first treatment period. The statistical model will 
be adjusted as described in Section 5.6.1. 
Further statistical analyses of actigraphy data are defined outside the scope of this SAP. 
The following tables and listing will be presented: 
Table 15.3.12.1.1.S Summary of Objective Activity Measures – Full Analysis 
Table 15.3.12.1.2.S Summary of Objective Activity Measures – Per Protocol 
Table 15.3.12.2.1.T Summary of Objective Activity Measures – Full Analysis 
Table 15.3.12.2.2.T Summary of Objective Activity Measures – Per Protocol 
Objective activity measures will be summarised using default summary statistics at each visit. The 
absolute and relative change from baseline will be summarised at each post-baseline visit. 
Table 15.3.13.1.1 Analysis of Objective Activity Measures – Full Analysis 
Table 15.3.13.1.2 Analysis of Objective Activity Measures – Per Protocol 
Table 15.3.13.2.1 Analysis of Objective Activity Measures (First Period) – Full Analysis 
Table 15.3.13.2.2 Analysis of Objective Activity Measures (First Period) – Per Protocol 
Estimates of each modelled effect will be displayed with standard errors, t-values and p-values. Contrast 
estimates will be displayed for the difference between each pair of treatments. 
Listing 16.2.9.4 Objective Activity Measures– Enrolled 
5.6.8 
Subject Diary Data 
Over the course of the trial, subjects will fill out paper-based diaries concerning their daily sleep and 
IMP intake patterns. One screening diary and three treatment diaries will be issued at visit VS1, and 
visits VR, V1C, and V2C respectively, and collected at visits VR, V1C, V2C, and V3B/EDV. The 
diaries will be filled in continuously from visit VS1 to V3B/EDV, including the washout periods after 
treatment periods I and II. 
Analysis of drug exposure data collected from subject diaries is discussed in section 5.4.1. 
Efficacy-related data collected from patient diaries will be summarized over the respective trial period 
(baseline, washout 1, washout 2, and treatment 1, 2, or 3) for the purpose of displaying them in 
summaries. Numeric variables will be standardized to amount per day, and for categorical variables 
subjects will be included in every category that occurred to them in the given period. 
If there are less than 3 non-missing values over the course of a treatment or washout period for a 
given variable, it will be set to missing for the respective period in summaries. For treatment periods, 
only the last 3 non-missing values per parameter will be aggregated in summaries order to capture the 
full effect of the IMP. 
All diary data will be listed. 
Listing 16.2.9.5 Diary Sleep Data – Enrolled 
Listing 16.2.9.6 Diary Exposure Data – Enrolled 


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5.6.8.1 
Diurnal Involuntary Sleep Attacks 
The number and total duration of diurnal involuntary sleep attacks will be recorded in the subject 
diaries. These data will be summarised as numeric variables as described in section 5.6.8. 
The following tables will be presented: 
Table 15.3.14.1.S Summary of Diurnal Involuntary Sleep Attacks – Full Analysis 
Table 15.3.14.2.T Summary of Diurnal Involuntary Sleep Attacks – Full Analysis 
The number and duration of diurnal involuntary sleep attacks will be summarised using default 
summary statistics for each trial period. The change from baseline will be displayed for each post-
baseline period. 
5.6.8.2 
Somnolence Episodes 
The number of somnolence episodes each day will be collected in the subject diaries. It will be 
summarised as a numeric variable as described in section 5.6.8. 
The following tables will be presented: 
Table 15.3.15.1.S Summary of Somnolence Episodes – Full Analysis 
Table 15.3.15.2.T Summary of Somnolence Episodes – Full Analysis 
The number of somnolence episodes will be summarised using default summary statistics for each trial 
period. The change from baseline will be displayed for each post-baseline period. 
5.6.8.3 
Other Efficacy-Related Variables 
Other efficacy-related variables collected in the subject diaries include: 
• 
Get-up time 
• 
Total time (hours) slept last night 
• 
Wake-up periods during night sleep: 
o Number (<5, between 5 and 10, >10) 
o Total duration (minutes) 
• 
Voluntary naps: 
o Number 
o Total duration (minutes) 
• 
Number of caffeinated drinks 
• 
Going-to-bed time 
Time in bed will be calculated as the difference in hours between the get-up time and the going-to-
bed time of the preceding day. Time in bed will not be calculated if either of the datetime values are 
completely or partially missing. 
Adjusted total time slept in hours will be calculated as follows: 
𝐴𝑑𝑗.  𝑡𝑜𝑡𝑎𝑙 𝑡𝑖𝑚𝑒 𝑠𝑙𝑒𝑝𝑡= 𝑚𝑖𝑛(𝑡𝑜𝑡𝑎𝑙 𝑡𝑖𝑚𝑒 𝑠𝑙𝑒𝑝𝑡,   𝑡𝑖𝑚𝑒 𝑖𝑛 𝑏𝑒𝑑−𝑤𝑎𝑘𝑒−𝑢𝑝 𝑝𝑒𝑟𝑖𝑜𝑑 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛) 
With the exception of the number of wake-up periods during night sleep, these data will be 
summarised as numeric variables as described in section 5.6.8. 


Sponsor: Theranexus S.A. 
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The following tables will be presented: 
Table 15.3.16.1.S Summary of Other Efficacy-Related Diary Data – Full Analysis 
Table 15.3.16.2.T Summary of Other Efficacy-Related Diary Data – Full Analysis 
The secondary diary data will be summarised for each trial period using default summary statistics or 
frequency tabulations, as appropriate. 
5.7 
Pharmacokinetic Analysis 
To assess the steady state pharmacokinetics of the IMP, blood samples will be collected upon subject 
arrival at study sites during visits VR, V1B, V1C, V2B, V2C, and V3B/EDV. Concentrations of 
flecainide and modafinil at each visit will be summarised. For summaries, concentrations below the 
lower limit of quantification (LLOQ) will be set to zero. Concentrations will be reported as collected in 
listings. 
To summarise pharmacokinetic data the geometric mean (GeoMean), geometric standard deviation 
(GSD), and geometric coefficient of variation (GCV) will be displayed. These statistics will be 
calculated using the following formulae: 
𝐺𝑒𝑜𝑀𝑒𝑎𝑛= √𝑦1 × 𝑦2 × … × 𝑦𝑛
𝑛
 
𝐺𝑆𝐷= 𝑒(𝑆𝐷(𝑙𝑛(𝑦1),𝑙𝑛(𝑦1),…,𝑙𝑛(𝑦𝑛))) 
𝐺𝐶𝑉= √𝑒𝐺𝑆𝐷2 −1 ×  100%,  
where n – number of observations, SD – standard deviation, ln – natural logarithm. Values of ‘0’ will 
be removed from the calculation of the geometric mean, GSD, and GCV. The ratios GeoMean ÷× GSD 
will be displayed in addition to these statistics. 
Evaluability of pharmacokinetic data 
PK samples performed at the end of treatment periods will be analysed if an IMP intake was performed 
in the morning before the PK sample. 
PK samples performed at the end of washout periods will be analysed if the last IMP intake is 6 or 
more days before the PK sample, and if the preceding end-of-treatment PK sample is evaluable 
according to the above rule. 
Deviations from these rules will be considered as major protocol deviations in relation to PK analysis. 
 
The following tables and listing will be presented: 
Table 15.4.1.S Summary of Pharmacokinetics Concentrations – PK Analysis Set 
Table 15.4.2.T Summary of Pharmacokinetics Concentrations – PK Analysis Set 
The concentrations of modafinil and flecainide at each visit will be summarised using the geometric 
mean, geometric standard deviation, and geometric coefficient of variation in addition to the default 
summary statistics. 
Listing 16.2.5.2 Pharmacokinetics Concentrations – Enrolled 
 
6. INTERIM ANALYSIS 
No interim analysis is planned. 


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7. CHANGES TO THE ANALYSIS AS LAID DOWN IN THE PROTOCOL AND 
AMENDMENTS 
The definition of the Per Protocol set was changed to include subjects with major protocol deviations, 
if they have at least one treatment period unaffected by a major protocol deviation. Per Protocol analysis 
will be performed on all trial periods unaffected by a major protocol deviation. 


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8. 
REFERENCES 
 
1. SAS® Institute Inc., Cary, North Carolina, United States of America, Version 9.4. 
2. MedDRA – Medical Dictionary for Regulated Activities. International Federation of 
Pharmaceutical Manufacturers Associations (IFPMA), c/o TRW, VAR1/8A/MSSO, 12011 
Sunset Hills Road, Reston, VA 20190-3285, USA, version 21.0, March 2018. 
3. WHO – Drug Dictionary. World Health Organization Collaborating Center for International 
Drug Monitoring, P.O. Box 26, S-751 03 Uppsala, Sweden, March 2018 version 
4. C.H. Adler, J.N. Caviness, J.G. Hentz, M. Lind, J. Tiede, Randomized trial of modafinil for 
treating subjective daytime sleepiness in patients with Parkinson's disease, Movement 
disorders: official journal of the Movement Disorder Society, 18 (2003) 287-293. 
5. Christopher G. Goetz, Sheng Luo, Lu Wang, Barbara C. Tilley, Nancy R. LaPelle, Glenn T. 
Stebbins, Handling Missing Values in the MDS-UPDRS, Movement Disorders, 30 (2015) 
1632-1638 
 
 


Sponsor: Theranexus S.A. 
Protocol no. THN102-202 
Statistical Analysis Plan, Version Final 1.0 
21-FEB-2020 
 
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9. APPENDICES 
The following documents are attached as appendices to the SAP:  
1. THN102_202_AX3_Analysis_Plan_Draft_1.3_20200115 
2. THN102-202_Table_Shells_Final1.0_2020_02_21.docx 
3. THN102-202_Listing_Shells_Final1.0_2020_02_21.docx 
4. THN102-202_Figure_Shells_Final1.0_2020_02_21.docx 
 
9.1 
Tables  
Appendix tables defined below will be provided in separate .rtf files for each output. 
No 
Table Identifier, Title 
Output file 
Baseline Characteristics  
1 
Table 15.1.1.1.S Analysis Sets – Enrolled 
THN102-202-T-1501010100S-sets-en.rtf 
2 
Table 15.1.1.2.T Analysis Sets – Enrolled 
THN102-202-T-1501010200T-sets-en.rtf 
3 
Table 15.1.1.3 Reasons for Exclusions from Analysis Sets – 
Enrolled 
THN102-202-T-1501010300-sets-excl-en.rtf 
4 
Table 15.1.2 Screening Failures – Enrolled 
THN102-202-T-1501020000-scrfail-en.rtf 
5 
Table 15.1.3.1.S Subject Disposition – Randomised 
THN102-202-T-1501030100S-disp-rs.rtf 
6 
Table 15.1.3.2.S Subject Disposition – Safety 
THN102-202-T-1501030200S-disp-ss.rtf 
7 
Table 15.1.4.1 Number of Subjects by Country and Site – 
Enrolled 
THN102-202-T-1501040100-countrysite-en.rtf 
8 
Table 15.1.4.2 Number of Subjects by Country and Site – 
Randomised 
THN102-202-T-1501040200-countrysite-rs.rtf 
9 
Table 15.1.4.3 Number of Subjects by Country and Site – 
Safety 
THN102-202-T-1501040300-ocuntrysite-ss.rtf 
10 
Table 15.1.5.S Number of Subjects by Visit – Safety 
THN102-202-T-1501050000S-visits-ss.rtf 
11 
Table 15.1.6.1.S Major Protocol Deviations – Safety 
THN102-202-T-1501060100S-mpd-ss.rtf 
12 
Table 15.1.6.2.S Major Protocol Deviations – Full Analysis 
THN102-202-T-1501060200S-mpd-fas.rtf 
13 
Table 15.1.7.1.1.S Demographics – Safety 
THN102-202-T-1501070101S-demo-ss.rtf 
14 
Table 15.1.7.1.2.S Demographics – Full Analysis 
THN102-202-T-1501070102S-demo-fas.rtf 
15 
Table 15.1.7.1.3.S Demographics – Per Protocol 
THN102-202-T-1501070103S-demo-pp.rtf 
16 
Table 15.1.7.2.1.S Baseline Characteristics – Safety 
THN102-202-T-1501070201S-basechar-ss.rtf 
17 
Table 15.1.7.2.2.S Baseline Characteristics – Full Analysis 
THN102-202-T-1501070202S-basechar-fas.rtf 
18 
Table 15.1.7.2.3.S Baseline Characteristics – Per Protocol 
THN102-202-T-1501070203S-basechar-pp.rtf 
19 
Table 15.1.7.3.1.S Baseline Disease Stage – Safety 
THN102-202-T-1501070301S-hoehn-ss.rtf 
20 
Table 15.1.7.3.2.S Baseline Disease Stage – Full Analysis 
THN102-202-T-1501070302S-hoehn-fas.rtf 
21 
Table 15.1.7.3.3.S Baseline Disease Stage – Per Protocol 
THN102-202-T-1501070303S-hoehn-pp.rtf 
22 
Table 15.1.8.1.1.S Prior Medical Conditions – Safety 
THN102-202-T-1501080101S-mh-prior-ss.rtf 
23 
Table 15.1.8.1.2.S Prior Medical Conditions – Full Analysis 
THN102-202-T-1501080102S-mh-prior-fas.rtf 
24 
Table 15.1.8.2.1.S Ongoing Medical Conditions – Safety 
THN102-202-T-1501080201S-mh-ongoing-ss.rtf 
25 
Table 15.1.8.2.2.S Ongoing Medical Conditions – Full 
Analysis 
THN102-202-T-1501080202S-mh-ongoing-fas.rtf 
26 
Table 15.1.9.1.1.S Prior Medications – Safety 
THN102-202-T-1501090101S-priormed-ss.rtf 
27 
Table 15.1.9.1.2.S Prior Medications – Full Analysis 
THN102-202-T-1501090102S-priormed-fas.rtf 
28 
Table 15.1.9.2.1.T Concomitant Medications – Safety 
THN102-202-T-1501090201T-conmed-ss.rtf 
29 
Table 15.1.9.2.2.T Concomitant Medications – Full Analysis 
THN102-202-T-1501090202T-conmed-fas.rtf 


Sponsor: Theranexus S.A. 
Protocol no. THN102-202 
Statistical Analysis Plan, Version Final 1.0 
21-FEB-2020 
 
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30 
Table 15.1.10.1.1.T Treatment Duration (days) – Safety 
THN102-202-T-1501100101T-trtdur-ss.rtf 
31 
Table 15.1.10.1.2.T Treatment Duration (days) – Full 
Analysis 
THN102-202-T-1501100102T-trtdur-fas.rtf 
32 
Table 15.1.10.1.3.T Treatment Duration (days) – Per 
Protocol 
THN102-202-T-1501100103T-trtdur-pp.rtf 
33 
Table 15.1.10.2.1.T Treatment Compliance (eCRF) – Safety 
THN102-202-T-1501100201T-compl-ecrf-ss.rtf 
34 
Table 15.1.10.2.2.T Treatment Compliance (eCRF) – Full 
Analysis 
THN102-202-T-1501100202T-compl-ecrf-fas.rtf 
35 
Table 15.1.10.2.3.T Treatment Compliance (eCRF) – Per 
Protocol 
THN102-202-T-1501100203T-compl-ecrf-pp.rtf 
36 
Table 15.1.11.2.1.T Treatment Compliance (Diary) – Safety 
THN102-202-T-1501110201T-compl-diary-ss.rtf 
37 
Table 15.1.11.2.2.T Treatment Compliance (Diary) – Full 
Analysis 
THN102-202-T-1501110202T-compl-diary-fas.rtf 
38 
Table 15.1.11.2.3.T Treatment Compliance (Diary) – Per 
Protocol 
THN102-202-T-1501110203T-compl-diary-pp.rtf 
Safety Data 
39 
Table 15.2.1.1.1.S Overall Summary of TEAEs – Safety 
THN102-202-T-1502010101S-teae-sum-ss.rtf 
40 
Table 15.2.1.1.2.T Overall Summary of TEAEs – Safety 
THN102-202-T-1502010102T-teae-sum-ss.rtf 
41 
Table 15.2.1.2.T Incidence of TEAEs – Safety 
THN102-202-T-1502010200T-teae-ss.rtf 
42 
Table 15.2.1.3.T Incidence of Non-Serious TEAEs – Safety 
THN102-202-T-1502010300T-teae-nonserious-
ss.rtf 
43 
Table 15.2.1.4.T Incidence of Serious TEAEs – Safety 
THN102-202-T-1502010400T-tesae-ss.rtf 
44 
Table 15.2.1.5.T Incidence of Related TEAEs – Safety 
THN102-202-T-1502010500T-teae-rel-ss.rtf 
45 
Table 15.2.1.6.T Incidence of Related Serious TEAEs – 
Safety 
THN102-202-T-1502010600T-tesae-rel-ss.rtf 
46 
Table 15.2.1.7.T Incidence of TEAEs Leading to 
Discontinuation – Safety 
THN102-202-T-1502010700T-teae-disc-ss.rtf 
47 
Table 15.2.1.8.T Incidence of TEAEs Leading to Death – 
Safety 
THN102-202-T-1502010800T-teae-death-ss.rtf 
48 
Table 15.2.1.9.T Incidence of TEAEs by Severity – Safety 
THN102-202-T-1502010900T-teae-sev-ss.rtf 
49 
Table 15.2.4.1.1.T Summary of Clinical Laboratory Tests: 
Haematology – Safety 
THN102-202-T-1502040101T-lbh-ss.rtf 
50 
Table 15.2.4.1.2.T Summary of Clinical Laboratory Tests: 
Biochemistry – Safety 
THN102-202-T-1502040102T-lbb-ss.rtf 
51 
Table 15.2.4.1.3.T Summary of Clinical Laboratory Tests: 
Urinalysis – Safety 
THN102-202-T-1502040103T-lbu-ss.rtf 
52 
Table 15.2.4.2.1.T Clinical Laboratory Tests: Incidence of 
Haematology Abnormalities – Safety 
THN102-202-T-1502040201T-lbh-abnorm-ss.rtf 
53 
Table 15.2.4.2.2.T Clinical Laboratory Tests: Incidence of 
Biochemistry Abnormalities – Safety 
THN102-202-T-1502040202T-lbb-abnorm-ss.rtf 
54 
Table 15.2.4.2.3.T Clinical Laboratory Tests: Incidence of 
Urinalysis Abnormalities – Safety 
THN102-202-T-1502040203T-lbu-abnorm-ss.rtf 
55 
Table 15.2.4.3.1.T Clinical Laboratory Tests: Shift Table of 
Haematology Results – Safety 
THN102-202-T-1502040301T-lbh-shift-ss.rtf 
56 
Table 15.2.4.3.2.T Clinical Laboratory Tests: Shift Table of 
Biochemistry Results – Safety 
THN102-202-T-1502040302T-lbb-shift-ss.rtf 
57 
Table 15.2.4.3.3.T Clinical Laboratory Tests: Shift Table of 
Urinalysis Results – Safety 
THN102-202-T-1502040303T-lbu-shift-ss.rtf 
58 
Table 15.2.5.1.T Summary of Vital Signs – Safety 
THN102-202-T-1502050100T-vs-ss.rtf 
59 
Table 15.2.5.2.T Incidence of Vital Signs Abnormalities – 
Safety 
THN102-202-T-1502050200T-vs-abnorm-ss.rtf 
60 
Table 15.2.5.3.T Shift Table of Vital Signs Abnormalities – 
Safety 
THN102-202-T-1502050300T-vs-shift-ss.rtf 
61 
Table 15.2.6.1.T Summary of ECG Parameters – Safety 
THN102-202-T-1502060100T-ecg-ss.rtf 
62 
Table 15.2.6.2.T Summary of ECG Diagnoses – Safety 
THN102-202-T-1502060200T-ecg-diag-ss.rtf 
63 
Table 15.2.6.3.T Summary of ECG Abnormality 
Assessments – Safety 
THN102-202-T-1502060300T-ecg-abnorm-ss.rtf 
64 
Table 15.2.6.4.T Shift Table of ECG Abnormality 
Assessments – Safety 
THN102-202-T-1502060400T-ecg-shift-ss.rtf 


Sponsor: Theranexus S.A. 
Protocol no. THN102-202 
Statistical Analysis Plan, Version Final 1.0 
21-FEB-2020 
 
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Table 15.2.7.T Summary of Columbia-Suicide Severity 
Rating Scale – Safety 
THN102-202-T-1502070000T-cssrs-ss.rtf 
66 
Table 15.2.8.T Summary of MDS-UPDRS – Safety 
THN102-202-T-1502080000T-updrs-ss.rtf 
67 
Table 15.2.9.1.T Summary of QUIP-RS Items – Safety 
THN102-202-T-1502090100T-quiprs-item-ss.rtf 
68 
Table 15.2.9.2.T Summary of QUIP-RS Scores – Safety 
THN102-202-T-1502090200T-quiprs-score-ss.rtf 
69 
Table 15.2.10.1.T Summary of Physical Measurements – 
Safety 
THN102-202-T-1502100100T-phys-meas-ss.rtf 
70 
Table 15.2.10.2.T Summary of Physical Examination 
Findings – Safety 
THN102-202-T-1502100200T-phys-exam-ss.rtf 
Efficacy Data 
71 
Table 15.3.1.1.1.S Summary of Epworth Sleepiness Scale 
Score – Full Analysis 
THN102-202-T-1503010101S-ess-fas.rtf 
72 
Table 15.3.1.1.2.S Summary of Epworth Sleepiness Scale 
Score – Per Protocol 
THN102-202-T-1503010102S-ess-pp.rtf 
73 
Table 15.3.1.2.1.T Summary of Epworth Sleepiness Scale 
Score – Full Analysis 
THN102-202-T-1503010201T-ess-fas.rtf 
74 
Table 15.3.1.2.2.T Summary of Epworth Sleepiness Scale 
Score – Per Protocol 
THN102-202-T-1503010202T-ess-pp.rtf 
75 
Table 15.3.2.1.1 Analysis of Epworth Sleepiness Scale 
Score – Full Analysis 
THN102-202-T-1503020101-ess-a-fas.rtf 
76 
Table 15.3.2.1.2 Analysis of Epworth Sleepiness Scale 
Score – Per Protocol 
THN102-202-T-1503020102-ess-a-pp.rtf 
77 
Table 15.3.2.2.1 Analysis of Epworth Sleepiness Scale 
Score (First Period) – Full Analysis 
THN102-202-T-1503020201-ess-a-first-fas.rtf 
78 
Table 15.3.2.2.2 Analysis of Epworth Sleepiness Scale 
Score (First Period) – Per Protocol 
THN102-202-T-1503020202-ess-a-first-pp.rtf 
79 
Table 15.3.2.3.1 Analysis of Epworth Sleepiness Scale 
Score Adjusted for Carryover – Full Analysis 
THN102-202-T-1503020301-ess-a-carryadj-trt-
fas.rtf 
80 
Table 15.3.2.3.2 Analysis of Epworth Sleepiness Scale 
Score Adjusted for Carryover – Per Protocol 
THN102-202-T-1503020302-ess-a-carryadj-trt-
pp.rtf 
81 
Table 15.3.3.1.1.S Summary of Epworth Sleepiness Scale 
Responder Rate – Full Analysis 
THN102-202-T-1503030101S-ess-resp-fas.rtf 
82 
Table 15.3.3.1.2.S Summary of Epworth Sleepiness Scale 
Responder Rate – Per Protocol 
THN102-202-T-1503030102S-ess-resp-pp.rtf 
83 
Table 15.3.3.2.1.T Summary of Epworth Sleepiness Scale 
Responder Rate – Full Analysis 
THN102-202-T-1503030201T-ess-resp-fas.rtf 
84 
Table 15.3.3.2.2.T Summary of Epworth Sleepiness Scale 
Responder Rate – Per Protocol 
THN102-202-T-1503030202T-ess-resp-pp.rtf 
85 
Table 15.3.4.1.1 Analysis of Epworth Sleepiness Scale 
Responder Rate – Full Analysis 
THN102-202-T-1503040101-ess-resp-a-fas.rtf 
86 
Table 15.3.4.1.2 Analysis of Epworth Sleepiness Scale 
Responder Rate – Per Protocol 
THN102-202-T-1503040102-ess-resp-a-pp.rtf 
87 
Table 15.3.4.2.1 Analysis of Epworth Sleepiness Scale 
Responder Rate (First Period) – Full Analysis 
THN102-202-T-1503040201-ess-resp-a-first-
fas.rtf 
88 
Table 15.3.4.2.2 Analysis of Epworth Sleepiness Scale 
Responder Rate (First Period) – Per Protocol 
THN102-202-T-1503040202-ess-resp-a-first-pp.rtf 
89 
Table 15.3.5.1.1.S Summary of Absence of Residual 
Somnolence – Full Analysis 
THN102-202-T-1503050101S-ess-resid-fas.rtf 
90 
Table 15.3.5.1.2.S Summary of Absence of Residual 
Somnolence – Per Protocol 
THN102-202-T-1503050102S-ess-resid-pp.rtf 
91 
Table 15.3.5.2.1.T Summary of Absence of Residual 
Somnolence – Full Analysis 
THN102-202-T-1503050201T-ess-resid-fas.rtf 
92 
Table 15.3.5.2.2.T Summary of Absence of Residual 
Somnolence – Per Protocol 
THN102-202-T-1503050202T-ess-resid-pp.rtf 
93 
Table 15.3.6.1.1 Analysis of Absence of Residual 
Somnolence – Full Analysis 
THN102-202-T-1503060101-ess-resid-a-fas.rtf 
94 
Table 15.3.6.1.2 Analysis of Absence of Residual 
Somnolence – Per Protocol 
THN102-202-T-1503060102-ess-resid-a-pp.rtf 
95 
Table 15.3.6.2.1 Analysis of Absence of Residual 
Somnolence (First Period) – Full Analysis 
THN102-202-T-1503060201-ess-resid-a-first-
fas.rtf 
96 
Table 15.3.6.2.2 Analysis of Absence of Residual 
Somnolence (First Period) – Per Protocol 
THN102-202-T-1503060202-ess-resid-a-first-
pp.rtf 


Sponsor: Theranexus S.A. 
Protocol no. THN102-202 
Statistical Analysis Plan, Version Final 1.0 
21-FEB-2020 
 
I-DM-011-06-A1(SAP_template).docx 
Page 55 of 59 
SOP effective date: 18.04.2016 
Version 6 
97 
Table 15.3.7.1.1.S Summary of PVT Mean Response Time 
– Full Analysis 
THN102-202-T-1503070101S-pvt-fas.rtf 
98 
Table 15.3.7.1.2.S Summary of PVT Mean Response Time 
– Per Protocol 
THN102-202-T-1503070102S-pvt-pp.rtf 
99 
Table 15.3.7.2.1.T Summary of PVT Mean Response Time 
– Full Analysis 
THN102-202-T-1503070201T-pvt-fas.rtf 
100 
Table 15.3.7.2.2.T Summary of PVT Mean Response Time 
– Per Protocol 
THN102-202-T-1503070202T-pvt-pp.rtf 
101 
Table 15.3.8.1.1.S Summary of PVT Errors – Full Analysis 
THN102-202-T-1503080101S-pvt-err-fas.rtf 
102 
Table 15.3.8.1.2.S Summary of PVT Errors – Per Protocol 
THN102-202-T-1503080102S-pvt-err-pp.rtf 
103 
Table 15.3.8.2.1.T Summary of PVT Errors – Full Analysis 
THN102-202-T-1503080201T-pvt-err-fas.rtf 
104 
Table 15.3.8.2.2.T Summary of PVT Errors – Per Protocol 
THN102-202-T-1503080202T-pvt-err-pp.rtf 
105 
Table 15.3.9.1.1 Analysis of PVT Mean Response Time – 
Full Analysis 
THN102-202-T-1503090101-pvt-a-fas.rtf 
106 
Table 15.3.9.1.2 Analysis of PVT Mean Response Time – 
Per Protocol 
THN102-202-T-1503090102-pvt-a-pp.rtf 
107 
Table 15.3.9.2.1 Analysis of PVT Mean Response Time 
(First Period) – Full Analysis 
THN102-202-T-1503090201-pvt-a-first-fas.rtf 
108 
Table 15.3.9.2.2 Analysis of PVT Mean Response Time 
(First Period) – Per Protocol 
THN102-202-T-1503090202-pvt-a-first-pp.rtf 
109 
Table 15.3.10.1.1.S Summary of Montreal Cognitive 
Assessment Scores – Full Analysis 
THN102-202-T-1503100101S-moca-fas.rtf 
110 
Table 15.3.10.1.2.S Summary of Montreal Cognitive 
Assessment Scores – Per Protocol 
THN102-202-T-1503100102S-moca-pp.rtf 
111 
Table 15.3.10.2.1.T Summary of Montreal Cognitive 
Assessment Scores – Full Analysis 
THN102-202-T-1503100201T-moca-fas.rtf 
112 
Table 15.3.10.2.2.T Summary of Montreal Cognitive 
Assessment Scores – Per Protocol 
THN102-202-T-1503100202T-moca-pp.rtf 
113 
Table 15.3.11.1.1 Analysis of Montreal Cognitive 
Assessment Scores – Full Analysis 
THN102-202-T-1503110101-moca-a-fas.rtf 
114 
Table 15.3.11.1.2 Analysis of Montreal Cognitive 
Assessment Scores – Per Protocol 
THN102-202-T-1503110102-moca-a-pp.rtf 
115 
Table 15.3.11.2.1 Analysis of Montreal Cognitive 
Assessment Scores (First Period) – Full Analysis 
THN102-202-T-1503110201-moca-a-first-fas.rtf 
116 
Table 15.3.11.2.2 Analysis of Montreal Cognitive 
Assessment Scores (First Period) – Per Protocol 
THN102-202-T-1503110202-moca-a-first-pp.rtf 
117 
Table 15.3.12.1.1.S Summary of Objective Activity 
Measures – Full Analysis 
THN102-202-T-1503120101S-ax3-fas.rtf 
118 
Table 15.3.12.1.2.S Summary of Objective Activity 
Measures – Per Protocol 
THN102-202-T-1503120102S-ax3-pp.rtf 
119 
Table 15.3.12.2.1.T Summary of Objective Activity 
Measures – Full Analysis 
THN102-202-T-1503120201T-ax3-fas.rtf 
120 
Table 15.3.12.2.2.T Summary of Objective Activity 
Measures – Per Protocol 
THN102-202-T-1503120202T-ax3-pp.rtf 
121 
Table 15.3.13.1.1 Analysis of Objective Activity Measures – 
Full Analysis 
THN102-202-T-1503130101-ax3-a-fas.rtf 
122 
Table 15.3.13.1.2 Analysis of Objective Activity Measures – 
Per Protocol 
THN102-202-T-1503130102-ax3-a-pp.rtf 
123 
Table 15.3.13.2.1 Analysis of Objective Activity Measures 
(First Period) – Full Analysis 
THN102-202-T-1503130201-ax3-a-first-fas.rtf 
124 
Table 15.3.13.2.2 Analysis of Objective Activity Measures 
(First Period) – Per Protocol 
THN102-202-T-1503130202-ax3-a-first-pp.rtf 
125 
Table 15.3.14.1.S Summary of Diurnal Involuntary Sleep 
Attacks – Full Analysis 
THN102-202-T-1503140100S-sleepattack-fas.rtf 
126 
Table 15.3.14.2.T Summary of Diurnal Involuntary Sleep 
Attacks – Full Analysis 
THN102-202-T-1503140200T-sleepattack-fas.rtf 
127 
Table 15.3.15.1.S Summary of Somnolence Episodes – Full 
Analysis 
THN102-202-T-1503150100S-somnolence-fas.rtf 
128 
Table 15.3.15.2.T Summary of Somnolence Episodes – Full 
Analysis 
THN102-202-T-1503150200T-somnolence-fas.rtf 
129 
Table 15.3.16.1.S Summary of Other Efficacy-Related 
Diary Data – Full Analysis 
THN102-202-T-1503160100S-diary-other-fas.rtf 


Sponsor: Theranexus S.A. 
Protocol no. THN102-202 
Statistical Analysis Plan, Version Final 1.0 
21-FEB-2020 
 
I-DM-011-06-A1(SAP_template).docx 
Page 56 of 59 
SOP effective date: 18.04.2016 
Version 6 
130 
Table 15.3.16.2.T Summary of Other Efficacy-Related 
Diary Data – Full Analysis 
THN102-202-T-1503160200T-diary-other-fas.rtf 
Pharmacokinetic Data 
131 
Table 15.4.1.S Summary of Pharmacokinetics 
Concentrations – PK Analysis Set 
THN102-202-T-1504010000S-pc-pk.rtf 
132 
Table 15.4.2.T Summary of Pharmacokinetics 
Concentrations – PK Analysis Set 
THN102-202-T-1504020000T-pc-pk.rtf 
 
 


Sponsor: Theranexus S.A. 
Protocol no. THN102-202 
Statistical Analysis Plan, Version Final 1.0 
21-FEB-2020 
 
I-DM-011-06-A1(SAP_template).docx 
Page 57 of 59 
SOP effective date: 18.04.2016 
Version 6 
9.2 
Listings  
Appendix listings defined below will be provided to the sponsor in separate .rtf files for each output.  
No 
Listing Identifier, Title 
Output file 
Demographic and Study Population Data 
1 
Listing 16.2.1.1 Screening Failures – Enrolled 
THN102-202-L-16020101-scrfail-en.rtf 
2 
Listing 16.2.1.2 Subject Disposition – Randomised 
THN102-202-L-16020102-disp-rs.rtf 
3 
Listing 16.2.1.3 Subject Disposition – Safety 
THN102-202-L-16020103-disp-ss.rtf 
4 
Listing 16.2.1.4 Subject Visits – Enrolled 
THN102-202-L-16020104-visits-en.rtf 
5 
Listing 16.2.3 Exclusions from Analysis Sets – Enrolled 
THN102-202-L-16020300-sets-excl-en.rtf 
6 
Listing 16.2.2.1 Major Protocol Deviations – Safety 
THN102-202-L-16020201-mpd-ss.rtf 
7 
Listing 16.2.2.2 Inclusion Criteria Not Met and Exclusion Criteria 
Met – Enrolled 
THN102-202-L-16020202-ie-en.rtf 
8 
Listing 16.2.4.1 Demographics and Baseline Characteristics – 
Enrolled 
THN102-202-L-16020401-demo-en.rtf 
9 
Listing 16.2.4.2 Baseline Disease Stage – Enrolled 
THN102-202-L-16020402-hoehn-en.rtf 
10 
Listing 16.2.4.3 Medical History – Enrolled 
THN102-202-L-16020403-mh-en.rtf 
11 
Listing 16.2.4.4 Medications and Therapies – Enrolled 
THN102-202-L-16020404-cm-en.rtf 
12 
Listing 16.2.5.1 Exposure to IMP and Compliance – Safety 
THN102-202-L-16020501-imp-compl-ss.rtf 
Safety Data 
13 
Listing 16.2.6.1 Adverse Events: MedDRA Coding 
THN102-202-L-16020601-ae-cod.rtf 
14 
Listing 16.2.6.2 Adverse Events: General – Enrolled 
THN102-202-L-16020602-ae-en.rtf 
15 
Listing 16.2.6.3 Serious Adverse Events – Safety 
THN102-202-L-16020603-sae-en.rtf 
16 
Listing 16.2.6.4 AEs Leading to Discontinuation – Safety 
THN102-202-L-16020604-ae-disc-ss.rtf 
17 
Listing 16.2.6.5 AEs Leading to Death – Safety 
THN102-202-L-16020605-ae-death-ss.rtf 
18 
Listing 16.2.7.1 Laboratory Data – Haematology – Enrolled 
THN102-202-L-16020701-lbb-en.rtf 
19 
Listing 16.2.7.2 Laboratory Data – Biochemistry – Enrolled 
THN102-202-L-16020702-lbh-en.rtf 
20 
Listing 16.2.7.3 Laboratory Data – Urinalysis – Enrolled 
THN102-202-L-16020703-lbu-en.rtf 
21 
Listing 16.2.8.1 Vital Signs – Enrolled 
THN102-202-L-16020801-vs-en.rtf 
22 
Listing 16.2.8.2 Electrocardiogram – Enrolled 
THN102-202-L-16020802-ecg-en.rtf 
23 
Listing 16.2.8.3 Columbia-Suicide Severity Rating Scale – 
Enrolled 
THN102-202-L-16020803-cssrs-en.rtf 
24 
Listing 16.2.8.4 MDS-UPDRS Questionnaire – Enrolled 
THN102-202-L-16020804-updrs-en.rtf 
25 
Listing 16.2.8.5 QUIP-RS Questionnaire – Enrolled 
THN102-202-L-16020805-quiprs-en.rtf 
26 
Listing 16.2.8.6 Physical Measurements – Enrolled 
THN102-202-L-16020806-phys-meas-en.rtf 
27 
Listing 16.2.8.7 Physical Examinations – Enrolled 
THN102-202-L-16020807-phys-exam-en.rtf 
28 
Listing 16.2.8.8 Pregnancy Testing – Enrolled 
THN102-202-L-16020808-preg-en.rtf 
29 
Listing 16.2.8.9 Safety Laboratory Screening – Enrolled 
THN102-202-L-16020809-lab-scrn-en.rtf 
Efficacy Data 
30 
Listing 16.2.9.1 Epworth Sleepiness Scale – Enrolled 
THN102-202-L-16020901-ess-en.rtf 
31 
Listing 16.2.9.2 Psychomotor Vigilance Test – Enrolled 
THN102-202-L-16020902-pvt-en.rtf 
32 
Listing 16.2.9.3 Montreal Cognitive Assessment – Enrolled 
THN102-202-L-16020903-moca-en.rtf 
33 
Listing 16.2.9.4 Objective Activity Measures – Enrolled 
THN102-202-L-16020904-ax3-en.rtf 
34 
Listing 16.2.9.5 Diary Sleep Data – Enrolled 
THN102-202-L-16020905-diary-sleep-en.rtf 
35 
Listing 16.2.9.6 Diary Exposure Data – Enrolled 
THN102-202-L-16020906-diary-imp-en.rtf 


Sponsor: Theranexus S.A. 
Protocol no. THN102-202 
Statistical Analysis Plan, Version Final 1.0 
21-FEB-2020 
 
I-DM-011-06-A1(SAP_template).docx 
Page 58 of 59 
SOP effective date: 18.04.2016 
Version 6 
Pharmacokinetic Data 
36 
Listing 16.2.5.2 Pharmacokinetics Concentrations – Enrolled 
THN102-202-L-16020502-pc-en.rtf 
 


Sponsor: Theranexus S.A. 
Protocol no. THN102-202 
Statistical Analysis Plan, Version Final 1.0 
21-FEB-2020 
 
I-DM-011-06-A1(SAP_template).docx 
Page 59 of 59 
SOP effective date: 18.04.2016 
Version 6 
9.3 
Figures  
Appendix figures defined below will be provided to the sponsor in separate .rtf files for each output.  
No 
Figure Identifier, Title 
Output file 
Demographic and Study Population Data 
1 
Figure 15.1.1.S Flow Chart of Subject Disposition – Enrolled 
THN102-202-F-15010100S-disp-en.rtf 
2 
Figure 15.1.2 Flow Chart of Analysis Sets – Enrolled 
THN102-202-F-15010200-anlset-en.rtf 
Efficacy Data 
3 
Figure 15.3.1.1.S Subject-Level ESS Score Change from Baseline 
– Full Analysis 
THN102-202-F-15030101S-ess-subj-fas.rtf 
4 
Figure 15.3.1.2.S Subject-Level ESS Score Change from Baseline 
– Per Protocol 
THN102-202-F-15030102S-ess-subj-pp.rtf 
5 
Figure 15.3.2.1.T Mean ESS Score Change from Baseline by 
Period – Full Analysis 
THN102-202-F-15030201T-ess-mean-fas.rtf 
6 
Figure 15.3.2.2.T Mean ESS Score Change from Baseline by 
Period – Per Protocol 
THN102-202-F-15030202T-ess-mean-pp.rtf 
7 
Figure 15.3.3.1.S Subject-Level PVT Performance Change from 
Baseline – Full Analysis 
THN102-202-F-15030301S-pvt-subj-fas.rtf 
8 
Figure 15.3.3.2.S Subject-Level PVT Performance Change from 
Baseline – Per Protocol 
THN102-202-F-15030302S-pvt-subj-pp.rtf 
9 
Figure 15.3.4.1.T Mean PVT Performance Change from Baseline 
by Period – Full Analysis 
THN102-202-F-15030401T-pvt-subj-fas.rtf 
10 
Figure 15.3.4.2.T Mean PVT Performance Change from Baseline 
by Period – Per Protocol 
THN102-202-F-15030402T-pvt-subj-pp.rtf